Ultrarare genetic diseases often appear with a series of symptoms that might seem unconnected.
Brooke Harrison Ramirez’s pregnancy had been easy eight years ago, but baby Trinity’s troubles began right away: GERD (gastroesophageal reflux disease) so severe that she would frequently stop breathing. The first sign that something complicated was going on began at five months. “She started having bruises all over her body. These later grew and then within a day or two, turned into huge hematomas,” Brooke recalled. The baby could barely sleep or eat and Brooke and her mother took shifts in providing the round-the-clock care.
Then the pruritus started, an intense, unremitting itching emanating from deep within the skin. Brooke had to dress the child in special mittened onesies to keep her from tearing her skin off. In adults, pruritus leads to thoughts of suicide.
Fortunately, diagnosis was relatively fast for the rare disease world. Trinity’s local pediatrician sent her to the emergency room at Anne Arundel Medical Center, where they found highly abnormal clotting levels, indicating a liver problem. Then she was referred to Johns Hopkins Medical Center and finally to Cincinnati Children’s Hospital. Liver function tests, scans, liver biopsy, and extensive genetic testing, plus consideration of the little girl’s symptoms, led to her diagnosis at 7 months old: progressive familial intrahepatic cholestasis type 2 (PFIC2).
“Cholestasis” refers to a build up of bile in the liver. It triggers other symptoms, including jaundice, greasy loose stools, gallstones, and slow growth from the difficulty absorbing fats and the nutrients they carry. The bile buildup slowly kills the major cells of the liver (hepatocytes), causing scarring (cirrhosis) and elevates the risk of liver cancer. The itch is thought to arise from bile salts deposited in the skin.
I heard about Trinity from a news release I received last week that announced Brooke’s Facebook page, Trin Raising Awareness for PFIC2. So here’s a shout-out to help.
An Impaired Bile Acid Pump
PFIC is a good example of genetic heterogeneity – when mutations in any of several genes cause the same set of symptoms, typically because their protein products are part of the same biochemical pathway or physiological process. The types of PFIC are collectively rare, affecting one in every 50,000 to 100,000 children worldwide, so the incidence and prevalence of Trin’s PFIC2 is even rarer.
PFIC2 is due to inheriting two mutant copies of a gene called ABCB11 on chromosome 2, so it’s autosomal recessive – both sexes are affected, with mutations inherited from carrier parents. As is true for many of the ultrarare disorders, some cases reflect consanguinity (inbreeding). A child inherits identical recessive gene variants from ancestors that the parents share, like a great-great grandparent. The child is a homozygote. Such consanguineous cases of PFIC have been reported from the Faroe Islands, in Inuits from Greenland and Canada, and among the Amish. Affected kids may also inherit the same gene variants from parents who aren’t related or might not know that they are, or have two different variants (compound heterozygotes).
The implicated gene normally encodes an “export pump” protein that moves bile acids out of liver cells and into the forming green bile.
Bile helps digest fats and the fat-soluble vitamins A, D, E, and K. The liver uses cholesterol to produce bile acids, which are sent to the gallbladder for storage. Bile also contains bilirubin (a pigment released from old, breaking-down red blood cells), water, and wastes.
After a fatty meal, the gallbladder squeezes and squirts bile into the small intestine. At the distal end of the small intestine, proteins called ileal bile acid transporters (IBATs) pick up most of the bile acids and return them to the liver. Much of the rest of the bile winds up in feces.
In the various forms of PFIC, the bile acid transporters are too few, absent, or malfunction.
A Liver Transplant From Trinity’s Aunt
Although the origin of the itching isn’t well understood, a few “surgical diversion” procedures help some kids. At the end of 2011, still not yet a year old, Trinity underwent two surgeries to attempt to divert the bile from her liver.
But neither procedure alleviated the intense itching, and actually made everything worse, Brooke said. “Trinity then had a liver transplant in May 2012, and my sister was the living donor. The liver transplant eventually did ease the itching,” she added.
Liver transplant is the only treatment, used for all forms of PFIC. Most children will eventually go into liver failure, and the transplant is generally done before the age of 10. It works because the symptoms of these conditions come from one body part that is replaceable.
Results are generally considered quite good, reversing the life-altering effects of a failing liver. This review article followed 131 children up to 19 years (progress continues), finding 76.6% graft survival and 85.2% patient survival.
On the Horizon: Fighting the Itch
Even though liver transplant is the standard-of-care for children whose cirrhosis hasn’t progressed far, two drugs currently being tested might offer some relief from the itching, perhaps before a transplant.
Albireo Pharmaceuticals is testing a drug candidate, A4250, for PFIC types 1 and 2, in a phase 3 randomized, controlled clinical trial at more than 40 treatment centers worldwide. A pill, A4250 is a small molecule that is also being tested to alleviate the itch in Alagille syndrome and biliary atresia. Mirum Pharmaceuticals is also in phase 3 trials of a different drug candidate to target the same protein. Both new drugs stop the excess bile acids from going back to the liver from the end of the small intestine, but might not be effective for all patients.
In the repurposing arena, two case reports from 2015 suggest that steroids may be an effective treatment for the itching of PFIC2. The connection was discovered serendipitously. A 23-year-old woman found relief once she developed lupus and began taking steroids. And a 5-year-old boy ceased itching when he, too, began taking steroids for another condition, colitis.
In a 2017 article in the World Journal of Gastroenterology, three researchers in the Netherlands discussed several possible future routes to treating PFIC:
- Hepatocyte transplants, essentially bits of liver, might help to address the organ shortage problem.
- Liverlet patches coaxed to grow in the laboratory from progenitor cells or induced pluripotent stem (iPS) cells from a donor.
- A patient’s skin fibroblasts, grown in laboratory culture to produce iPS cells, which are corrected using gene therapy or, eventually, gene editing (CRISPR-Cas9), then infused into the patient.
The researchers also suggest modeling efforts to tackle PFIC after the success in treating cystic fibrosis. Drugs such as Kalydeco resulted from a thorough understanding of exactly how specific mutations and their combinations alter the ion channel that is abnormal in the cell membranes of the affected organs.
With all of these options looming, Brooke is optimistic and hopes that her Facebook page can bring attention that might lead to funding research.
“The future looks good for us as far as we know, but you can never predict anything. My husband, who is not her biological father, has been there through thick and thin for the last 4 years since we have been together. We now have three kids and Trin is so in love with her brothers. We have a 14-month-old and 2-month-old now. She is an amazing sister!”
Emily Ventura, President and Co-Founder of the PFIC Advocacy and Resource Network, whose 6-year-old daughter was diagnosed with PFIC, spoke at an Albireo presentation for Rare Disease Day in February.
“It’s difficult to convey the full impact that a disease like PFIC can have on a family. You may watch helplessly, as your child scratches herself through the night, then struggles in school the next day. At the same time, you worry about liver disease and how long you have until she needs a new liver. We need treatment options that help with symptoms and protect the liver. In the meantime, there’s a huge need to help families learn about PFIC and available strategies to support their children affected by this devastating disease.”
Thanks to Brooke Harrison for the lovely photos.