Pediatric PSC

PSC is short for primary sclerosing cholangitis. It is a rare chronic disease characterized by inflammation and scarring of the bile ducts outside and/or inside the liver. The liver makes a yellow/green liquid called bile, which is carried by tiny tubes (i.e., bile ducts) from the liver to the small intestine. Bile is important for the efficient absorption of the food we eat, especially fats and certain vitamins that dissolve in fat, such as vitamins A, D, E and K. With PSC, bile does not flow well through the bile ducts and pools in the liver. That causes damage to liver cells. The resulting injury may, over time progress to scarring, which when advanced, is called cirrhosis of the liver.

During the course of PSC, bile duct injury leads to elevation of specific enzymes which can be detected in blood, namely alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). Whereas GGT is very sensitive for detecting bile duct injury, it is not specific, i.e. it can be elevated for a variety of reasons, and not only because of PSC. Because ALP is present in both liver and non-liver tissues, notably in bone, it can be elevated in healthy growing children, thus making ALP less reliable for evaluating pediatric bile duct disease. Preliminary data suggest that GGT may thus be the better of the two blood tests to assess degree of inflammation and response to therapy.

PSC Partners Seeking a Cure hopes to bring maximum collaboration in the field of PSC research, because collaboration is a critical component to achieving progress in the research of rare diseases like PSC. By studying pediatric PSC, researchers gain a unique perspective in defining the natural history of the disease from its earliest onset and can maximize the time frame for evaluating response to new promising therapies.

Currently, no one knows the exact cause of PSC. There appear to be genetic, environmental and autoimmune components. PSC is more common in Caucasian males and those of Northern European (in particular Nordic) descent. It usually co-exists with inflammatory bowel disease (IBD), most often ulcerative colitis and sometimes Crohn’s disease, and the combined occurrence of PSC and IBD is found in approximately 80% of children. There is no clear correlation between the severity and onset of PSC and IBD, and both diseases can run separate clinical courses. IBD may be diagnosed before, at the same time, or after the diagnosis of PSC. Sometimes there are no IBD symptoms, yet colonoscopy and biopsy may show microscopic inflammation of the colon. Families with IBD have a higher chance of having a child with PSC, and having a first-degree relative with PSC increases the risk for PSC at least four-fold, although the overall absolute risk is still very low. As a parent, there is nothing you could have done differently to prevent PSC in your child.

Most children with PSC are in early stages of the disease process and have no symptoms. Blood tests or imaging may identify an abnormal biliary system in the liver. Over time, symptoms associated with poor bile flow and liver disease may develop. These include:

• Intense persistent itching
• Fatigue
• Pain on right side of the abdomen, possibly extending around the back, or in upper middle of abdomen
• Jaundice and icterus (yellowing of the skin and eyes, respectively)
• Diarrhea
• Weight loss
• Poor growth
• Abnormal liver blood tests
• Hepatomegaly (an enlarged liver)
• Splenomegaly (an enlarged spleen)
• Chills and fever: signs of bacterial infection in bile ducts requiring immediate medical attention

Additionally, signs that PSC has progressed to cirrhosis and that further treatments, including liver transplantation, may be indicated, include:

• Ascites: accumulation of fluid in abdomen
• Hepatic encephalopathy: neurologic or psychologic impairment (e.g. personality changes, intellectual impairment, and sleep disturbances) due to liver dysfunction
• Varices: swollen veins in the gastrointestinal tract, most often esophagus and stomach, that are prone to bleeding
• Easy bruising and bleeding

Most children with PSC have inflammatory bowel disease (Crohn’s disease or ulcerative colitis), which may present with:

• Chronic diarrhea
• Blood in the stool
• Poor growth
• Abdominal pain

PSC is suspected when liver blood tests are abnormal, especially in a child known to have inflammatory bowel disease (IBD) and or autoimmune hepatitis (AIH). PSC is confirmed when scarring, dilation and irregularity of the bile ducts are observed on imaging tests or liver biopsy. Blood tests for PSC include conjugated or direct bilirubin; gamma-glutamyltranspeptidase (GGT); alanine aminotransferase (ALT); and aspartate aminotransferase (AST). Children with advanced disease may have anemia (low hemoglobin), low platelet count, and prolonged time to clot blood (an elevated INR).  Imaging tests include magnetic resonance cholangiopancreatography (MRCP), which is noninvasive, has no radiation exposure, and is a “first-line” test. Endoscopic retrograde cholangiopancreatography (ERCP)  is a procedure performed under anesthesia using a camera scope inserted into the mouth to inject dye into the bile ducts while x-rays are being taken. When imaging tests are abnormal, a patient has “large duct” PSC. Ultrasound and computed tomography (CT scan) are sometimes also performed but cannot be used to diagnose PSC. Most children need liver biopsy to exclude autoimmune hepatitis, a common additional liver inflammation problem that occurs with PSC. Some PSC patients have disease only in the smallest bile ducts within the liver. If imaging is normal but PSC is still suspected, a liver biopsy is done. These patients have “small duct” PSC.

PSC is 10-20 times less common in children than in adults. Almost half of children have another liver problem called autoimmune hepatitis (AIH) in addition to PSC, compared to only 4% of adults. Children do not generally present with serious bile duct strictures or cancers, whereas adults may have these problems when diagnosed. Overall, children tend to present with milder disease, but as they grow older, their disease and its complications look more and more like adult PSC.

Since PSC is usually a slowly progressing chronic disease, serious symptoms are not ordinarily seen in childhood. However, every child is different, and some do progress to cirrhosis or to significant obstruction of the bile ducts prior to adulthood. Special considerations must be given to maintain normal nutrition, growth and maturity in children with PSC, especially if the child has IBD.

There are other diseases that can resemble PSC since they also affect the bile ducts. These include neonatal PSC, which is a very rare disorder that may present early in infancy and often is associated with serious immune system problems, progressive familial intrahepatic cholestasis (PFIC, especially type 3), cystic fibrosis, IgG4 cholangitis, and certain neoplasms (such as Langerhans cell histiocytosis). Your pediatric gastroenterologist/hepatologist would be aware of these conditions and should consider them to ensure a correct diagnosis.

Small duct PSC is PSC that affects only the small bile ducts within the liver and not the large ducts outside the liver. In small duct PSC, liver imaging, including MRCP and ERCP, may be normal. Diagnosis is typically made with liver biopsy. Liver scarring usually develops more slowly in small duct PSC compared to PSC involving bile ducts both inside and outside the liver.

Currently there is no approved medication to prevent the progression of liver disease in PSC. Ursodeoxycholic acid (Ursodiol, Urso Forte, Actigall, UDCA) may improve liver enzymes and itching in pediatric PSC; oral vancomycin may improve laboratory tests and clinical symptoms. Neither is proven to treat PSC or prevent disease progression.

Most therapies are supportive and directed at managing complications (portal hypertension, dominant stricture, itching, nutritional deficiencies, and cholangitis) rather than treating the underlying cause of PSC. Currently, liver transplantation is the only way to treat progressive PSC. However, with new research, several potential therapies are being tested.

The care for a PSC patient is generally supportive:

• treating co-existing inflammatory bowel disease to remission
• steroids, azathioprine or other immunosuppressants to control autoimmune hepatitis when it is present
• rifampin, naltrexone and other medications to control itching
• ERCP procedures to break open bile duct blockages (balloon dilation or stent placement)
• endoscopy procedures (variceal banding) or propranolol to prevent bleeding from esophageal varices (bulging blood vessels)
• a healthy, balanced diet to maintain good nutrition, weight, and muscle mass
• mental health support (therapy, coping strategies, or medicines) for depression or anxiety

For updated information on medications for PSC, always check http://pscpartners.org/clinical-trials/ and https://ClinicalTrials.gov.

Several therapies have been tested, but have not been definitively proven to be of benefit, especially for long-term outcome, and may still be used in patients:

• Ursodeoxycholic acid (Ursodiol, Urso Forte, UDCA, Actigall). Some pediatric studies have shown that Urso may improve liver enzymes and itching in a sub-group of patients
• Oral Vancomycin may improve laboratory tests and clinical symptoms, but more research is needed
•  Other oral antibiotics to prevent recurrent infections of the bile ducts in the setting of duct obstructions may be beneficial in select circumstances
• Immunosuppressants (steroids, azathioprine) may be indicated in patients with PSC and biopsy-proven overlap with autoimmune hepatitis or elevated IgG4, but there is no evidence that steroids or any immunosuppressants are effective in PSC

• Rifampin perhaps reduces itching by enhancing the clearance of substances causing itching in liver disease. Cholestyramine and Colesevelam are medications that reduce the reabsorption of bile acids from the intestines in order to reduce the bile acid pool and decrease pruritus. Antihistamines may reduce itching and produce a sedative effect which can be especially useful at night. Anti-opiates (naltrexone) are centrally-acting antipruritic medications that block endogenous opioids and are sometimes prescribed for itching.

• Other treatments

There is little scientific evidence to support alternative therapies, such as herbs and extracts, as treatment for PSC, although they are currently under investigation. Since some herbs may be harmful to the liver or may alter the effectiveness of other medications, always consult your physician before starting an over-the-counter medicine.

• ERCP is used with balloon dilatation and/or stent placement for dominant bile duct strictures.

• Endoscopic procedures

Endoscopic  procedures are sometimes used to prevent bleeding from esophageal varices.

• Liver transplantation is currently the only potentially curative therapy for PSC.

Farnesoid X receptor (FXR) agonists, provide hope for the future of PSC therapy. One of these compounds, obeticholic acid (OCA), has been shown to improve liver disease in primary biliary cholangitis (PBC), a bile duct disease mostly affecting adult women. Trials in PSC are currently underway, and other drugs in this class are in development.

An abnormal or “dysbiotic” microbiome (the ensemble of microorganisms in the body) is thought to be an important factor in the development of both IBD and PSC. Therapeutic manipulation of the microbiome composition through probiotics, prebiotics, synbiotics, other drugs, or microbiome transplantation have promise for providing novel therapeutic approaches in PSC and are actively being studied.

Several promising new drugs for the treatment of PSC are in various stages of development in adults, and may be ready for trials in pediatric PSC patients in the near future. See http://pscpartners.org/clinical-trials/ and https://ClinicalTrials.gov for more information.

Common indications for liver transplantation are cirrhosis, recurrent cholangitis, itching that cannot be controlled, and complications such as recurrent bleeding of varices (abnormally dilated vessels in the esophagus, stomach, and/or less commonly, other parts of the digestive tract), ascites (fluid in the abdominal cavity) that is not responsive to medications, and poor quality of life. There is no reliable way to predict which patients will have progressive disease. Generally, patients with cirrhosis and portal hypertension (an enlarged spleen, esophageal varices or abdominal ascites) or patients who need bile duct procedures like ERCP balloon dilations for severe bile duct scarring and infections are more likely to need liver transplantation.

Special considerations must be given to maintaining normal nutrition and growth in children with PSC. Although there is no special diet for PSC, the diet should be a healthy balance of protein, carbohydrates and fat. Some children, particularly those who are severely jaundiced, would benefit from and should receive supplementation with medium-chain triglycerides (MCT), which do not require intestinal bile for absorption, fat-soluble vitamins (A, D, E, and K), calcium and phosphorus. Fatty foods, processed foods, and preservatives should generally be avoided. Salt restriction may be needed for treatment of ascites. Medications that may harm the liver, as well as herbal supplements, alcohol and recreational drugs, need to be avoided. Immunizations for viral hepatitis (hepatitis A and B) should be administered. Prudent use and doses of acetaminophen and any other medications should be vetted with your child’s gastroenterologist and/or hepatologist. A clinical dietician can be of help in determining the appropriate plan for your child.

Children should be seen by their gastroenterologist and/or hepatologist regularly, and more often if the disease appears to be active (e.g. persistently abnormal blood or other tests) and/or progressing. A history and physical exam are performed at this time, focusing on growth, and signs and symptoms of progressive liver disease, together with blood tests and surveillance liver imaging, given the increased risk of liver and bile duct cancer in patients with PSC (although less common in children than in adults with PSC). Endoscopic tests may be recommended to assess for varices in the esophagus or stomach (via upper endoscopy, i.e. EGD) or for evidence of inflammatory bowel disease or colon cancer (via colonoscopy) given the increased risk of both in patients with PSC.

The majority of children with PSC can have a normal quality of life, and do not experience any liver-related symptoms or pain. If and when the spleen becomes enlarged, there may be some physical activity limitations, such as avoidance of contact sports. A spleen guard may be helpful to prevent the risk of the enlarged spleen getting torn during activity, but this has not been studied or proven to be necessary. These issues regarding activities and lifestyle should be discussed with your child’s hepatologist/gastroenterologist. Children with progressive disease may require more frequent monitoring, clinic visits, hospital admissions and occasionally liver transplantation.

Medical emergencies in PSC:

• Fever, chills and jaundice (signs of bacterial infection in bile ducts, seek immediate medical attention)
• Vomiting blood or seeing dark black blood in the stool (signs of burst blood vessels in the esophagus and stomach, go to the emergency room)

Any time your child experiences fever or chills, significant right upper quadrant abdominal pain, or rapidly progressive jaundice, he/she should be examined by the doctor to rule out infection of the bile ducts, known as acute bacterial cholangitis. The diagnosis of acute cholangitis often requires blood tests, a blood culture, and an imaging test. Empiric antibiotic therapy may be given.

Another urgent condition is variceal bleeding, which may present with vomiting blood (red or “coffee ground”-like) or rectal bleeding (red blood or alternatively black tarry stools also called melena). New jaundice, darkening urine, pale stools, or unexplained persistent abdominal pain should also be reported to your child’s gastroenterologist/hepatologist.

Pediatric PSC patients are usually cared for by a pediatrician specially trained in childhood liver disease, i.e. a pediatric hepatologist. Many pediatric gastroenterologists who care for pediatric IBD are also trained to care for patients with PSC, often in collaboration with a pediatric hepatologist. Many larger pediatric medical centers have gastroenterology and hepatology programs, as well as an active liver transplantation program, to provide comprehensive care to children with PSC. Additional information may be available on the medical center’s website. Most physicians and centers that are involved in PSC collaborative research studies on childhood PSC and other liver diseases provide excellent care for pediatric PSC patients. The PSC Partners Patient Registry has a list of hepatologists consulted by PSC patients. If you join the registry, you can see the list by clicking on healthcare providers at www.pscpartners.org/patient-registry. Also check the www.ClinicalTrials.gov website to see participating physicians and centers.

Your child and your family may benefit from support groups and counseling, as dealing with a new diagnosis of a chronic disease may be challenging for children and adolescents.

Each year, PSC Partners Seeking a Cure holds an Annual Conference in a different medical center in the United States that treats and researches PSC. The conferences provide education and support for patients and caregivers, as well as updates on recent research developments. The conference offers a pediatric stream that includes presentations by pediatric specialists, interactive sessions for parents, and social activities for teens with PSC. Conference attendees regularly describe the conference as “family reunions,” and attendees highly value the experience of networking with a community of people who understand what is involved in coping with and treating PSC. Because PSC is rare, the support and understanding of our community is an invaluable resource for patients and their caregivers alike.

We provide an individual mentor program for caregivers and teens. If you’re interested in having a mentor, please send us an email or give us call.

The PSC community gathers on the PSC Partners public and private Facebook sites where every question gets multiple responses. Find us on Facebook at PSC Partners Seeking a Cure.

We’re also on Twitter @PSCPartners.

Information on PSC, the PSC community and PSC-related events can be found at www.pscpartners.org .

You can participate in the PSC Partners Patient Registry which provides de-identified data to researchers to advance PSC research www.pscpartnersregistry.org.

For medical information on PSC and related diseases, please visit our PSC Partners literature site which is updated daily as new studies are published www.pscpartners.org/research.

Would you be interested in taking brochures to your doctors and medical centers? You will find the abbreviated version of this document in our Pediatric PSC brochure at www.pscpartners.org/brochures or you can ask us to send you brochures.

Feel free to send us an email at contactus@pscpartners.org or call us at (303) 771-5227 to learn more about the many ways that PSC Partners can help you and your child navigate life with PSC.