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 little 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. In individuals with PSC, sometimes bile does not flow well through the liver, which 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 bile duct injury, it is not specific, i.e. it can be elevated for a variety of reasons, not only PSC. Because ALP is present in both liver and non-liver tissues, notably bone, it can be elevated in healthy growing children, which can make it 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’s hope is to bring maximum collaboration in this field, and studying children with PSC brings a unique aspect of defining the natural history of the disease from its earliest onset and maximizes the time frame for evaluating response to newer 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 low. As a parent, current knowledge holds that there is nothing you could have done differently to prevent PSC in your child.

Many patients with PSC do not have any 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
• 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
• Splenomegaly: enlarged spleen
• Easy bruising and bleeding

Ordinarily, PSC is diagnosed following liver lab tests in a child with IBD or autoimmune hepatitis or as a follow-up for abnormal liver lab tests obtained for other reasons. PSC can be diagnosed by a combination of blood tests (e.g. alkaline phosphatase, ALP), abdominal imaging (e.g. magnetic resonance cholangiopancreatography [MRCP], a special MRI of the liver and bile ducts), and/or liver biopsy (not required in all cases).

PSC is less common in children than in adults. There are differences between pediatric and adult PSC, including the more common occurrence of autoimmune hepatitis-PSC overlap syndrome in children vs. adults (25% vs. 10%) and a higher prevalence of markers of autoimmune disease in pediatric PSC. Also, other autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, are more common in children than in adults with PSC. Dominant strictures of the common bile duct (severe narrowing of a large bile duct) as well as cancers of the bile ducts and large intestine, are rare in children when compared to adults. These observations have raised the question of whether childhood PSC is a different disease from adult PSC, which itself may be a collection of several related disorders.

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 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 a liver biopsy. Liver scarring usually develops more slowly in small duct PSC compared to usual PSC.

There is currently no medical cure for PSC. Most therapies are supportive and directed at managing complications (portal hypertension, dominant stricture, itching, nutritional deficiencies, and cholangitis) rather than the underlying cause of PSC. However, 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 select patients:

• Urso

Ursodeoxycholic acid (Ursodiol, Urso Forte, UDCA, Actigall) is a synthetic, water-soluble bile acid that is taken orally. The dose is usually 20 mg/kg body weight per day (often divided into twice a day dosing). Some pediatric studies have shown that it may improve liver enzymes and itching. The effect of UDCA on the long-term outcome in children with PSC has not yet been determined and is under study in a multicenter trial sponsored by the FDA. Other synthetic bile acids are currently under investigation.

• Vancomycin

Oral Vancomycin has been shown to improve laboratory tests and clinical symptoms in adult trials and in two pediatric studies from one institution. Larger randomized controlled studies are underway.

• Antibiotics

Other oral antibiotics to prevent recurrent infections of the bile ducts in the setting of duct obstructions may be beneficial in select circumstances.

• Immunosuppresants

Immunosuppressants (steroids, azathioprine) may be indicated in patients with PSC and biopsy-proven overlap with autoimmune hepatitis, but there is no evidence that steroids or any immunosuppressants are effective in PSC.

• Rifampin

Rifampin is thought to reduce 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, 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 no 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

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

• Liver transplant

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

A new class of drugs, called farnesoid X receptor (FXR) agonists, provides 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.

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. Only a small percentage of children (20%) will need a liver transplant during childhood, at an average time of seven years after diagnosis of PSC. The one-year patient and graft (transplanted liver) survival rates in children with PSC after liver transplantation are superior compared to patients with other liver diseases (99% vs. 91% patient and 93% vs. 86% graft survival). The five-year survival rate for patients is 87% and 76% for the graft. PSC may recur in approximately 10% of children who undergo liver transplantation for PSC.

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 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/hepatologist.

Children should be seen by their gastroenterologist/hepatologist at least twice a year, 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 have a normal quality of life, do not experience any liver related symptoms, and can enjoy a well-balanced, healthy diet. 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 a liver transplantation.

Any time your child experiences high fevers 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, that is, 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. 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.

PSC Partners Seeking a Cure holds an Annual Conference in a different medical center that treats and researches PSC. The conferences provide education and support for patients and caregivers, as well as updates on recent research developments. 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.

The PSC community also 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 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 contact us at contactus@pscpartners.org.