Pediatric Liver Disease FAQs

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What is Cirrhosis?

by Jeffery Punch, MD

Cirrhosis is often described as scar tissue, but cirrhosis is more than just scar tissue. The term cirrhosis is an anatomic description of the liver. It is defined as fibrosis (scarring) plus nodule formation (regeneration). Fibrosis alone does not qualify as cirrhosis. Fibrosis, like all scarring, basically never goes away. Thus cirrhosis is a pattern, not a disease or a specific phenomenon.

Cirrhosis can happen after any disease that causes liver cell death. Exactly why the regenerating nodules are not able to replace the function of the liver is not clear, although it may be the scarring itself that prevents recovery. We do know that if part of a normal liver is removed, the remaining liver will grow back to just the right size and function normally. This remarkable ability is not understood. Other organs like the kidneys, heart, and lungs are not able to regenerate. They can hypertrophy, (cells get larger) but they do not have cellular division that results in significant "regrowth" (more cells) like the liver does. This regrowth is what happens when a living donor gives part of their liver to be transplanted.

Two problems happen in patients with cirrhosis -- liver failure and portal hypertension. The liver failure causes fatigue, jaundice (yellow skin), and encephalopathy (a state of confusion that progresses to coma). The portal hypertension causes bleeding and ascites (fluid accumulation in the abdomen). These things happen in many forms of liver disease, not just in cirrhosis.

The scarring never goes away, but the liver has "reserve," meaning it can do all the body requires even though it is not working at 100 percent. The people that have long-standing (months to years) liver disease and develop the complications of cirrhosis that I mentioned will not, in general, recover. Some people can get a more sudden, "acute" form of liver failure (over days to weeks) and develop these complications, but these people do have the potential to recover on their own in some circumstance

Dr. Punch is a transplant surgeon at the University of Michigan and member of the C.L.A.S.S. Scientific Advisory Committee.

What is Alagille syndrome?

Alagille syndrome is a multi-system hereditary disorder. It often presents with clinical symptoms involving the liver during infancy and early childhood. Alagille syndrome is named after the French pediatric liver specialist who first recognized the clinical features of the syndrome.

Seen throughout the world in many races, Alagille syndrome is more commonly reported in boys, although girls are also affected. Alagille syndrome is the most common form of the inherited disorders which cause reduced bile flow within the liver.

Genetic research of the chromosomes of patients with Alagille syndrome has found mutations in the Jagged 1 gene.

Diagnosis

The diagnosis of Alagille syndrome usually depends upon finding several different components of the syndrome in an individual. The classic syndrome involves five distinct findings, including:

  • Chronic cholestasis (reduced bile flow). Symptoms usually begin in infancy with jaundice, itching, and cholesterol deposits in the skin (xanthomas). A liver biopsy shows that there are not enough bile ducts within the liver.
  • Congenital heart disease. Usually peripheral pulmonic stenosis, although other heart disorders such as Tetralogy of Fallot and coarctation of the aorta have been reported.
  • Bone defects. Usually "butterfly" or Hemi-vertebrae in the spine.
  • Eye findings. Usually an extra thickening of a line, known as the Schwalbe’s line, on the surface of the eye. Less common eye findings include retinal pigment changes.
  • Typical facial features. Often with deep set eyes, frontal bossing, bulbous tip of the nose, a down-turned mouth, and a small mandible with pointed chin.

Note: Not all patients with Alagille syndrome demonstrate all of these different findings.

Complications and Treatments

The management of Alagille syndrome is aimed primarily at preventing complications and treating symptoms. Because Alagille patients have reduced bile flow, they are at risk to develop fat soluble vitamin deficiency. Supplementation of fat soluble vitamins (A,D,E,K) and monitoring serum levels of these vitamins is warranted in these children. They can also have difficulty absorbing fat from their diet. In infancy, formulas rich in medium chain triglycerides (MCT) should be utilized to maximize fat absorption. The goal is to maximize the growth and development of these children.

Itching (pruritus) associated with reduced bile flow can be significant and difficult to treat. The use of drugs such as phenobarbital, cholestyramine and ursodeoxycholic acid (Actigall) may be helpful in individual patients. Other drugs such as Atarax and Benadryl may give temporary symptomatic relief.

Surgery may on occasion be necessary to obtain an adequate sample of liver tissue to examine the bile duct system. The Kasai portoenterostomy, used for biliary atresia, does not replace bile ducts within the liver and has no value for the patient with Alagille syndrome. Partial external biliary diversion has been occasionally used for the treatment of "unstoppable itching" and severely elevated cholesterol levels. In this surgical procedure, a connection is made between the gallbladder and the skin so bile may be drained to the outside of the body. The success of this procedure for Alagille syndrome has not been as dramatic as for other forms of inherited liver disease.

Liver transplantation has been used successfully for selected patients with Alagille syndrome.

What is biliary atresia?

Biliary atresia is the congenital absence or closure of the ducts that drain bile from the liver.

Cells within the liver secrete a liquid called bile, which is made up of cholesterol, bile salts and waste products, including bilirubin. A network of tubular structures and tiny ducts form the biliary system to drain bile from the liver to the small intestine where it aids in the digestive process. Biliary atresia is the closure or disappearance of the biliary system.

Biliary atresia is a progressive inflammatory process that begins very soon after birth. In the most common form, called extrahepatic biliary atresia, the delicate ducts outside the liver are affected first. White blood cells invade the ducts, which become damaged and may whither or completely disappear. Bile is trapped inside the liver and rapidly causes damage and scarring to the liver cells. Further scarring of the liver tissue may result in cirrhosis.

On average, there is one case of biliary atresia out of every 15,000 live births. Females are affected slightly more often than males. In the United States, approximately 300 new cases are diagnosed each year.

What causes biliary atresia?

The cause of biliary atresia is unknown. Auto-immune mechanisms may be partly responsible for the progressive process that takes place. Recent research suggests that a viral infection in susceptible infants could result in biliary atresia. About 10% of cases have other associated congenital defects in the heart, blood vessels, intestine, or spleen.

Although the cause is uncertain, it is known that biliary atresia affects only newborns; it is not hereditary; it is not contagious; and it is not preventable. Parents should be assured that biliary atresia is not caused by anything the mother did during pregnancy.

Diagnosis

The usual history is a full term infant who appears normal at birth but develops jaundice after the age of 2 to 3 weeks. The infant has yellow eyes and skin, light-colored stools and dark urine caused by the build up of bilirubin in the blood. The abdomen may be swollen with a firm, enlarged liver. Weight loss and irritability develop as the level of jaundice increases.

Many tests are needed to rule out other possible causes of jaundice and diagnosis biliary atresia:

  • Blood tests may show abnormal results which indicate liver dysfunction with increased bilirubin (a chemical marker in the blood for jaundice).
  • An ultrasound test may detect an absent or tiny gall bladder.
  • In another test, called a HIDA scan, a special radioactive dye that acts like bilirubin is injected into the infant’s vein. In biliary atresia, the dye is taken up by the liver but cannot flow through the damaged biliary system to the small intestine.
  • A special needle may be used to take a tiny piece of liver, which under a microscope may indicate features typical of an obstruction to the biliary system.
  • Surgical exploration of the baby’s abdomen is necessary in most cases of suspected biliary atresia to definitively make the diagnosis.

Treatment

Once the diagnosis is confirmed, the preferred treatment is to remove the atretic biliary ducts outside the liver and attach the small intestine directly to the liver at the spot where bile is found or expected to drain. The segment of intestine that connects to the liver also connects to the rest of the intestine and forms a Y connection called a "Roux-en-Y hepatoportojejunostomy," or Kasai procedure.
Bile flow is re-established in approximately 80% of infants who are operated on when younger than 3 months of age. Of these, about 50% will have some bile drainage and as many as 30% will have complete bile drainage with a return to normal bilirubin. About 20% of infants will not be helped by the Kasai procedure. In these cases, the only other treatment option is a liver transplant.

Early diagnosis of this disease is very important. If surgery is performed before the baby is 2 months old, success is much more likely. After 3 months, success of the operation is poor. For this reason, all infants who are jaundiced after the age of 4 weeks should be evaluated for biliary atresia.

Complications

The most common complication associated with the Kasai procedure is ascending cholangitis, a bacterial infection of the biliary tree. Bacteria normally found in the small intestine moves up the Roux-en-Y causing infection. Signs include unexplained fever, increased jaundice, or lighter stools. Intravenous and long-term oral antibiotics are used to prevent and treat ascending cholangitis.

Adequate bile flow is needed for the digestion and absorption of dietary fats and fat-soluble vitamins, including vitamins A, D, E, and K. When bile flow is reduced, poor growth and malnutrition may result. Special formulas containing medium-chain triglycerides (an easily digested form of dietary fat) and water-soluble vitamin supplements are often prescribed to maximize the child’s growth and development.

Formation of scar tissue eventually leads to portal hypertension in many children. Portal hypertension refers to increased pressure in the veins between the intestines and spleen to the liver. Complications include problems with bleeding and clotting; enlarged weak veins in the esophagus and stomach; and accumulation of fluid in the abdominal cavity called ascites. When these complications can no longer be treated effectively, the child is referred for liver transplantation.

What is the outcome for children with biliary atresia?

If left untreated, the result of blocked bile flow is damage to the liver such that few children survive beyond the age of two. When bile flow is only partly restored by surgery, the complications of cirrhosis will gradually develop. If the Kasai procedure is successful in draining the liver and returning the bilirubin back to normal, children may live many years with normal growth and activities. Some will grow into adulthood and some may never need a transplant.

More often, despite successful surgery, slow, progressive damage to the liver continues. When progressive cirrhosis occurs, it will eventually require liver transplantation.

Liver transplantation plays an important role in the long-term treatment of biliary atresia. Pediatric liver transplantation has evolved into a highly successful therapy and now offers significant hope for all children born with biliary atresia.

Why does your child need all those blood tests?

by Frank R. Sinatra, MD

Blood tests: why your child needs all those sticks

Blood tests are feared by children, dreaded by parents, and disliked by nurses. Despite what you might think, doctors don't like blood tests very much either. Unfortunately, many important aspects of liver function can only be evaluated by periodic blood testing.

The liver is a complex organ with several major activities, including synthesis of proteins, such as albumin and the proteins necessary for normal blood clotting, and the removal of potential toxins, such as bilirubin and numerous drugs. The liver is also important in the maintenance of normal blood sugar (glucose) concentrations.

Blood tests, therefore, are used to evaluate the ability of the liver to make albumin (serum albumin) and clotting factors (prothrombin time and partial thromboplastin time), to remove potential toxins (serum bilirubin) and to maintain normal blood sugar concentrations (serum glucose). In addition, measurement of certain proteins released into the circulation by injured liver cells or bile duct cells can be used to identify or monitor liver injury. These proteins are called "liver enzymes" and include AST (or SGOT), ALT (or SGPT), alkaline phosphatase and GGT-P.

Other blood tests commonly used in the management of children with chronic liver disease include the complete blood count (CBC), serum electrolytes (sodium, potassium, chloride, and bicarbonate) and "kidney function tests" (BUN and creatinine). Blood tests are also used to measure the level of certain drugs (such as cyclosporine and tacrolimus) and vitamins (such as vitamins A, E, and D).

Tests of Synthetic Function

Serum Albumin. Albumin is the major blood protein made by the liver. It is important for maintaining normal blood volume. When serum albumin levels are low due to the liver’s inability to make sufficient albumin or because of abnormal loss in the kidney or intestines, fluid may leak out of the blood vessels and produce abnormal tissue fluid or "edema." When excess fluid collects in the abdominal cavity it is known as "ascites." Albumin is also important in the blood transport of many drugs, hormones, and other chemicals.

Blood Clotting Studies. Most of the proteins necessary for normal blood clotting are produced by the liver. With decreased liver function, the production of these proteins decreases and bleeding may occur. The results of blood clotting studies are usually expressed in terms of seconds, or how long it takes the blood to clot under certain conditions. The longer it takes the blood to clot, the higher the prothrombin time (PT) or partial thromboplastin time (PTT). Results may also be expressed relative to a normal control (INR). In this case, a normal value is close to 1.0. A patient in whom the clotting time was twice as long as the control would therefore have an INR of 2.0; a patient who clotted in half the control time would have an INR of 0.5.

Tests of Detoxification

Serum Bilirubin. Bilirubin is the yellow pigment produced by the breakdown of red blood cells and removed from the circulation by the liver. Doctors are usually interested in knowing the values for two forms of bilirubin: the unconjugated ("indirect") form that has not been changed by the liver and the conjugated ("direct") form that has been chemically changed or "conjugated" by the liver. When liver function decreases, the blood level of bilirubin may rise sufficiently high to cause yellow discoloration of the eyes and skin known as "jaundice."

Tests of Liver Injury

Liver Enzymes (AST, ALT, Alkaline Phosphatase, and GGT-P). Liver injury of many types often results in the release of normal liver proteins (enzymes) into the blood. Measurements of the various enzymes can be used to detect such problems as hepatitis, drug toxicity, and transplant rejection. Although not specific, the height and the particular pattern of increase of the various enzymes will often provide a clue as to the type and severity of liver injury. Liver enzymes are also used to follow the progress of chronic liver disorders.

Other Blood Tests Commonly Obtained in Children with Liver Disease

In addition to the so-called "liver function tests," doctors often need to closely follow tests of "electrolyte balance," kidney function, and blood cell status. Electrolytes include sodium, potassium, chloride, and bicarbonate and are very important in maintaining normal function of the heart, brain, and skeletal muscles. These values can change rapidly in response to changes in intake, unusual losses (such as vomiting or diarrhea) or kidney abnormalities. The doctor may need to measure electrolyte levels several times a day in a sick patient in order to provide appropriate intravenous fluid therapy.

BUN and creatinine measurements are used to monitor kidney function with increasing levels indicating a worsening of kidney function.

The complete blood count CBC) allows the doctor to evaluate the red blood cells (hemoglobin and hematocrit), white blood cells (white blood count) and platelet count. This provides important information concerning bone marrow function, blood loss, infection, and bleeding due to decreased platelets.

Finally, measurement of antibiotic and cyclosporine levels allow the doctor to adjust drug doses in order to maintain adequate blood levels and to avoid potentially toxic levels.

It is important to remember that blood tests must be evaluated in the context of the medical history and physical examination, and that isolated blood test results may be misleading. Also, pediatric normal values are often different than "normal values" listed by laboratories dealing primarily with adults. Your doctor will be able to interpret the test results in the context of your child’s individual case.

Someday we may be able to use a "Star Trek Dr. McCoy" device to measure blood chemistries without drawing blood. Until then we are stuck with the sticks.

Dr. Sinatra is Professor of Pediatrics, University of Southern California School of Medicine and Head, Pediatric Gastroenterology and Nutrition at Women's and Children's Hospital - Los Angeles County + USC Medical Center.

Will my future children have PFIC?

By William Berquist, MD

I have a 17 month old son who had a liver transplant seven months ago due to PFIC type II. What are the chances of my future kids having it? Is screening available?

PFIC (progressive familial intrahepatic cholestasis) type II disorder classically recurs in families and a gene mutation has been identified. Genetic consultation is strongly recommended. Your pediatrician, pediatric hepatologist or transplant center should be able to refer you to a competent genetic counselor.

What is NASH and what are some treatments for it?

By William Berquist, MD

NASH is Non-Alcoholic Steatohepatitis or fatty liver and is associated with obesity. Other causes are nutritional imbalance. Proper nutrition and adequate vitamin E are felt to be the proper means to improve the condition.

What are the success rates for a biliary diversion?

By William Berquist, MD

My 18 month old daughter has Intrahepatic Cholestasis, and is very healthy other than her terrible itching. She is currently taking Actigall and Rifampin, but the itching persists. Her doctor has mentioned the possibility of a Biliary Diversion, can you tell me anything about this procedure including the success rate? Also, has anyone with this disease ever died from having a high bile acid count?

The itching is due to retained bile salts or other products and biliary diversion permits a means to prevent accumulation of bile salts in tissue. Biliary Diversion has variable success depending on the type of liver disease, the surgery, age and other variables. Loss of bile will affect absorption of nutrients and attention towards nutritional issues is important. A high bile count is not a primary cause of death, but it is definitely not good for children who are developing and growing.

Can cirrhosis cause low platelet counts like ITP?

By William Berquist, MD

My daughter was diagnosed with cirrhosis of the liver at age 18 months via liver biopsy. It was previously believed that she could have ITP. She had bone marrow aspirations prior to the liver biopsy and ITP was ruled out. She continues to have low platelet counts. My main question: Does a person with ITP also have cirrhosis? How would it be decided that cirrhosis is the reason for all of her complications and not ITP?

Idiopathic Thrombocytopenic Purpura (ITP) refers to a clinical situation where an individual has low platelet counts but the cause is unknown. The marrow or "factory" of the platelets is not working well or there may be other causes. In cirrhosis the liver becomes hardened due to scar tissue or fibrosis from some type of injury: infections, loss of oxygen, or toxic injury from chemicals or metabolic problems just to name a few causes. Blood backs up in the portal veins that lead to the liver due to the resistance created by the fibrosis. The spleen, as a part of the portal system, enlarges. The enlarged spleen, which is like a blood filter, starts trapping platelets and lowers the platelet count (which will resemble ITP) You may wish to discuss more of the details of your daughter's condition with your doctor to determine if she has an enlarged spleen. The condition is called hypersplenism when there is a low platelet count due to a large spleen.

Is it typical for liver function tests to fluctuate?

By William Berquist, MD

My 2-year-old son has been diagnosed with liver disease of unknown origin. His liver function tests show an elevated AST & ALT that changes frequently. His doctor does not seem concerned. I am told that he may get better and we may never know what caused the problem. Today, I noticed that he is becoming jaundiced again. Is this typical of pediatric liver disease? Also, he has been referred to an endocrinologist because of the possibility of rickets. Is it typical for a child to keep getting normal/abnormal/normal/abnormal lab results? My concern is the high values are considered extremely high.

There are some liver disorders which may result in intermittently abnormal liver tests: BRIC or benign recurrent intrahepatic cholestasis or gallstones for example. Rickets are a sign of vitamin D malabsorption and a sign of more prolonged liver dysfunction. These issues may lead to serious consequences, but not in all cases. Recommendation: seek consultation with a pediatric gastroenterologist or hepatologist.

What is autoimmune hepatitis?

By William Berquist, MD

I just found out that my niece was diagnosed with auto-immune hepatitis and cirrhosis of the liver. Please provide any info you have regarding auto-immune hepatitis in children.

Autoimmune hepatitis is a form of chronic hepatitis that may often present without symptoms. It responds generally well to prednisone and azothiaprine with a favorable prognosis if detected early. Sometimes it resolves and the patients may not require further immunosuppression. Autoimmune markers, absence of other causes, and a confirmatory liver biopsy are necessary. One must be careful of checking for Wilson's Disease which could be present in the over 3 year old group.

What can be done to relieve itching?

By William Berquist, MD

I have a 21 month old daughter who had a Kasai procedure at 11 weeks of age. Her bilirubin is normal. Over the last few months, however, she has become increasingly "itchy" and scratches herself to the point of bleeding. Any suggestions would be appreciated.

Itching is associated with retention of bile salts made by the liver. This is called "pruritus." Some of the other contributing factors or causes include eczema, dermatitis, dry skin, fatty acid deficiency and assorted allergies. Ursodeoxycholate (Ursodiol, Actigall) is used to help alleviate the symptoms. Certainly a trial off and on again with any medication (with physician guidance), soap or type of clothing fabric (cotton is best) may be tried. Other common treatments include rifampin (an antibiotic), antihistamines (Benadryl, Atarax), and cholestyramine which binds the bile salts. Proper skin care and consultation with pediatrics or dermatology is important, too. Just because the jaundice is gone does not mean that the bile flow or other complications related to liver injury and biliary atresia might not remain problems. If the itching is a problem, I trust you would review the situation with your daughter's physician.

What are liver cysts?

By William Berquist, MD

My son has a cyst on his liver. He had surgery to remove it. They said it was a simple cyst and should not come back, but unfortunately it has reappeared. If they took the cyst off his liver how can it continue to reappear?

There are many types of liver cysts. Some may be vascular, some contain bile, some have tissue fluid and some have parasites in them. Simple cysts are benign and may be followed by ultrasound at regular intervals (every 6-12months). If they do not cause symptoms such as abdominal pain they may be left alone. Vascular cysts may bleed and enlarge causing symptoms and may require resection after appropriate studies (possibly an angiogram or MR or CT may help). Care on biopsies must be emphasized as needles could precipitate a bleed.

Can a tick bite cause an enlarged liver?

By William Berquist, MD

My 10-year-old daughter went to the doctor for fever and headache. She had been bitten by a tick the week before. The doctor found her liver to be enlarged and has ordered blood tests. What could this be? Rocky Mountain Spotted fever has been ruled out.

The liver may become enlarged in infectious conditions. The liver contains many cells which trap foreign organisms and this may set up an enlarged, sometimes tender liver. The possibilities should be investigated by your primary physician. The liver enzymes and functional status should be checked. An ultrasound of the liver may be helpful.

What is neonatal hepatitis?

By William Berquist, MD

Neonatal hepatitis is an inflammatory reaction within the liver in newborn infants. It presents with jaundice and a large liver. Infectious causes (particularly viruses) might cause it but often no agent is found. Most cases resolve, but some cases progress and may even require liver transplantation.

What is pediatric primary sclerosing cholangitis?

By William Berquist, MD

My 9-year-old son has been diagnosed with possible primary sclerosing cholangitis. I am interested in any information you have about this disease in children. Are there any specialists in this field?

Primary sclerosing cholangitis refers to a pattern of inflammatory changes associated with the bile ducts inside and outside the liver. It is often associated with inflammatory bowel disease but may be seen in a number of other conditions. It may be diagnosed by liver biopsy and cholangiograms (radiographs of the biliary tree). Sometimes it must be treated by liver transplantation. Therapy includes ursodeoxycholate (Actigall, Ursodiol). Most centers with pediatric hepatologists and liver transplant programs are familiar with this disease in children.

What is "rickets"?

By William Berquist, MD

Rickets is a general term that refers to vitamin D deficiency in children. The more common and classic form in normal children was due to the lack of vitamin D and sunlight resulting in a bending of weight bearing bones and the appearance of nodular ends of the bones. Rickets is rare in healthy children in the United States.

Vitamin D deficiency is common in children with liver and kidney disorders. In cholestatic liver disorders where there is significant jaundice, bile salts necessary for the absorption of fat and fat soluble vitamins (including vitamin D) do not get into the intestine. Vitamin D is then lost or not absorbed. In addition, the liver processes vitamin D into an active form, so as the liver disease advances, even if vitamin D is absorbed it is not activated.

Since Vitamin D helps in calcium absorption and bone mineralization, the bones become weak and bend. The growth plates of bones enlarge and become more nodular. Diuretics, used to manage ascites (abnormal fluid retention), may lead to calcium loss in the urine. Kidney disease may affect calcium and phosphorus balance as well as Vitamin D activation.
With so many variables, including calcium intake, degree of cholestasis, presence of kidney disease, degree of liver disease, and use of diuretics, it may be expected that the degree of rickets and bone disease may vary from patient to patient.

Generally, it is advisable to follow vitamin D, calcium, and phosphorus levels in children with chronic liver disease and to add some vitamin D to the diet or by supplements.

Rickets is a complex issue to solve in some patients with advanced liver disease. Successful liver transplant, combined with good nutrition, will lead to a cure assuming that there is not persistence of other factors which contribute to rickets.

end faq