Paediatric Hepatology

What is jaundice ?

Jaundice is a yellow coloring of the eyes and skin. This yellow coloring is the result of a buildup of a chemical in the blood called bilirubin. It is a common symptom in newborn babies and is usually not a sign of serious illness. In older children, it can be a sign of a liver disease or a blood disorder.

Condition mimicking jaundice ?

Jaundice should not be confused with carotenemia, which is an orange- yellow coloring in the skin caused by too much carotene in the diet. Carotene is a natural food coloring found in fruits and vegetables that have a lot of Vitamin A. It is the natural chemical in plants that causes them to be yellow or orange. The easiest way to tell if a child has carotenemia instead of jaundice is to look at the white part of his eyes. If the child is jaundiced, the white part of the eyes will also be yellow, but with carotenemia, the white parts stay white. The bottom line is if the white part of your child’s eyes look yellow, you should contact his pediatrician or family practitioner for an evaluation.

What will happen if I ignore jaundice in newborns?

There are a lot of causes of excess bilirubin (hyperbilirubinemia) in the blood. If left untreated, most of the time the bilirubin with continue to increase slightly but will not reach dangerous levels. However, in some cases the bilirubin will continue to increase and can then act like a poison (toxin) to the nervous system, especially the brain. This is called kernicterus and can lead to deafness, seizures, or developmental delay.Fortunately kernicterus is rare because hyperbilirubinemia is usually easy to monitor and treat before dangerous blood levels are reached.

How does bilirubin get in the blood?

Bilirubin in a natural breakdown product of blood cells. Everyday, old red blood cells are destroyed and replaced with new ones. Each red blood cell lives about 120 days. Usually the rate of destruction and creation are in balance so that the amount of bilirubin from the destroyed blood cells is kept under control by the liver, which serves to clear bilirubin from the blood stream. Bilirubin is then taken up into the liver where it is converted (conjugated) to another form that is then excreted into the gut. This conjugated bilirubin is then broken down by bacteria and is what gives stool its brown to green coloring. Conjugated bilirubin can also be broken down again into an unconjugated form that reenters the blood stream.

If the body suddenly starts destroying red blood cells (a condition called hemolysis) faster than the liver can clear the bilirubin from the blood, the result can be hyperbilirubinemia and a yellow-orange coloring will be seen in the eyes and skin. Another way that bilirubin can accumulate in the body is if the liver is not working properly because of infection or some other condition and the conjugated bilirubin is not getting released into the intestine. This is called cholestasis. Again, the skin and eyes will get a yellow color, and sometimes the bowel movements with be white or clay colored instead of brown, green or yellow.

What tests should be done?

There are some simple blood tests that can help doctors tell these two types of hyperbilirubinemia apart. One blood test measures the total amount of bilirubin in the blood and the other measures the bilirubin that has been conjugated. The difference between these two measurements is used to calculate the unconjugated bilirubin. Another method used to measure total bilirubin in the blood uses a device held onto the skin and does not require a needle stick. The drawback to this method is that is can only be used as a screening tool and cannot replace the blood test in infants whose jaundice is getting worse.

What are the causes of jaundice in newborns?

In very young babies, jaundice is quite common. Most often the cause is physiologic, meaning it is not related to hemolysis or cholestasis, but rather to the slow transition of getting bilirubin cleared via the liver rather than the placenta once the baby is delivered. This type of jaundice usually first appears in the second or third day of life and peaks within the first week of life. The total level seldom reaches an amount worth getting concerned about or requiring treatment. Other causes of jaundice include hemolysis (secondary to blood group / Rh incompatibility between motherand baby or some enzyme deficiencies gencies, or polycythernia, breastfeeding jaundice or breast milk jaundice (see below), secondary to metabolic disorders such as hypothyroidism, galactosemia, cortisol deficiency etc..

What is breast milk jaundice?

Breastfeeding jaundice and breast milk jaundice are two other types of hyperbilirubinemia in infants. Breast feeding jaundice describes the fact that breastfed babies with physiologic jaundice generally reach higher levels of total bilirubin compared to formula-fed babies. There are many theories why this is the case, but regardless, even breast-fed babies with physiologic jaundice seldom get high enough levels of bilirubin to cause any problems. Breastmilk jaundice, on the other hand, usually appears during the second to third week of life and is believed to be caused by a hormone in breastmilk that interferes with the natural elimination of bilirubin. Some babies with breastmilk jaundice may get levels of bilirubin high enough to warrant treatment. Since it has been demonstrated that stopping breast-feeding for just twentyfour hours can dramatically decrease the level of bilirubin in the blood, some doctors advocate having the mother stop breast-feeding for a day if breastmilk jaundice is a concern. Others do not recommend this practice because they believe it causes mothers to quit breast-feeding too soon out of concern that there is “something wrong” with their milk.

When to treat of jaundice in newborns?

Although most causes of jaundice in babies are benign and don’t require treatment, newborns can also have hemolysis or cholestasis as a cause of their jaundice. For example, if the mother’s blood is a different type than her baby’s, she can pass antibodies against the baby’s blood across the placenta to the baby. These antibodies can attack the baby’s red blood cells and cause them to break down rapidly. Because there are many potential causes of jaundice in an infant, doctors pay close attention to newborns who show an excessive rise in bilirubin or a particularly lengthy course or if jaundice is found on the first day of life.

What are the treatments for jaundice?

Depending on the cause, the treatments may be fairly simple. In young infants with jaundice, the doctor will check the mother’s blood type and the baby’s blood type as well as a blood count to make sure that the jaundice is not related to hemolysis. She will also check both total and conjugated bilirubin in the baby’s blood to determine if the cause could be related to cholestasis. If the blood tests are consistent with physiologic jaundice, the doctor may monitor the baby to see if the bilirubin levels are rising and may recommend that the baby get direct or indirect sunlight daily. If the bilirubin reaches a high enough level, the doctor may order that the baby be placed under special lights (phototherapy) to help bring down the level. But if the bilirubin continues to rise despite phototherapy, the baby may need a partial or complete blood exchange which is done in a hospital setting. This involves taking some of the baby’s blood and replacing it with salt water (saline) or with someone else’s blood (transfusion).

For patients with jaundice from cholestasis, treatment is aimed at the cause of the cholestasis. There is no danger of kernicterus in these patients, and they do not benefit from photo therapy. In fact, photo therapy in these patients can give them an odd bronze coloring (bronze baby syndrome) that takes a very long time to fade.

Biliary atresia is when the bile duct ise not adequately formed / fibrotic since birth. This results in jaundice in newborn. The total and mostly direct bilirubin is raised. There are three types of biliary atresia :

• Type I: Atresia limited to CBD proximal ducts are patient.
• Type II: Dilated bile ducts at porta, atresia below
• Type III: 90% Atresia of HD, CD, CBD without cystically dilated bile ducts at porta.

This carries the worst prognosis

Symptoms

The newborn baby present with jaundice soon after birth and is accompanied by dark urine which stains the diaper/cloth and light colored stool. Baby is otherwise active, growing and feeding well . On examination the doctors finds the liver to be enlarged.

Treatment

1. Kasai’s Portoenterostomy.
2. Liver Transplantation.

Kasai’s Portoenterostomy

• Kasai et al. observed that minute bile duct remnants or residual channels are present in the fibrous tissue within the porta hepatis. These channels are often in continuity with the intrahepatic ductal system and therefore should provide drainage
• If flow is not established rapidly in these ducts, progressive obliteration ensues.
• Biliary drainage is attempted by excision of the obliterated extrahepatic ducts and apposition of the resected surface of the transected porta hepatis to the bowel mucosa in the Roux-en-Y loop
• Roux-en-Y drainage using a 35- to 40-cm isoperistaltic retrocolic jejunal limb is preferred because this limb may be used for later transplantation if necessary.
• This limb should be fashioned from the most proximal portion of the jejunum, allowing bile to return to the proximal intestine, improving nutrient and medication absorption.

Outcomes post-Kasai

• A proportion of patients with biliary atresia derives long-term benefit from Hepatico-Porto-Enterostomy (HPE). Normal liver function tests and an absence of portal hypertension is observed in only 9% of the children.
• In most patients, however, variable degrees of hepatic dysfunction persist, often because of severe intrahepatic cholangiopathy.
• The long-term prognosis is related directly to the establishment of successful bile flow and the disappearance of jaundice, as suggested by a retrospective study showing increased long-term survival with the native liver in children with serum Bilirubin less than 1 mg/dL within 3months of Hepatico-Porto-Enterostomy.
• Although HPE may be helpful, about 80% of such children eventually require liver transplantation
• Even in patients with transient bile flow whose jaundice does not resolve, some benefit, namely growth to a size sufficient for transplantation, is often achievable.
• The unusual patient with “agenesis” in porta hepatis specimens does not respond to Kasai drainage Procedures.
• Kasai operation should remain the first-line treatment of biliary atresia.
• Early performance of this operation and treatment in an experienced center should reduce the need for liver transplantation in infancy and childhood and provide children with the best chance of survival.
• High survival rates for patients with biliary atresia can be achieved through the complementary and sequential utilization of early primary therapy with the Kasai porto-enterostomy followed by liver transplantation if necessary.

Prognostic Factors

The success of surgery is dependent on several facts such as:-

• Age at operation.
• Bile flow has been reestablished in more than 80% of infants who were referred for surgery within 45- 60 days after birth.
• Success rate drops dramatically, to under 20%, in those older than 90 days at the time of operation.
• Size of the ducts visualized in tissue from the porta hepatitis.

1. Microscopic patency of more than 150 <em>? </em>should determine successful postoperative bile flow

• Experience and operative technique of the surgeon

1. Type II and I have better outcome than type III
2. Role of steroids following HPE.

• Analyses of individual or combined centers’ experience have suggested improved bile drainage and survival in infants receiving corticosteroids after HPE.
• If a patient had poor bile flow initially; re-operation is usually unsuccessful in establishing flow.

Complications:

• Cholangitis

1. 30-60% incidence
2. C/f- sepsis, jaundice, acholic stool, abdominal pain
3. Treatment- I/v antibiotics

• Portal hypertension

1. Incidence in 2/3 of pt. Even after successful HPE
2. Treatment – endoscopic therapy, TIPS rarely

• Hyper-spleenism
• Intra-hepatic biliary cavities-

1. May occur up to years after op
2. Manifests when cyst gets infected\
3. Treatment- I/v antibiotics and drainage of cyst

• Malignancies- cholangiocarcinoma, hepatoblastoma and hepatocellular carcinoma are more frequent after succesfull HPE.

When is liver transplant needed?

Liver transplantation is necessary in infants who manifest by progressive:-

• Hepatocellular decompensation
• Jaundice
• Refractory growth failure with
• Hepatic synthetic dysfunction Ihypoalbuminemia/ coagulopathy
• Intractable portal hypertension with recurrent gastrointestinal hemorrhage or
• Hypersplenism

Biliary atresia is the leading cause of liver transplantation in children especially in west.

Our experience of liver transplantation with biliary atresia :-

In our experience first 100 pediatric transplant. 80% of children transplanted &lt;2 yrs had biliary atresia and 18% &gt;2 years of age had biliary atresia.

Outcome : the survival post liver transplant in biliary atresia patients is ….. in a median fu of ….. 9upto .. yrs

Hepatitis A

The Hepatitis A is the commonest cause of infective jaundice in children in India.

How do you get hepatitis A infection?

It’s a food born infection, that is results due to contamination food and water.

What’s the symptoms?

It could be asymptomatic or have mild symptoms or end up with liver failure. Usually 1 in 1000 children and 1 in 100 develop liver failure. Patients with chronic liver disease also have a more serious outcome. Once liver failure develops it very critical. Even at the best of centre which are experts in the management of liver failure, one can salvage only 50% -60% of the cases. Rest cannont be saved without a liver transplant.

Prevention?

• Vaccine : Hepatitis A vaccination can be prevent by vaccination. It can be given after 1 year of age. The dose is 720U in children and 1440 U in adults. 2 dose are require at an interval of 6 month.
• Hygiene : Hand washing, Boiling water before use. Use of R.O /filters.

Symptoms can be vague and mimic the flu. Most people with hepatitis A usually have:

• Extreme tiredness
• Loss of appetite
• Muscle aches and pains
• Nausea and vomiting
• Low-grade fever

Several days later, symptoms of liver problems will occur.

• Dark urine
• Light-colored bowel movements
• Yellow skin jaundice. This is less common in children under age 6.
• Yellowing of the white part of the eyes (scleral icterus)
• Stomach pain
• Itchy skin

Children with hepatitis A may also have the following symptoms:

• Cold symptoms
• Cough, sore throat
• Sore throat

What are the symptoms of liver failure?

People over age 50 and those with chronic liver disease may have a more severe of hepatitis A called fulminant hepatitis A infection. Symptoms can include:

• Blood clotting problems
• Confusion and changes in alertness
• Liver function continues to get worse
• Yellowing of the skin and eyes that gets worse

What is the outcome of liver transplant in acute liver failure?

In western world the results are poorer to liver transplant in non fulminant probably due to the waiting time for cadaveric graft. In our experience in living related liver transplant outcome is excellent with 95% survival.

What are the indications of liver transplantation in acute liver failure?

When there is marked congulopathy (IMR &gt;4) the survival without liver transplantation is dismal, so liver transplantation is indicated. King’s college criteria are also useful to prognosticate patients with liver failure these criteria are as follows:-

• Prothrombin Time &gt; 100 Sec
• Or any three of the following

1. Prothrombin time &gt;50 sec
2. Bilirubin &gt; 17.5 mg%
3. Age &lt;10 yrs
4. Cryptogenic or Drug-induced
5. Jaundice for more 7 days before onset of encephalopathy

When Will Hepatitis A Symptoms Go Away?

How long symptoms last can vary from person to person. Symptoms can range from mild to severe.

• Mild hepatitis A may last one to two weeks.
• Most patients are much better within three weeks.
• Young children who develop symptoms usually get better within two months.
• Severe infection can cause problems for several months. You may need to stay in the hospital.
• Some patients can have protracted symptoms that can last more than three months or relapsing symptoms for three to nine months.

Hepatitis B and C very specific for children and may differ from adults. Dr. Neelam Mohan has lots of experience of management of Hepatitis B and C in children and she is the author of guidelines at the world congress for management of these conditions.

Hepatitis B and Hepatitis C are viruses that infect the liver and gradually damage it leading to cirrhosis of liver and / or hepatocellular carcinoma.

Once the marker is positive that is HbsAg positive or HCV Ab positive then the doctor will carry out further tests to identify the infectivety of the virus and determine when and how to treat it. Test that are usually carried out are blood tests , ultrasound and liver biopsy.

Treatment is usually with interferon injections (Peg interferon preferably), oral drugs (Lamuvidine, Adefovir, Ribavirin) are usually combined with these injections.

There is risk of progression to cirrhosis of liver or hepatocellular carcinoma with chronic hepatitis B and chronic hepatitis C infections.

• Liver enzymes are AST (SGOT), ALT (SGPT)
• Increase in liver enzymes can result from acute or chronic liver disease.
• Raised liver enzymes can result from a variety of causes affecting the liver which could be infective / metabolic / autoimmune disorders/ infiltrative disorders / fatty liver disease/drugs /toxins/storage disorders etc..
• Any obstruction of the biliary tract ( bile duct / gall bladder) could also lead to raised liver enzymes.
• Abnormality in liver enzymes should be urgently evaluated by an expert hepatologist, a pediatric hepatologist is the best choice for children and adolescents upto 18 years as the etiology is much different than adults.
• Early diagnosis of liver diseases is very useful and delay can lead to increase in severity of liver disease.

Cirrhosis means there is extensive scarring of the liver tissue. Scarred areas are not working. Cirrhosis of liver results from a variety of conditions. Common causes include cholestatic liver diseases such as biliary atresia, metabolic liver diseases such as Wilson’s, tyrosinemia, glycogen storage disorders, other etiologies such as chronic hepatitis B/C etc.In this condition you need to be consulting a Pediatric hepatologist that is a liver specialist, to manage various complications associated with cirrhosis. Most of these children would eventually require liver transplantation though some of the metabolic disorders like Wilson’s may respond well to medical treatment provided an early diagnosis is made.

A patient with cirrhosis might vomit blood.

This is called Haematemesis. It could result from oesophageal varices abnormal veins in food pipe resulting from portal hypertension, secondary to liver disease.

One needs to do UGI Endoscopy to diagnose the underlying condition and treat accordingly- by banding of varices / endoscopic sclerotherapy.

We all have genes inherited from our parents which decide whether we are tall, short, fair, dark, etc. Some genes we inherit are “recessive”, that is, we carry the gene but it does not show up in us anywhere. When we have children, if our partner carries exactly the same recessive gene, there is a one in four chance in every child we have that these recessive genes will match up and become “dominant” showing in the child. Often the matching of recessive genes leads to nothing more extraordinary than, perhaps, a red-haired child of dark haired parents. However, if the recessive genes are carriers of a metabolic disorder, the child will have a metabolic disease although his/her parents do not.

Other metabolic diseases usually affect only boys and are carried by the mother. These are known as X linked, being carried on the sex chromosome. If the child is male there is a 1 in 2 chance that he will be affected. Climb strongly recommends that expert genetic advice is given when a diagnosis is made.

Common metabolic liver disease : Galactosemia, Tyrosinemia, Leukodystrophies, Glycogen Storage Diseases, Wilson’s disease, Hyperammonemia, organic acidaemias and other like Gaucher’s, Leigh’s, Tay Sachs, Cystinosis, Batten’s, Schilders, Sandhoff’s, Alpha One Antitrypsin Deficiency, and the optic acidaemias.

Treatment : Much progress has been made, to treat metabolic diseases with diet or drugs to restore the chemical balance or through organ transplantation. Bone marrow or liver transplantation in some cases means that the donor marrow or liver can introduce the enzyme missing in the recipient but this form of therapy is available for a very limited number of disorders and is not without risk. Direct infusions of the missing enzyme is another method of treatment that has been used successfully in one or two disorders such as Gaucher’s disease, Nieman Pick’s.

What’s Wilson’s disease?

This is one of the commonest metabolic liver disease seen in India. Its an autosomal recessive disorder with a frequency of 1 in 30,000 and the defective gene is ATP 7B gene on chromosome 13. It is a defect of copper metabolism. Usually presents beyond 3-5 years of age with either abnormal liver function tests, chronic liver disease or acute liver failure. Occasionally may be asymptomatic and detected on sibling screening. Besides liver it involves brain, eyes and kidneys and may present with neurological symptoms.

Specific treatment includes chelation therapy with penicillamine or trientene. However, liver transplant is indicated in fulminant liver failure and decompensated chronic liver disease and those not responding to medical therapy.

Obesity Liver Disease

With improvement in economic status, food availability and increased western dietary habits, obesity is being increasingly recognized in Indian children.

• Cardiovascular disease
• Diabetes mellitus
• Liver disease
• Joint disease, etc.

Liver is involved in 10-20% of children with obesity and severity of involvement increases with degree of obesity. Liver involvement in obese children includes:

• Liver enlargement with deposition of fat in liver cells (fatty liver / steatosis)
• Fatty liver with inflammation (steato-hepatitis)
• Steatohepatitis in due course of time can progress to cirrhosis and liver failure.