THE THE LIVER. Assessing the Silent Progress of Liver Disease

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1 THE THE LIVER Assessing the Silent Progress of Liver Disease The liver is the second largest organ in the human body after skin and is the largest internal organ. The liver is first visible in a developing embryo during the fourth week of pregnancy. As the fetus develops, the liver divides into two sections, called the right and left lobes. Ultimately, the right lobe will be six times bigger than the left. By the time a baby is born, the liver constitutes about 5 percent of the baby's total weight. The liver grows with the child and in adults it weighs three to four pounds. If you feel the right lower edge just under your rib cage, you may detect a firm mass that makes a solid sound when you give it a good tap. That is your liver. It has the consistency of foam rubber when healthy. In a child with liver disease, it is often firmer. The liver, tucked under the diaphragm and ribs, extends across to the left side of the body over the top edge of the stomach. The gall bladder and its ducts are just under the right side of the liver. The liver s blood supply is unique; it comes from both the heart and the digestive tract directly through a large blood vessel called the portal vein. Each of the two main lobes contain smaller units called lobules. Most livers have 50,000 to 100,000 lobules that consist of a vein surrounded by tiny liver cells, called hepatocytes. These cells purify the blood, remove wastes, toxins and poisons and store healthy nutrients for the PKIDs PHR 207

2 body to use when needed. The liver s tasks are many. It converts sugar glucose into glycogen and stores it until the body needs it. It also stores vitamins, minerals and iron until the body requires them. Liver cells produce proteins and lipids or fatty substances that include triglycerides, cholesterol and lipoproteins. The liver makes bile acids that break down the fat in food. These bile acids are necessary for the body to absorb vitamins A, D and E, all of which are found in fat. It removes chemicals, alcohol, toxins and medicine from the bloodstream and sends them to the kidneys as urea to be excreted as urine or to the intestines to be excreted as stool. How the Liver Works When food is eaten, the nutrients travel down the throat, into the stomach and then on to the intestines. These organs break up and dissolve the food into small pieces that can be absorbed into the bloodstream. Most of these small particles travel from the intestines to the liver, which filters and converts the food into nourishment that the bloodstream delivers to cells that need it. The liver stores this nourishment and releases it throughout the day, as the body needs it. The proteins, fats, enzymes and other chemicals the liver creates from nutrients are critical to a person s health. For instance, the liver produces the proteins that are necessary for blood to clot. When the liver cannot produce these clotting components, a person could bleed to death. The liver also produces bilirubin, a reddish-yellow pigment formed by the breakdown of hemoglobin in worn-out red blood cells. The blood carries this to the liver where it combines with bile and is passed on to the duodenum to be excreted. When the liver is damaged and it cannot screen out the reddish-yellow bilirubin in the body, jaundice occurs and a person develops a yellowish color in the whites of their eyes and in their skin. The liver produces albumin, a protein found in blood, and cholesterol that is critical to 208 PKIDs PHR

3 THE LIVER the make-up of the outer membrane of cells. When liver cells are damaged and cannot perform these functions, they release certain enzymes into the blood. Doctors test for the presence of all of these enzymes and other liver-related substances in the bloodstream to determine if the liver is damaged or diseased. When the Liver Is Diseased Because the liver is so complex, it is susceptible to a wide variety of adverse effects caused by an excess of alcohol or drugs, infections such as viral hepatitis, cancer and other metabolic disorders. But the liver is also resilient; it has a remarkable ability to regenerate itself following injury or inflammation and it has nutrient reserves it can tap when it is damaged. When a liver is under siege from viral hepatitis, its liver cells are damaged or destroyed. This type of injury can initially be tolerated and resisted, due to the liver s ability to regenerate and compensate for the damage. This phase of liver disease is called compensated liver disease because the liver is able to continue all its functions. When the liver begins to lose the battle, and it is not able to regenerate liver tissue and its filtering and nutrient storing abilities are damaged by scar tissue, this end-stage of liver disease is called decompensated liver disease, because the liver cannot compensate for the ongoing damage. During the early stages of chronic viral hepatitis, before a child s immune system begins to actively respond to the hepatitis virus and liver damage is just beginning, patients usually feel no pain. This is why chronic viral hepatitis is called a silent disease it may cause no physical symptoms at all for decades, even though liver damage may be occurring. Once doctors discover that a viral hepatitis infection is present, they determine which hepatitis viral antigens, antibodies and DNA or RNA levels are present to see how long the infection has been present and whether the body is actively fighting it. If a child s immune system has not yet responded to the virus, they are considered to be in the immune tolerant stage. Next, doctors look for any visible signs of liver damage and they feel a child s liver to determine if it is enlarged, which could signal inflammation. PKIDs PHR 209

4 Another step they take is to draw a blood sample. When the liver and its cells are injured, they release certain enzymes and other substances into the bloodstream. Doctors examine a patient s blood (serum) to see if there are any elevated or below normal levels of liver enzymes, proteins and other compounds in the bloodstream. The term Liver Function Tests or LFTs refers to tests that analyze how well the liver is functioning. The term is also commonly used to refer to tests that measure liver enzymes, which can indicate liver cell damage. Here are some of the liver enzymes, clotting compounds and bile byproducts that doctors evaluate to assess the health of a person s liver. Alanine Aminotransferase (ALT) Liver cells produce the ALT enzyme. ALT levels increase when liver cells are damaged or are dying. The higher the ALT levels, the more cell death or inflammation of the liver is occurring. However, ALTs are not always good indications of how well the liver is functioning; only a liver biopsy can reveal that. ALT levels can remain low even when the liver is inflamed or is developing scar tissue, or during a child s immune tolerant stage of the disease. Aspartate Aminotransferase (AST) Like the ALT enzyme, AST is an enzyme produced by liver cells, but AST is also produced by muscles and it can be elevated in conditions other than liver disease. For example, AST is often elevated during a heart attack. In many cases of liver inflammation, the ALT and AST levels are equally elevated. In some conditions, such as alcoholic hepatitis, AST levels may be higher than ALT levels. AST levels can be normal, yet there can be liver damage occurring. This test adds one more perspective to the picture of liver disease. Alkaline Phosphatase Alkaline phosphatase is an enzyme produced in the bile ducts, intestines, kidney, placenta and bone. This enzyme is measured to help doctors determine if a disease could be concentrated in the bile duct or in the liver. When this enzyme level is high, and when ALT and AST levels are fairly normal, there may be a problem in the bile duct, such as an obstruction. Some bone disorders can also cause alkaline phosphatase levels to rise. 210 PKIDs PHR

5 THE LIVER Gamma-Glutamyltranspeptidase (GGT) This enzyme, like alkaline phosphatase, is produced in the bile ducts and may become elevated when there is a bile duct disorder. Elevations in GGT and alkaline phosphatase usually suggest bile duct disease. Measurement of GGT is an extremely sensitive test; it can be elevated when there is any liver disease. Elevated GGT levels are also caused by drugs (even when taken at prescribed levels) and they are often elevated in heavy drinkers, even when there is no liver disease. Bilirubin Doctors also measure bilirubin, the reddish-yellow pigment formed by the breakdown of hemoglobin in worn-out red blood cells. Normally, the liver conjugates bilirubin and it is excreted in bile and passes through the duodenum to be excreted. Bilirubin levels in the blood can be elevated due to over-production, decreased uptake by the liver, decreased conjugation, decreased secretion from the liver or blockage of the bile ducts. In cases of increased production, decreased liver uptake or decreased conjugation, the unconjugated, or so-called indirect bilirubin, will be primarily elevated. In cases of decreased secretion from the liver or bile duct obstruction, the conjugated, or so-called direct bilirubin, will be primarily elevated. Many different liver diseases can cause elevated bilirubin levels. In the case of chronic liver disease, bilirubin levels are usually stable until a significant amount of liver damage has occurred and cirrhosis is present. In acute liver disease, the bilirubin is usually increased relative to the severity of the acute process. In bile duct obstruction, or diseases of the bile duct, the alkaline phosphatase and GGT levels are often elevated along with bilirubin. Albumin Albumin is the major protein that the liver synthesizes and secretes into the blood. Low albumin levels indicate poor liver function. Albumin levels are usually normal in chronic liver diseases until cirrhosis and significant liver damage occur. Albumin levels are low when there is malnutrition and show increased losses with gastrointestinal and kidney disease. PKIDs PHR 211

6 Prothrombin Time (PT) The prothrombin protein enables blood to clot. When bleeding occurs, prothrombin is changed by a complex series of reactions into the insoluble protein thrombin. When liver function is severely abnormal, the synthesis and secretion of clotting proteins into the blood is decreased. The prothrombin time is a type of blood clotting test performed in the laboratory and it is prolonged when the blood concentrations of some of the clotting factors made by the liver are low. In non-cholestatic chronic liver diseases, the prothrombin time is usually not elevated until cirrhosis and significant liver damage occur. In cholestatic liver disease, patients have a decreased ability to absorb vitamin K. This vitamin K deficency can lead to prolonged prothrombin time. In acute liver diseases, the prothrombin time can be prolonged and return to normal as the patient recovers. Platelet Count Platelets are the smallest of the blood cells (actually fragments of larger cells known as megakaryocytes) that are involved in clotting. When the spleen becomes enlarged as a result of portal hypertension due to decreased blood flow through the liver because of scarring, platelets can accumulate in the enlarged spleen. In chronic liver diseases, the platelet count usually falls only after cirrhosis has developed. The platelet count can be abnormal in many conditions other than liver diseases. Alpha Fetoprotein (AFP) Though not part of a Liver Function Test, many doctors perform this test to measure alpha fetoprotein (AFP) levels in children and adults with chronic hepatitis B and sometimes hepatitis C. AFP, produced by the liver, is more commonly measured to diagnose or monitor fetal distress or fetal abnormalities in pregnant women. But when chronic hepatitis or liver disease is present, doctors measure the AFP levels in a blood sample because elevated levels may signal liver tumors or cancer. Often doctors perform an ultrasound and an AFP test every six months or more often in high-risk patients, such as those with abnormal Liver Function Tests or those with confirmed cirrhosis in order to detect and treat liver cancer at is earliest (and most treatable) stage. 212 PKIDs PHR

7 THE LIVER However, some doctors test AFP levels in young patients with chronic hepatitis B annually, even if liver enzymes are normal and there is no indication of liver damage, scarring or cirrhosis. They use this test because even when Liver Function Tests are normal, cirrhosis and even cancerous tumors can form on the liver. Elevated AFP levels may indicate the silent presence of tumors and cancer. During the 1990s, researchers conducted AFP tests twice yearly on 14,529 adult patients with hepatitis B and C and non-hepatitis-related cirrhosis. According to a report presented to the 51 st Annual Meeting of the American Association for the Study of Liver Diseases in October 2000, a total of 4,339 of these patients were considered to be at risk for cancer. Twice a year, their AFP levels were measured and they were examined with ultrasounds. The tests and ultrasounds identified liver cancers in 237 of the 4,339 patients. AFP levels were elevated above 400 ng/ml in 29.6 percent of them. Alpha fetoprotein levels are obtained at least yearly in my patients with chronic hepatitis B so they can be compared to previous values (test results), said Dr. Philip Rosenthal, director of the Pediatric Liver Transplant Program and Pediatric Hepatology at the University of California, San Francisco. Data have shown in patients with chronic hepatitis B infection, a rise in AFP can signal a tumor and the need to investigate and then resect (surgically remove) the tumor as early as possible to improve prognosis. I try to get alpha fetoprotein levels at least yearly and ultrasound exams baseline and then every one to two years if the insurance company will let me. If the AFP is rising, then a repeat ultrasound should be obtained and compared to the previous studies as quickly as possible. Dr. Maureen Jonas, a pediatric gastroenterologist specializing in hepatitis at Children s Hospital Boston, also performs annual AFP tests in children with chronic hepatitis B, even when Liver Function Tests and liver enzymes are normal. I don't recommend annual AFP in cases of hepatitis C unless there is cirrhosis, and not just abnormal ALT levels, she said. Dr. Jonas AFP testing protocol is based on experience in adults. It may be a bit aggressive for children, but I have no hard data on which to base other recommendations. What Causes Elevated Liver Enzymes in People with Viral Hepatitis? ASTs and ALTs are sensitive indicators of liver damage but higher-than-normal levels of these liver enzymes should not be automatically equated with chronic or long-term PKIDs PHR 213

8 liver disease. Sometimes the levels can be normal when damage is present, but are usually elevated in acute injury. Patients with acute viral hepatitis A, which is a short-term illness that rarely causes permanent liver damage, may temporarily develop very high AST and ALT levels. But most patients with acute viral hepatitis A recover fully without any residual liver disease. In contrast, children and adults with chronic hepatitis C infection may have only a mild elevation in their AST and/or ALT levels. However, some of these patients may have quietly developed liver disease, with scarring and even cirrhosis. Many infants and young children infected with hepatitis B have normal ALT levels until their immune systems recognize and attack the virus residing in the liver cells. The highest levels of AST and ALT are found when numerous liver cells die. This occurs in such conditions as acute viral hepatitis B, pronounced liver damage inflicted by toxins as from an overdose of acetaminophen or prolonged collapse of the circulatory system (shock) when the liver is deprived of fresh blood bringing oxygen and nutrients. AST and ALT serum levels in these situations can range anywhere from 10 to 100 times the upper limits of normal. A host of medications can also cause abnormal liver enzyme levels, such as: Anti-seizure medications such as phenytoin, valproic acid, carbamazepine and phenobarbital. Acetaminophen (such as Tylenol). Antibiotics such as the tetracyclines, sulfonamides, isoniazid (INH), sulfamethoxazole, trimethoprim, nitrofurantoin, etc. Cholesterol-lowering drugs such as the statins and niacin. Cardiovascular drugs such as amiodarone. Anti-depressant drugs of the tricyclic type. When liver enzyme abnormalities are drug-related, the enzymes usually normalize within weeks or months of stopping the medications. Stages of Liver Disease When liver function and enzyme test results are abnormal, doctors will next want to find out why. Once the cause is known, a doctor will determine if the liver is inflamed, if it 214 PKIDs PHR

9 THE LIVER has developed any fibrosis or scar tissue, if scarring in the liver has advanced to cirrhosis, or if the liver has become cancerous. During the early stages of liver disease there are certain areas of the liver that may be prone to inflammation and scarring, including the lobules and the area where the large portal vein and its branches enter the liver, called the portal triad. During the intermediate stages of liver disease, the fibrosis tissue or scarring expands and bridges between portal areas. In the late stage of liver disease, the scarring is so extensive that it expands to the central area of the liver and the liver changes its shape or architecture due to the scarring and tissue regeneration attempts. Doctors assign grades to the degree of inflammation and liver cell damage and they identify stages of liver scarring and cirrhosis. These stages and grades are assessed as: none, minimal, mild, moderate or severe. Liver Fibrosis When hepatitis viruses begin to replicate in the liver, the body s immune system may recognize the presence of this foreign entity or antigen and immediately mount a counter attack, targeting the infected liver cells in which the virus has set up shop and begun replicating. In the case of hepatitis B, it is the body s immune system attack on the infected liver cells that causes the inflammation and scarring in a liver not the virus. When there is chronic or long-term hepatitis B, D or C, the body s battle with the virus can be prolonged, and the liver may form scar tissue, called liver fibrosis, as it fights the virus-infected liver cells over a period of many months or years. A liver with moderate scarring or fibrosis. To date, there is no clear linear pattern that defines the rate or the location within the liver where fibrosis or scarring occur during chronic hepatitis infections. The rate of scarring varies from individual to individual. If untreated, liver scarring can spread throughout all of the liver s lobes and impede the function of the liver. However, if treated in time, doctors have recently discovered that scarring (fibrosis) is reversible. They are now closely PKIDs PHR 215

10 studying how fibrosis occurs in the liver in an effort to develop effective anti-fibrotic therapies. Fibrosis by itself does not impair liver function until it becomes so extensive throughout the liver that it forms nodules and the liver becomes cirrhotic. How Scar Tissue Is Formed A liver contains hepatocytes or liver cells, a porous lining, tissue macrophages called Kupffer cells and stellate cells (formerly called Ito cells or lipocytes or fat-storing cells). The stellate cells make up about 15 percent of the liver s resident cells. In a healthy liver, these stellate cells are quiescent or fairly inactive cells that store vitamin A and perform a variety of functions in the liver, including maintaining the liver s membrane around different liver sections. But when there is injury to the adjacent membrane or Kupffer cells, the stellate cells become activated and begin to proliferate in response to the damage. They shed their vitamin A and basically reconstitute themselves and begin producing fibrous material or scar tissue. The scar tissue created by the stellate cells accumulates and increasingly hinders liver functions. During recovery from hepatitis and liver injury, researchers report the number of activated stellate cells declines. Researchers suspect they either return to their quiescent stage or the activated stellate cells disappear. Meanwhile the integrity of the liver is restored and the scar tissue may even disappear. Cirrhosis During severe viral hepatitis infections, when liver cells are dying and the liver is being extensively scarred over a prolonged period of time, cirrhosis can develop. This is the seventh leading cause of death in the United States, according to the National Institute of Diabetes and Digestive and Kidney Diseases. Because of the ongoing damage to the liver, scar tissue slowly replaces normal functioning liver tissue, progressively diminishing blood flow through the liver. As the normal liver tissue and functions are lost, nutrients, hormones, drugs and poisons are no longer synthesized and filtered by the liver. Production of vital proteins, clotting components and other substances also declines. 216 PKIDs PHR

11 THE LIVER As more and more scarring occurs, a large area of the liver may become scarred and only a very small amount of blood will be able to pass through. As cirrhosis worsens and blood flow is increasingly impeded, pressure in the blood vessels in the stomach and lower throat increase, and there may be enlargement of the spleen. This is known as portal hypertension. Slower blood flow through the liver may increase pressure in the abdomen from fluid buildup. This condition is called ascites. Cirrhosis is severe scarring of the liver. It can even change the shape or architecture of the liver. Other symptoms, due to improper cleansing of blood by the liver, may include itching or a lessened ability to think clearly. A person can even lapse into a coma due to accumulation of toxins in the blood. The liver can compensate for a significant amount of damage, but eventually liver function will decline markedly. When cirrhosis is severe, it is called decompensated cirrhosis, because the liver can no longer compensate for the extensive scarring. How Doctors Evaluate Cirrhosis When doctors evaluate a person with cirrhosis, they grade the liver disease based on how extensive the scarring is throughout the liver, what areas of the liver are scarred, if there are any lesions and whether continual scarring and liver tissue regeneration have altered the architecture or shape of the liver. A liver biopsy that extracts liver cells through a needle usually examines just one area of the liver for scar tissue and damaged liver cells. But cirrhosis varies in severity and location. When examining liver tissue, doctors look at the fibrous bands of scar tissue that surround nodules of regenerating liver cells. Cirrhosis is described as micronodular if the nodule diameter is less than 3 mm and macronodular if it is more than 3 mm. Patients with severe cirrhosis risk liver failure and development of liver cancer, also called hepatocellular carcinoma or HCC. PKIDs PHR 217

12 Is Cirrhosis Reversible? Historically, doctors viewed cirrhosis as a late and irreversible stage of liver disease. Most of the cirrhotic patients that doctors treated were adults, mostly male, who were alcoholic or injecting drug users or who had other health problems. In these men, cirrhosis was irreversible and death from liver disease was often inevitable. Today, as doctors expand their experience with diseased livers and find effective drugs to treat children who have no other coinfections or history of alcohol abuse, they are beginning to suspect that cirrhotic livers may be more resilient then previously thought. Cirrhosis may even be reversible once the infecting virus is vanquished or under control. In an editorial in the Feb. 8, 2001 issue of The New England Journal of Medicine, the journal s editors wrote, In many cases, patients with cirrhosis are asymptomatic, with normal findings on physical examination, and the disorder is detected initially because of elevated serum liver enzyme levels or a positive serologic test for hepatitis B or C virus. Advances in the treatment of liver diseases have made it increasingly apparent that medical treatment may be beneficial even for patients with advanced histologic changes, including cirrhosis. Furthermore, in some cases fibrosis and even frank [clear] cirrhosis have appeared to regress with treatment. Liver Cancer Liver cancer is the second most common cancer in the world. It is most common in Africa, Asia and Southern Europe. In the United States, approximately three out of every 100,000 people will develop liver cancer each year. The hepatitis B and C viruses can sometimes cause cancer because they change a liver cell s DNA the genetic code that instructs the cell how to reproduce when they take over liver cells to replicate. In the case of hepatitis B, on a molecular level, the X gene protein in the virus is believed to play a role in causing cancer and tumors, possibly through its interaction with the P53 tumor-suppressor gene. Cancerous tumors form in the liver during liver cancer. 218 PKIDs PHR

13 THE LIVER Children and adults chronically infected with hepatitis B, C or D (a hepatitis B infection is needed before hepatitis D is contracted) are at increased risk of liver cancer. Without proper treatment, about 20 percent of patients who have cirrhosis will go on to develop liver cancer. According to cancer studies, about 75 to 95 percent of patients who develop liver cancer have had cirrhosis. The symptoms of liver cancer can be similar to those of cirrhosis, including jaundice, fatigue, drowsiness and weight loss. Patients frequently have abdominal pain and abdominal masses. Liver cancer may also spread through the bloodstream, causing cancer in other tissues and areas of the body. If the cancer is small, it is often removed through surgery. Because the liver can regenerate, it's sometimes possible to remove a great deal of liver tissue without long-term ill effects. But often, by the time liver cancer is identified and surgically removed, the cancer is so widespread or systemic that it may recur in the liver after surgery. How Doctors Diagnose Liver Disease To prevent liver scarring, cirrhosis and liver cancer, doctors want to identify and track liver disease in children and adults as early as possible. In addition to identifying which hepatitis antigens and antibodies are present and measuring liver enzymes and looking for tumors through an AFP test, doctors have other tools to monitor and diagnose liver disease. Doctors look at a patient s health history and they physically examine the patient to check for a swollen liver or for any abnormalities. They may also perform an ultrasound examination to check for swelling, scarring or tumors in different areas of the liver. Also known as ultrasonic imaging, this test sends sound pulses into the body. The returning echoes are collected and a picture is produced from them. An ultrasound examination of the liver measures the liver s size and determines whether the liver disease is more advanced than what blood tests might indicate. The ultrasound can reveal abnormal texture, discrete lesions and cirrhosis. Some doctors perform a baseline ultrasound on children, even when their Liver Function Tests are normal, to have as a reference. Then, as years pass or if liver enzymes increase, doctors have the original ultrasound to compare to future ultrasound PKIDs PHR 219

14 examinations. In addition to these tests, physicians may order more specific liver tests such as an autoimmune test that can determine the specific cause of a liver disease. But to date, the best vehicle for assessing the true condition of the liver is a liver biopsy. When Is a Biopsy Recommended? When to order a liver biopsy is an area of contention within the medical community, especially when deciding whether to recommend a liver biopsy in a child. Nearly all doctors agree that a liver biopsy should be routinely ordered when tests reveal elevated liver enzymes over several months. The liver enzyme elevation that merits a liver biopsy and treatment can range from 1.5 times to twice the levels that are normal for a child of that age and weight. But when liver enzymes are only slightly elevated or when there are flares of elevated enzymes doctors face a dilemma of when or whether to order a biopsy. They must decide when the value of the information gained from the biopsy outweighs the medical risks of the procedure itself. At the crux of this dilemma is the fact that liver damage can occur, especially in children, without tests revealing any tell-tale signs of liver cell damage or scarring. A child s ALT or AST readings may be normal or near normal even when hepatitis viruses are rapidly infecting liver cells and causing inflammation and scarring. Because there is no linear correlation between liver enzyme levels and the amount of liver damage, doctors cannot judge how much damage is occurring in the liver simply by looking at blood tests. In the case of hepatitis C, many doctors recommend a biopsy to obtain a timeline in the natural history of an individual s disease. A patient s blood tests and ultrasounds can remain normal until there is less than 20 percent of the liver functioning. According to the American Digestive Health Foundation, about 30 percent of chronically infected patients with hepatitis C have persistently normal ALT levels. Liver Function Tests can be perfectly normal, and yet there can be significant fibrosis, even cirrhosis, said Dr. Philip Rosenthal. Liver Function Tests are only as good as the moment the [blood] is drawn. They cannot reflect previous evidence of inflammation 220 PKIDs PHR

15 THE LIVER and scarring. The tests alone do not determine the need for a liver biopsy. So what, other than abnormal tests, justifies a liver biopsy in a child? The general health of the child, any coinfections, any other test results including the status of the virus antigens and antibodies, and a physical examination all contribute to the decision to order a liver biopsy. Why a Liver Biopsy? Many of the uncertainties that surround the health of a chronically infected child s liver are dispelled when a liver biopsy is performed. Many medical centers that are conducting clinical trials in the treatment of viral hepatitis may also require liver biopsies in order to monitor and assess the therapy s impact on the liver. All treatment trials of interferon, lamivudine and combination interferon and ribavirin have greatly relied on liver biopsies before and after treatment to assess the effects of the drug therapy. When undergoing treatment or participating in a clinical trial, a child may have one biopsy before treatment begins and a second after treatment concludes to gauge the effectiveness of the drug. Biopsies are generally not performed during the treatment period because the liver may be changing rapidly in response to the treatment. Patients who have undergone liver transplantation often require numerous liver biopsies in the early weeks and months following the surgery to accurately diagnose if the new liver is being rejected or whether other problems have developed. A parent of a young child who underwent a liver biopsy observed, I really do believe the biopsy is tougher on parents than on the child. Assuming your child's liver is in decent shape and blood clots properly, there is little risk if an experienced pediatric gastroenterologist or hepatologist conducts the procedure. While the procedure scared my daughter, I really don t think there was much pain associated. When she got home, she was back to doing her own thing. And there is some comfort in knowing the true status of your child's liver, and the biopsy is the only real way to know this, the mother added. How Is a Sample of Liver Tissue Taken? A liver biopsy is a diagnostic procedure used to obtain a small amount of liver tissue. The doctor examines the liver cells under a microscope to assess the health of the liver PKIDs PHR 221

16 and determine if there is inflammation, scarring, lesions or cirrhosis. This is the best tool available for diagnosing the progression of liver disease. The most common way a liver sample is obtained is by inserting a special biopsy needle through a small incision into the liver to retrieve liver tissue. This liver biopsy procedure is commonly used in the United States when children and adults are in the early to mid-stages of liver disease. When the liver is badly damaged, the blood cannot clot properly and the risk of internal bleeding increases. Also, when the liver s architecture or structure has been distorted by scarring, risks associated with biopsies increase. In these scenarios, doctors may perform a laparoscopic biopsy or transvenous biopsy to retrieve liver tissue samples. In a laparoscopic biopsy, the physician inserts a special tube called a laparoscope through an incision in the abdomen. The laparoscope sends images of the liver to a monitor. The physician watches the monitor and uses instruments within the laparoscope to retrieve tissue samples from one or more parts of the liver. Physicians use this type of biopsy when they need tissue samples from specific parts of the liver. In a transvenous biopsy, a tube called a catheter that contains a biopsy needle is inserted into a vein in the neck and guided to the liver. The needle then collects liver tissue samples. Physicians use this procedure when patients have advanced liver disease, including blood-clotting problems or fluid in the abdomen. How a Liver Biopsy Is Performed Why a Liver Biopsy? Dr. Luis Balart, Chief of Gastroenterology at Louisiana State University Health Sciences Center in New Orleans, explained, This is an important parameter that must be part of the evaluation process in these individuals. Only a liver biopsy can truly stage [diagnose] the disease and be capable of forecasting with any degree of certainty what the future course may hold for a particular patient. Just as important, liver biopsy findings and staging can provide a firm basis from which to make a decision as to whether treatment is warranted immediately or if watchful waiting is an option. Most biopsies are performed in an out-patient hospital setting or with an overnight hospital stay, especially for young children. 222 PKIDs PHR

17 THE LIVER Either the day before or the morning of the biopsy, the hospital lab or doctor s office staff will take a blood sample. Doctors will look at the blood sample to evaluate a patient s red and white blood cell count, platelets and prothrombin time, which indicate whether a person is at increased risk of clotting problems and internal bleeding. These tests are performed again shortly after the biopsy procedure and again the day after the biopsy to test for any internal bleeding, especially in children. Usually one week before the surgery, a patient must stop taking aspirin, ibuprofen and any anticoagulants. A patient must not eat or drink anything for about eight hours before the biopsy, which is often very difficult for young children. Once in the hospital, if the patient is a child, he or she is sedated either through conscious sedation or by being completely anaesthetized. This is a difficult time for parents and children alike. Children will often have to be restrained and may cry while being anaesthetized. Before the procedure, both the doctor and the anesthesiologist should have met with parents to review the procedure. If older teens are able to hold still during the procedure (they must also hold their breath during the needle pass), just their skin and area under the skin where the needle will pass quickly through is anaesthetized. Adults also usually receive a local anesthetic if they can lie still and hold their breath during the procedure. The physician and a radiologist will determine the best site, depth and angle of the needle puncture by physical examination and through an ultrasound. The doctor may actually draw an outline of the liver on the abdomen and then make an X where the incision will be made and the needle inserted. An ultrasound will usually be used during much of the biopsy procedure to guarantee proper placement of the needle. Some doctors say an ultrasound-guided biopsy guarantees the best possible location for the biopsy and reduces risk of accidentally puncturing the neighboring gall bladder or lung, especially in small children. I think today most liver biopsies should be ultrasound or CT-guided [using Computed Tomography imaging or CAT] depending on the circumstances and the institution, said Dr. Philip Rosenthal. In a normal anatomic liver, percussion and biopsy without guidance can be done. Personally, I like using ultrasound guidance. This is especially true in a transplanted liver in which the normal anatomy has been changed, or if a piece of a liver has been used for the transplant. PKIDs PHR 223

18 These liver cells, extracted during a biopsy, are healthy. These liver cells show moderate scarring. These liver cells show extended scarring. These liver cells show evidence of cancerous growths or tumors. Generally, doctors make only one pass with the thin needle to extract between two to three inches of liver tissue. The risk of injury increases with the number of needle passes. The actual biopsy will take five seconds or less. The entire procedure generally takes about 20 minutes. According to reports, about half of adult patients who undergo a biopsy experience no 224 PKIDs PHR

19 THE LIVER pain after the procedure, while the other half report they experience a brief localized pain that may spread to the right shoulder. Because children are generally sedated, there are few reports of children experiencing pain shortly after the procedure. After the biopsy, a dressing is placed over the small incision and the patient must lie on his or her right side, to keep pressure on the incision site for three to four hours. During this time, blood tests are performed again to make sure there is no internal bleeding and blood pressure is taken frequently. This post-biopsy period is often a difficult time for parents who must keep their restless young children still. Videos are ideal distractions for older children. Younger children usually require the constant presence of reassuring parents and favorite blankets and animals. Within a couple hours, the patient will be able to eat. At home, the dressing will be able to be removed within a couple of days. Patients are instructed to take it easy for the first week, and to apply some pressure to the side with cushions or pillows as this aids healing, helps prevent bleeding and may make the patient more comfortable. The doctor will have specific instructions. For 14 days after the biopsy, patients should remain within one hour of a major hospital and they should carry information to alert medical staff that they have recently had a biopsy. Following the biopsy, the doctor will call and meet with the family to review the results and discuss the next treatment step. Guidelines for Liver Biopsies in Children According to a survey conducted by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, the reported rates of major complications in children who underwent liver biopsies over a 50-year period ranged from zero to 4.5 percent. The incidence of post-biopsy hemorrhage requiring transfusion ranged from zero to 2.8 percent. Other major complications in children, like in adults, have included internal bleeding, bile leak if the gallbladder is nicked and ascitic fluid leak from the abdomen. Three pediatric deaths were reported as a result of the procedure. The Society examined liver biopsies in order to establish a recommendation on whether PKIDs PHR 225

20 biopsies on children, who tend to be more high-risk than adults for this procedure, should be conducted on an out-patient or in-patient hospital setting. The Society decided that, because of potentially increased risks, and the greater difficulty of detecting and managing shock, infants and children requiring liver biopsy should not be compelled to have liver biopsy as outpatients. However, the Society agreed that an out-patient liver biopsy may be considered if, in the judgment of the attending physician, certain conditions are met. Young patients with underlying conditions such as active malignancy, AIDS, bone marrow transplantation and ischemic liver disease are at significantly higher risk for a complication or poor outcome following percutaneous liver biopsy, and generally are not considered candidates for a liver biopsy in an out-patient setting, the group recommended. The Society also stated that children who receive liver biopsies in an out-patient setting should remain at the facility for at least six hours following the procedure for frequent monitoring. This is the same recommendation made for adults by the American Gastroenterological Association. According to studies in adults, severe complications occur in only 0.57 percent of patients who undergo a liver biopsy. The risk of internal bleeding decreases, they found, if the doctor who is conducting the biopsy uses ultrasound to guide the procedure, according to an American Association for the Study of Liver Diseases report. Preparing Children for Biopsies Based on the age of the child, preparation and the constant presence of their parents can help ease the liver biopsy experience. According to experts, parents should try to explain the procedure in age-appropriate ways, perhaps using a doll as a model. Stress the procedure is not a punishment, but a way to make sure they are as healthy as possible. Prepare yourself and your child for a period of fasting. His or her food and fluid will probably be restricted for up to eight hours or more before the procedure. You must sign an informed consent form giving permission for biopsy. Before the biopsy, blood samples will be taken from your child to ensure his or her blood will clot properly. Take the child s favorite toys, blankets and other objects of comfort to the hospital to 226 PKIDs PHR

21 THE LIVER help them with the experience. Ask the doctor to describe in detail what will take place when you arrive at the hospital with your child, so you both are prepared for the inevitable fasting period, blood tests, waiting, anesthetic, the biopsy itself and the recovery. Be sure to bring toys or videos that your child will want during the post-operative recovery period. Also ask about what food will be allowed during this recovery time. Your child will be hungry and may want their favorite food. How Liver Biopsies Are Evaluated The Histologic Activity Index (HAI) or Knodell Score is the method many doctors use to evaluate a liver sample. This is a standardized interpretation that has shown little variation between interpreting doctors. While some of the judgments in the HAI are subjective, the evaluation is straightforward and numeric values are assigned so a liver s health can be accurately assessed before and after treatment, or over a period of months or years. Doctors use this standardized grading system to allow consistent comparison between biopsies in the same patient that are performed and interpreted by different doctors and for biopsies of large populations participating in clinical studies. The test evaluates the liver specimen based on: Degree of inflammation. Evidence of bridging or growth of scar tissue. Liver cell injury or death (necrosis) in different areas of the liver including the portal area where the portal vein flows. Change in the architecture or general shape of the liver. The degree of fibrosis (scarring) that is present in the tissue sample. In HAI results, grade refers to inflammation and stage refers to fibrosis or scarring. These terms are universally accepted. PKIDs PHR 227

22 These are the four features that are evaluated by the HAI and the range of their scores. Zero indicates non-existent and high scores reflect severe indications: Periportal and bridging necrosis 0 to 10 Intralobular degeneration and necrosis 0 to 4 Portal Inflammation 0 to 4 Fibrosis (Scarring) 0 to 4 All four scores are added and can range from 0 to 22. This final tally becomes a patient s HAI score and indicates the severity of the liver disease. (See Lab Test Results section for more information.) Portal inflammation refers to the inflammation of liver cells that surround the portal tract. The portal tract is the area where the artery, vein and bile duct enter the liver. Focal or lobular necrosis/inflammation refers to liver cell damage that exists between the portal regions. Intralobular degeneration and necrosis refers to the cell damage that extends across more than one liver lobule. An individual s HAI score serves as a baseline or reference point as doctors recommend either a drug therapy or continued watchful waiting. Doctors encourage patients and parents to focus less on numbers and more on the description of scarring and the nomenclature such as bridging, nodules (which are signs of cirrhosis) and widespread cirrhosis, which signify more advanced liver disease. 228 PKIDs PHR

23 THE LIVER Bibliography Balart L. Featured in Medscape's Ask the Experts. Medscape/features/ResourceCenter/HepC/AskExperts/public/ExpertsPanel.html. Editorial: Is Liver Fibrosis Reversible? The New England Journal of Medicine. Feb. 8, 2001; Vol. 344, No. 6. Friedman SL. Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury. Journal of Biological Chemistry. Vol. 275, Issue 4, , Jan. 28, The Hepatitis Information Network. Jonas, Dr. Maureen, pediatric gastroenterologist, Children s Hospital, Boston. Interview. Jonas MM. Hepatitis C Infection in Children. New England Journal of Medicine. 1999; 341: MacMahon B, Sherman M, Di Bisceglie A. Hepatitis B and Hepatocellular Carcinoma. Presentation at the NIH Workshop on the Management of Hepatitis B: Sept. 8-10, 2000, Bethesda, MD. Outpatient Liver Biopsy in Children: A Medical Position Statement of the North American Society for Pediatric Gastroenterology and Nutrition. Journal of Pediatric Gastroenterology and Nutrition. Volume 23, (c) 1996, Lippincott-Raven Publishers. Preparing Children for Operations. Dr. Greene s House Calls. com/default.asp. Percutaneous Liver Biopsy. University of Michigan Health System. umich.edu/1welcome/index1.htm. Rosenthal, Dr. Philip, Professor of Pediatrics and Surgery, Medical Director of the Pediatric Liver Transplant Program and Pediatric Hepatology at the University of California, San Francisco. Interview. PKIDs PHR 229

24 230 PKIDs PHR

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