Table of contents

Laboratory diagnosis of liver diseases Liver transaminases Cholestasis Liver synthetic functions Liver excretory functions Liver serum markers Imaging in diagnosis of liver diseases Abdominal ultrasound Computed tomography MRI Liver scan ERCP MRCP PCT Liver biopsy in diagnosis of liver diseases References

1 1 2 2 4 5 6 6 7 8 8 8 9 9 9 11

Laboratory investigations for liver diseases

Laboratory tests in liver diseases are generally effective for the following: Detecting hepatic dysfunction, assessing the severity of liver injury, monitoring the course of liver diseases and the response to treatment, and refining the diagnosis. These tests can be done as following:

Aminotransferases
Liver transaminases serum concentrations are normally low. However, if the liver is damaged, the hepatocyte cell membrane becomes more permeable and some of the enzymes leak out into the blood stream. The two transaminases commonly measured are alanine transaminase (ALT) and aspartate transaminase (AST). These levels previously are called the serum glutamate-pyruvate transaminase (SGPT) and the serum glutamate-oxaloacetate transaminase (SGOT) respectively. (1) The normal levels for AST and ALT are < 40 IU/L and < 45 IU/L respectively. Very high elevations of the transaminases suggests severe liver damage, such as viral hepatitis, liver injury from lack of blood flow, and injury from drugs or toxins. Most disease cause ALT to rise higher than AST, levels over 1000 can be associated with ischemic hepatitis. (2) AST also present in red blood cells, and cardiac and skeletal muscle, So ALT is more liver-specific than AST, but it has a longer plasma half-life and found mainly in the cytoplasm where AST is found in mitochondria and cytoplasm. Therefore, a rise in AST is an early indication of liver damage and is a useful marker in detecting onset of recovery or rejection after liver transplantation. These enzymes may be normal in compensated cirrhosis; elevated aminotransferases are often the first indication of the development of nonalcoholic fatty liver disease (NAFLD) in an obese child. Elevated aspartate aminotransferases and/or alanine are also found in muscular dystrophy, and this diagnosis should be considered if there are no other signs of liver disease. (3) There are many other factors besides liver injury that could affect the levels of AST and ALT. For example, males have higher transaminase levels than females. And, African-American men have higher AST levels compared with Caucasian men. People appear to have higher transaminase levels in the morning and afternoon than in the evening. Food intake does not appear to have a significant effect on transaminase levels. Thus, levels do not significantly differ in the fasting and non-fasting state. Finally, transaminase levels may vary from day-to-day. (4) AST/ALT ratio: This ratio is sometimes useful in differentiating between causes of liver damage: When greater than 2.0, it is more likely to be associated with alcoholic hepatitis, when less than 1.0, it is more likely to be associated with viral hepatitis. The ratio is less useful in scenarios where the liver enzymes are not elevated, or where multiple conditions co-exist. It is also known

as the "De Ritis Ratio", named after De Ritis, who performed early analysis on transaminases. (5)

Cholestasis
Urthophosphoric monoester phosphohydrolase, better known as alkaline phosphatase, can normally be detected in serum and in extracts prepared from many different tissues, notably bone, liver, intestine, kidney, and placenta. In adults serum alkaline phosphatase is predominantly of hepatic origin; a small but variable amount of the intestinal isoenzyme can be demonstrated. The normal value is 20 to 140 IU/L. Children have higher values, as bones that are still growing produce higher levels of ALP. During some growth spurts, levels can be as high as 500 IU/L. Increased serum alkaline phosphatase is mainly due to either disease of the bone in which there's increase in the osteoblastic activity or a disease of liver when there's outflow of bile flow either intrahepatic or extrahepatic. (6) In the investigation of liver disease in children measurements of the more specific 5'ribonucleotide phospho-hydrolase (5-nucleotidase) are preferable, since this enzyme is predominantly of hepatic origin and its normal range of activity in serum does not show variation with age. Normal values are 0-11 U/L. High level ascertains cholestatic disorder or hepatic metastasis. (7) A 3 rd marker for cholestasis is a liver enzyme known as Gamma-glutamyltransferase. It is produced by the liver cell microsomes and is widely distributed in cells that are involved in the secretion and absorption of bile. It is a useful laboratory marker as an indicator of early liver cell damage or cholestatic disease. In the pediatric population, it is a useful marker to differentiate neonatal hepatitis from extrahepatic biliary atresia, as it's increased with atresia. The reference range for GGT is age dependent. In normal full-term neonates the activity at birth is approximately six to seven times the upper limit of the adult reference range. The activity then declines, reaching adult levels by the age of 5-7 months. (8)

Liver synthetic functions:

Albumin As serum albumin has a long half-life; hypoalbuminemia is often taken as a
sign of chronic liver disease. However, a patient with compensated chronic liver disease may have an abrupt decrease in serum albumin concentration during an acute illness such as sepsis or mild flulike illness. This is caused partly by an acute decrease in synthesis below that already present because of the parenchymal liver disease, possibly regulated by cytokines such as tumor necrosis factor and interleukin-1. Hypoalbuminemia also occurs in the cases of protein-losing enteropathy, chronic infection, malnutrition, and nephrotic syndrome. In the absence of other nonhepatic etiologies, serum albumin levels may be useful in assaying hepatic synthetic function.

Coagulation Disorders Abnormal hemostasis is a common complication of liver disease.

Mechanisms resulting in these defects include: (1) Diminished hepatic synthesis of coagulation factors V, VII, IX, X, and XI, prothrombin, and fibrinogen (reflected in prolongation of the PT); (2) Dietary vitamin K deficiency due to inadequate intake or malabsorption (3) dysfibrinogenemia; (4) Enhanced fibrinolysis due to decreased synthesis of a 2 -plasmin inhibitor;(5) Disseminated intravascular coagulation (DIC); and (6) Thrombocytopenia due to hypersplenism. (9) (10) Because of the large functional reserve of the liver, failure of hemostasis may not arise except in severe or chronic liver diseases. Thus, testing for a coagulation defect is not a screening procedure. Rather, it serves as a means of following the progress of the liver disease or for assessing the risk of bleeding before an invasive and traumatic diagnostic procedure is undertaken (11) As storage capacity of vitamin K in the liver is limited, depletion occurs quickly when absorption is impaired, and the PT increases above normal ranges. A prolonged PT (normal PT ranges from 11 to 13.5 seconds) is not specific for liver disease because it is seen in various congenital deficiencies of coagulation factors and in acquired conditions such as consumption of clotting factors (as in DIC) and ingestion of drugs that affect the PT complex. Factor VIII, being made in nonhepatic tissues, is helpful in differentiating the depression of clotting factor activity and prolongation of hemostasis caused by severe liver disease alone (normal factor VIII) from that caused by accompanying DIC (depressed factor VIII activity from consumption). DIC is more common in children with end-stage liver failure because of the increased risk of infection from general debilitation and synthetic deficiencies of plasma proteins such as complement and opsonins normally made by the liver. In the presence of normal factor VIII activity, prolongation of the PT indicates plasma clotting factor deficiency from impaired hepatic synthesis or secondary to vitamin K deficiency, recent intake of antibiotics that alter the intestinal flora should be queried. Because the plasma half-life of several of the clotting factors is short (such as 35 hours for factor VII), the PT will rapidly reflect changes in hepatic synthetic function, such as may occur in acute liver failure, and thereby provides a good indicator of ultimate prognosis. (12) The PT test is not a sensitive index of chronic liver disease because even in severe cirrhosis, levels may be normal or only slightly prolonged. On the other hand, the PT test has high prognostic value, particularly for patients with acute hepatocellular disease. A persistently abnormal PT in a previously well child can be the single laboratory test that draws attention to the possibility of the development of acute liver failure. However, not all patients with prolonged PTs prove to have evidence of acute liver failure. In children with chronic cholestatic liver

disease, an abnormal PT level refractory to maximal vitamin K therapy and decreasing serum albumin should raise for consideration for further assessment. Fibrinogen levels are usually normal in hepatic disease because it is made both in the liver and in extrahepatic sites. Low levels of fibrinogen are seen in liver disease accompanied by DIC when there is consumption of fibrinogen and other clotting factors. Conversely, high levels of fibrinogen may be seen in patients with hepatic diseases because fibrinogen is an acute phase reactant or because of elevations in cholestatic disease.

Lipids and Lipoproteins The liver plays a central role in production and
degradation of lipoproteins. Lipoprotein abnormalities are common in chronic cholestatic disorders of either intrahepatic or extrahepatic etiology (13) (14) leading to marked elevation of cholesterol level in plasama. (15)

Liver excretory functions

Bilirubin is the major breakdown product of hemoglobin released from senescent erythrocytes. Initially it is bound to albumin, transported into the liver, conjugated to a watersoluble form (glucuronide) by glucuronosyl transferase, excreted into the bile, and converted to urobilinogen in the colon. Urobilinogen is mostly excreted in the stool; a small portion is reabsorbed and excreted by the kidney. Bilirubin can be filtered by the kidney only in its conjugated form (measured as the direct fraction); thus increased direct serum bilirubin level is associated with bilirubinuria. Increased bilirubin production and excretion (even without hyperbilirubinemia, as in hemolysis) produce elevated urinary urobilinogen levels. There are no normal levels of bilirubin as it is an excretion product, and levels found in the body reflect the balance between production and excretion. (16) Hyperbilirubinemia occurs as a result of (1) overproduction; (2) impaired uptake, conjugation, or excretion of bilirubin; (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts). Mild rises in bilirubin may be caused by hemolysis and Gilbert's syndrome. Moderate rise in bilirubin may be caused by pharmaceutical drugs (especially antipsychotic, some sex hormones, and sulfonaides), hepatitis Chemotherapy, and biliary stricture (benign or malignant). Very high levels of bilirubin may be caused by neonatal hyperbilirubinaemia, where the newborn's liver is not able to properly process the bilirubin causing jaundice, also by large bile duct obstruction, e.g. stone in common bile duct, severe liver failure with cirrhosis, Crigler-Najjar and Dubin-Johnson syndromes. (17) The initial steps in evaluating the patient with jaundice are to determine whether (1) hyperbilirubinemia is conjugated or unconjugated, and (2) other biochemical liver tests are abnormal. Essential clinical examination includes history (especially duration of jaundice, pruritus, associated pain, fever, weight loss, risk factors for parenterally transmitted diseases, medications, ethanol use, travel history, surgery, pregnancy), physical examination

(hepatomegaly, tenderness over liver, palpable gallbladder, splenomegaly, gynecomastia, testicular atrophy), blood liver tests (see below), and complete blood count. Jaundice is defined as yellow skin and sclera pigmentation caused by elevation in serum bilirubin level (also termed icterus), it becomes clinically evident at a serum bilirubin level of 3 mg/dL. Yellow skin discoloration also occurs with elevated serum carotene levels but without pigmentation of the sclera. Normally infants usually show a rise of bilirubin during the first day of life a case known as physiological jaundice. Unconjugated hyperbilirubinaemia in a neonate can lead to accumulation of bilirubin in certain brain regions, a phenomenon known as kernicterus, with consequent irreversible damage to these areas manifesting as various neurological deficits, seizures, abnormal reflexes and eye movements. The neurotoxicity of neonatal hyperbilirubinemia manifests because the blood-brain barrier has yet to develop fully, and bilirubin can freely pass into the brain interstitium. Breast-feeding was significantly associated with hyperbilirubinemia, even in the first three days of life. The 95th percentile for bottle-fed infants is a serum bilirubin level of 11.4 mg/dL v 14.5 mg/dL for the breast-fed population. Investigations for the cause of hyperbilirubinemia in healthy breast-fed infants may not be indicated unless the serum bilirubin level exceeds approximately 15 mg/dL, whereas in the bottle-fed infant, such investigations may be indicated if the serum bilirubin exceeds approximately 12 mg/dL.(18) (19)

Liver Serum markers

Viral markers
Hepatitis A: HAV Ab IgM: Positive result defines

a recent HAV infection it may be negative in early infection.

HAV Ab Total: Positive result indicates past

infection and immunity to HAV. (20) (21)

Hepatitis B: HBsAg: Used to diagnose acute or

chronic infection. It is the first marker to appear in an acute infection. Persistence for > 6 months indicates chronic infection (carrier). HBsAb: indicates convalescence post-recent acute HBV infection, Used to assess protective immunity after Hepatitis B vaccination. HBcAb IgM: Will show if patient is in the window period when HBsAg negative andHBsAb negative HBeAg: Marker of active HBV replication, Marker of infectivity. HBcAb Total: Indicates past infection with HBV, Usually persists for life.

HBV DNA by PCR (qualitative or quantitative) : Demonstrate viral replication . Predict likelihood of therapy response (quantitative), Identify emergence of anti-viral resistance (quantitative). HBV Genotype: Determine epidemiology and prognosis, Identify mutations associated with antiviral resistance. (20) (21) (22) Hepatitis C: HCV Ab (Enzyme immunoassay) (EIA) : is the most commonly used method to detect antibody. May represent only evidence of HCV infection , Positive in acute or chronic infection . RIBA (Recombinant immunoblot) HCV Ab : This test is more specific than EIA test Conditions giving false-positive EIA may give an indeterminate or non-specific RIBA result , Since a positive EIA or RIBA does not prove the presence of HCV infection, Positive serologic tests require confirmation with HCV RNA testing. HCV PCR: This test detects the presence of HCV RNA circulating in the blood and is a measure of virus replication in the liver, assesses the infectivity of a patient (confirm active HCV infection). (23) (24)

Serum auto immune hepatitis markers:

Anti-nuclear antibodies (ANA) and smooth muscle antibodies (SMA): most commonly used for the diagnosis of AIH-1 by indirect immunofluorescence (IIF) assay, these auto-antibodies are detected in significant titers (1:80 in adults and 1:40 in children), while ANA alone are detected in 15% and SMA alone in 35%. Anti-neutrophil cytoplasmic autoantibodies (ANCA): they are detected by IIF, Auto-antibodies against liver-kidney microsomes type 1 (anti-LKM1): the characteristic serologic marker for the diagnosis of AIH-2 Antibodies against soluble liver antigens (anti-SLA): Autoantibodies to SLA are also known as anti-liver-pancreas antigen (anti-LP) antibodies. The anti - SLA auto-antibodies cannot be detected by IIF on common substrate. A competitive ELISA or a radioimmunoassay usually detects these auto-antibodies. Auto-antibodies against anti-SLA have been proposed as a specific marker for a third type of Autoimmune Hepatitis (AIH-3). (25)

Serum Tumor markers:

Alpha-Fetoprotein: AFP is a useful marker in hepatocellular carcinoma and germ cell tumors, the

only conditions associated with extreme elevations greater than500 ng/ml. In both tumors it has

value in diagnosis and monitoring of therapy. The AFP is less frequently elevated in other malignancies such as pancreatic cancers, gastric cancers, colonic cancers, and bronchogenic cancers. This elevation was not necessarily associated with liver metastases. Des-gamma-carboxy Prothrombin: DCP is a marker of hepatocellular carcinoma (HCC); it was present in 91% of HCC patients, while not being detectable in other liver diseases. DCP is the least sensitive to risk factors for HCC (such as cirrhosis, and hence the most useful in predicting HCC. It differentiates HCC from non-malignant liver diseases. Reference Interval: 0.0-7.4 ng/mL. (26)

Imaging in diagnosis of liver disease

Abdominal ultrasound (U/S)
Ultrasound uses sound waves to provide images of the liver, gallbladder, and bile ducts. It is the least expensive and safest technique for creating images Using trans-abdominal ultrasound, the examiner can measure liver size. It also shows the shape of the liver which is normally pyramidal, and the surface which is normally smooth with no protruded lumps or indentations. It also provides information about the texture (echogenicity) which can reflect changes in the liver parenchyma, as in cases of hepatic steatosis and liver cirrhosis which shows diffuse hyperechogenicity, and focal liver lesions which have different echogenicity from the surrounding liver tissue, Thus abdominal ultrasound is better for detecting focal lesions, than for diffuse abnormalities. Using ultrasound, a doctor can readily detect gallstones in the gallbladder. Ultrasound of the abdomen can distinguish whether jaundice is caused by bile duct obstruction or by liver cell malfunction. If ultrasound shows ducts that are dilated (widened), the cause is obstruction. Ultrasound also provides guidance when inserting a needle to obtain a tissue sample for biopsy. A type of ultrasound, called Doppler ultrasound, can show blood flow in the blood vessels of the liver. Doppler ultrasound can detect blockages in the liver's arteries and veins, particularly the portal vein, which brings blood from the intestine to the liver. Doppler ultrasound can also detect the effects of high blood pressure in the portal vein (portal hypertension). (27)

Simple x-ray abdomen usually cannot detect disorders of the liver, gallbladder, or biliary
tract; it just shows liver or spleen enlargement. So, it isnt considered of any diagnostic value.

Computed Tomography (CT)

It is a non-invasive, diagnostic imaging procedure that uses a combination of x-rays and

computer technology to produce cross-sectional images (often called slices), both horizontally and vertically, of the body. CT scans may be done with or without contrast. Contrast is a substance taken by mouth and/or injected into an intravenous (IV) line that causes the particular organ or tissue under study to be seen more clearly. An important recent advance is the introductionof helical or spiral CT scanning. There is a risk for allergic reaction to the dye if the child is allergic to or sensitive to medications, contrast dye, or iodine. In some cases, the contrast dye can cause kidney failure. Importance of CT in diagnosis of lever diseases: 1-A CT scan of the liver and biliary tract may be performed to assess the liver and/or gallbladder and their related structures for tumors and other lesions, injuries, bleeding, infections, abscesses, unexplained abdominal pain, obstructions, or other conditions, particularly when another type of examination, such as x-rays, physical examination, and ultra sound is not conclusive. 2-CT can be used for the same purposes as U/S but detects smaller focal lesions in the liver, especially when combined with contrast injection. 3CT scans of the liver and biliary tract may also be used to visualize placement of needles during biopsies of the liver or during aspiration (withdrawal) of fluid from the area of the liver and/or biliary tract. 4-CT is able to provide images of hepatic vasculature. 5-A CT scan of the liver may be used to distinguish between obstructive and non obstructive jaundice. Another use of CT scans of the liver and biliary tract is to provide guidance for biopsies and/or aspiration of tissue from the liver or gallbladder.

Magnetic Resonance imaging (MRI)

It is one of the newest diagnostic medical imaging technologies that uses strong magnets and pulses of radio waves to manipulate the natural magnetic properties in the body to generate a visible image. MRI creates precise images of the body based on the varying proportions of magnetic elements in different tissues. MRI images have greater natural contrast than radiological methods, all of which depend on the differing physical properties of tissues. This sensitivity allows MRI to distinguish fine variations in tissues deep within the body. It is also particularly useful for spotting and distinguishing diseased tissues (tumors and other lesions) early in their development. MRI does not depend on potentially harmful ionizing radiation, as do standard x ray and computed tomography scans. There are no known risks specific to the procedure, other than for people who might have metal objects in their bodies. (28)(29) Despite its many advantages, MRI is not routinely used because it is a somewhat complex and costly procedure. Generally, MRI is prescribed only when serious symptoms or negative results from other tests indicate a need. MRI scanning should not be used when there is the potential for an interaction between the strong MRI magnet and metal objects that might be embedded in a patient's body. The force of magnetic attraction on certain types of metal objects

(including surgical steel) could move them within the body and cause serious injury. Metal may be embedded in a person's body for several reasons. (30)

Liver scan
A radioactive tracer substance is put into a vein in the arm. It moves through the blood to the liver. Areas of the liver where the tracer collects in large amounts show up as bright spots in the pictures. Areas where the tracer collects in low amounts or does not show up are seen as dark spots. The pattern in which the tracer spreads through the liver can help find cysts, abscesses, certain types of tumors, or problems with liver function. It also can be used to show the condition of the liver after a belly injury. Allergic reactions to the radioactive tracer are rare. Most of the tracer will be passed from child body (through urine or stool) in a day. In some cases, the child may develop soreness or swelling at the injection site. There is always a small chance of damage to cells or tissue from being exposed to any radiation, even the low level radioactive tracer used for this test. Normal amounts of the radioactive tracer are found in the liver. No areas of large or small amounts of tracer are seen. So, the liver is normal in size, shape, and location. The tracer pattern may shows a cyst, an abscess, a collection of blood (hematoma), a lump made up of blood vessels (hemangioma), or a tumor. The liver may be enlarged because of a disease or may have an abnormal shape because a tumor is pressing against the organ. Certain types of tumors may cause large amounts of tracer to collect in the liver; other tumors may cause no tracer to collect in the liver. (31)

Endoscopic Retrograde CholangioPancreatography (ERCP)

In this endoscopic technique, fiber-optic duodenoscopeis passed into the first part of the duodenum, the ampulla of Vater is identified, the pancreatic and biliary ducts are cannulated, and radiographic contrast medium is injected. The technique has an 80% success rate in skilled hands and is invaluable for the assessment of extrahepatic biliary disease in older children (e.g., choledochal cysts, primary sclerosing cholangitis) and the assessment of chronic pancreatitis. Although this technique should be of value in the differential diagnosis of neonatal cholestasis, technical difficulties in cannulating the bile ducts in small infants may lead to equivocal information being obtained. The development of a prototype fiber-optic duodenoscope (7.5 mm in diameter) has improved the diagnostic yield in this group of patients. In general, the diagnostic value of this technique has been superseded by that of MRI, which is noninvasive, but ERCP retains an important role in therapy as removal of common bile duct

stones, insertion of biliary and pancreatic stents, and sphincterotomy. But these therapeutic procedures have limited application in children. (32)

Magnetic resonance cholangiopancreatography (MRCP)

It is a medical imaging technique uses magnetic resonance imaging to visualize the biliary and pancreatic ducts in a non-invasive manner. This procedure can be used to determine if gallstones arelodged in any of the ducts surrounding the gallbladder. MRCP is a much less invasive investigation than ERCP. Although both techniques can image the ductal system in detail, MRCP also allows imaging of the surrounding parenchyma. (33)

Percutaneous transhepaticcholangiography(PTC)
This technique is useful for identifying biliary disease if the intrahepatic bile ducts are dilated secondary to obstruction and ERCP is impossible or unsuccessful. A thin needle (Chiba) is passed through the liver, the bile ducts or gallbladder is punctured and radiographic contrast medium is injected. External drainage of the biliary tree, dilation of biliary strictures, and the insertion of biliary stents are all possible using this technique and are useful both before and after transplantation.

Liver biopsy in diagnosis of liver diseases

A liver biopsy is a short procedure to remove a small piece of liver tissue. It can then be examined under a microscope and tested chemically in the laboratories. A percutaneous liver biopsy is carried out by inserting a needle through the skin (percutaneously). While your child is under anaesthetic, the doctor will use an ultrasound scan to find the best place from which to take the biopsy. When this has been locatated, a local anaesthetic injection will be used to numb the area, before inserting the needle. It will then be removed containing a small plug of liver tissue. This will then be sent to the laboratories for detailed examination. The incision site will be closed by strong sticky plasters, and then covered with a dressing. At the end of the procedure, local anaesthetic will be used to numb the area so it is not painful for the first few hours. (34)

Indication: The biopsy helps diagnose many liver diseases; also helps assess the stage (early, advanced) of liver disease. This is especially important in hepatitis C infection. The biopsy also helps detect: Cancer, Infections, also helps to detect the cause of abnormal levels of liver enzymes that have been found in blood tests, the cause of an unexplained liver enlargement, metabolic disorder and unexplained persistant jaundice. (34) Precaution before procedure: Your child will need to come into hospital the day before the procedure and should be able to go home the day after the procedure, unless he or she needs any further investigations or treatment. Your childs doctor will see you when you arrive at the hospital to explain the procedure in more detail, discuss any questions you may have and ask you to sign a consent form. An anaesthetist will also see you to discuss your childs anaesthetic. Your child will need to have a general anaesthetic. This means that your child will not be able to have any food or milk for six hours before the procedure, although he or she can have clear fluids up to three hours beforehand. Some children are at risk of low blood sugar levels when they do not eat or drink, so they will be given a glucose solution through a drip (intravenously). Before the test is done, you may be given a medicine to prevent pain or to calm you tell your health care provider about: bleeding problems, drug allergies, medications you should stop antiinflammatory or NSAID. You must sign a consent form. Blood tests are sometimes done to test your blood's ability to clot. You will be told not eat or drink anything for the 8 hours before the test. (35) Complication: Every anesthetic carries a risk of complications, but this is very small. Sometimes after a general anesthetic, a child may feel sick and could actually vomit. He may also complain of a headache, sore throat and feeling dizzy. These side effects are usually short lived. Liver biopsy carries some specific risks; pain is the most common side effect of liver biopsies. Usually, it is a dull ache rather than a sharp pain, and is easily helped by pain relief medicines. There is also a small risk of bleeding. If this occurs, it usually starts within a few hours of the biopsy, but can rarely happen up to 15 days after the procedure. It can also cause injury to the lung, gallbladder or kidney. (35)

References:
(1) Giboney PT (March 2005). "Mildly elevated liver transaminase levels in the asymptomatic patient". Am Fam Physician71 (6): 110510. PMID 15791889. (2) "Transaminasemia: semantic confusion of a clinical dilemma". Calif Med114 (6): 457. June 1971. PMC 1501958. PMID 5578107. (3) Maddrey, Willis C.; Schiff, Eugene R.; Sorrell, Michael F. (2007). Schiff's diseases of the liver. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 924. ISBN 0-7817-6040-2. (4) "Mildly Elevated Liver Transaminase Levels in the Asymptomatic Patient - March 15, 2005 American Family Physician". Retrieved 2009-07-11. (5) Raurich JM, Prez O, Llompart-Pou JA, Ibez J, Ayestarn I, Prez-Brcena J (July 2009). "Incidence and outcome of ischemic hepatitis complicating septic shock". Hepatol. Res.39 (7): 7005. Doi :10.1111/j.1872-034X.2009.00501.x. PMID 19473435. (6) (British Medical Journal 30 March 1986) (7) (Berk PD, Korenblat KM. Approach to the patient with jaundice or abnormal liver test results. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 150.) (8) (Kratz A, Ferraro M, Sluss PM, et al: Case records of the Massachusetts General Hospital: laboratory values. N Engl J Med 2004; 351(15):1549-1563) (9) Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Coagulation disorders in liver disease. Semin Liver Dis2002;22:8396. (10) Kaul VV, Munoz SJ. Coagulopathy of liver disease. Curr TreatOptions Gastroenterol 2002;3:4338. (11) Segal JB, Dzik WH. Transfusion Medicine/Hemostasis ClinicalTrials Network. Paucity of studies to support thatabnormalcoagulation test results predict bleeding in the setting of invasiveprocedures: an evidence-based review.Transfusion 2005;45:141325. (12) Kujovich JL. Hemostatic defects in end stage liver disease. CritCare Clin 2005;21:56387. (13) Dixon JL, Ginsberg HN. Hepatic synthesis of lipoproteins andapolipoproteins. Semin Liver Dis 1992;12:36472. (14) Miller JP. Dyslipoproteinemia of liver disease. BaillieresClinEndocrinolMetab 1990;4:80732. (15) Sabesin SM. Cholestatic lipoproteins: their pathogenesis and significance.Gastroenterology 1982;83:7049.

(16) Pirone, C; Quirke, JME; Priestap, HA; Lee, DW (March 2009). "Animal pigment bilirubin discovered in plants". Journal of the American Chemical Society 131 (8): 2830. doi:10.1021/ja809065g. PMC 2880647. PMID 19206232. (17) Baranano DE, Rao M, Ferris CD, Snyder SH (2002). "Biliverdin reductase: a major physiologic cytoprotectant". Proc. Natl. Acad. Sci. U.S.A. 99 (25): 160938. doi:10.1073/pnas.252626999. PMC 138570. PMID 12456881. (18) Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M. (2008). "Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis". J. Immunol. 181 (3): 188797. PMID 18641326. (19) Rolinski B, Kster H, Ugele B, Gruber R, Horn K (1 October 2001). "Total bilirubin measurement by photometry on a blood gas analyzer: potential for use in neonatal testing at the point of care". Clin. Chem. 47 (10): 18457. PMID 11568098. (20) William DePond, MD President & Chief Medical Officer (21) Dourakis SP, et al. Autoimmune hepatitis associated with the antiphospholipid syndrome. Eur J Gastroenterol Hepato, 2001. (22) Al-Khalid JA, et al. Current concepts in the diagnosis, pathogenesis, and treatment of autoimmune hepatitis. Mayo Clin Proc, 2001. (23) Kalliopi Zachou et al., Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of (24) http://www.tc-cancer.com/tumormarkers.html (25) Volk ML, Hernandez JC, Su GL, Lok AS, Marrero JA (2007). "Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3". Cancer Biomark 3 (2): 7987. PMID 17522429. (26) Lamerz R, Runge M, Stieber P, Meissner E (1999). "Use of serum PIVKA-II (DCP) determination for differentiation between benign and malignant liver diseases". Anticancer Res. 19 (4A): 248993. PMID 10470180. (27) Christoph F.Dietrich, Ultrasound of the liver, EFSUMB-European course book (28) Faulkner, William H. Tech's Guide to MRI: Basic Physics, Instrumentation and Quality Control. Malden: Blackwell Science, 2001. (29) Goldman, L., and Claude Bennett, eds. Cecil Textbook of Medicine. 21st Edition. Philadelphia: W. B. Saunders, 2000: pp 977970. (30) Roth, Carolyn K. Tech's Guide to MRI: Imaging Procedures, Patient Care and Safety. Malden: Blackwell Science,2001.

(31) Kathleen romito , Jerome B. Semo, . WebMD Medical Refrence by healthwise staff (32) Halefoglu AM. Magnetic resonance cholangiopancreatography: useful tool in the evaluation of pancreatic and biliary disorders.World J Gastroenterol 2007;13:252934. (33) Hekimoglu K, Ustundag Y et al. MRCP vs. ERCP in the evaluation of biliary pathologies: review of current literature. J Dig Dis. 2008 Aug;9(3):162-9. (34) Lomas DJ. The liver. In: Adam A, Dixon AK, eds. Grainger & Allison's Diagnostic Radiology: A Textbook of Medical Imaging. 5th ed. New York, NY: Churchill Livingstone; 2008:chap 35. (35) Liver. Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger & Fordtrans Gastrointestinal and Liver Disease. 9th ed. Philadelphia, Pa: Saunders Elsevier; 2010:section IX.