How to Investigate a Case of Liver Disease

8/6/2019 How to Investigate a Case of Liver Disease

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Table of contents

Laboratory diagnosis of liver diseases 1

Liver transaminases 1

Cholestasis 2

Liver synthetic functions 2

Liver excretory functions 4

Liver serum markers 5Imaging in diagnosis of liver diseases 6

Abdominal ultrasound 6

Computed tomography 7

MRI 8

Liver scan 8

ERCP 8

MRCP 9

PCT 9

Liver biopsy in diagnosis of liver diseases 9

References 11


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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, cannormally 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 bedemonstrated. The normal value is 20 to 140 IU/L. Children have higher values, as bones that arestill growing produce higher levels of ALP. During some growth spurts, levels can be as high as500 IU/L. Increased serum alkaline phosphatase is mainly due to either disease of the bone inwhich 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 variationwith age. Normal values are 0-11 U/L. High level ascertains cholestatic disorder or hepaticmetastasis. (7)

A 3 rd marker for cholestasis is a liver enzyme known as Gamma-glutamyltransferase . Itis produced by the liver cell microsomes and is widely distributed in cells that are involved in thesecretion and absorption of bile. It is a useful laboratory marker as an indicator of early liver celldamage 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 referencerange for GGT is age dependent. In normal full-term neonates the activity at birth isapproximately six to seven times the upper limit of the adult reference range. The activity thendeclines, 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 asign of chronic liver disease. However, a patient with compensated chronic liver disease mayhave 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, chronicinfection, malnutrition, and nephrotic syndrome. In the absence of other nonhepatic etiologies,serum albumin levels may be useful in assaying hepatic synthetic function .


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Coagulation Disorders Abnormal hemostasis is a common complication of liver disease.Mechanisms resulting in these defects include: (1) Diminished hepatic synthesis of coagulationfactors 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 -plasmininhibitor;(5) Disseminated intravascular coagulation (DIC); and (6) Thrombocytopenia due tohypersplenism . (9) (10)

Because of the large functional reserve of the liver, failure of hemostasis may not arise except insevere 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 isundertaken (11)

As storage capacity of vitamin K in the liver is limited, depletion occurs quickly whenabsorption is impaired, and the PT increases above normal ranges. A prolonged PT (normal PTranges from 11 to 13.5 seconds) is not specific for liver disease because it is seen in variouscongenital 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, beingmade in nonhepatic tissues, is helpful in differentiating the depression of clotting factor activityand prolongation of hemostasis caused by severe liver disease alone (normal factor VIII) fromthat caused by accompanying DIC (depressed factor VIII activity from consumption).

DIC is more common in children with end-stage liver failure because of the increasedrisk of infection from general debilitation and synthetic deficiencies of plasma proteins such ascomplement and opsonins normally made by the liver. In the presence of normal factor VIIIactivity, prolongation of the PT indicates plasma clotting factor deficiency from impaired hepaticsynthesis or secondary to vitamin K deficiency, recent intake of antibiotics that alter theintestinal flora should be queried. Because the plasma half-life of several of the clotting factors isshort (such as 35 hours for factor VII), the PT will rapidly reflect changes in hepatic syntheticfunction, 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 persistentlyabnormal PT in a previously well child can be the single laboratory test that draws attention tothe possibility of the development of acute liver failure. However, not all patients with prolongedPTs prove to have evidence of acute liver failure. In children with chronic cholestatic liver


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disease, an abnormal PT level refractory to maximal vitamin K therapy and decreasing serumalbumin should raise for consideration for further assessment.

Fibrinogen levels are usually normal in hepatic disease because it is made both in theliver 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 levelsof fibrinogen may be seen in patients with hepatic diseases because fibrinogen is an acute phasereactant or because of elevations in cholestatic disease.

Lipids and Lipoproteins The liver plays a central role in production anddegradation of lipoproteins. Lipoprotein abnormalities are common in chronic cholestaticdisorders 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 senescenterythrocytes. Initially it is bound to albumin, transported into the liver, conjugated to a water-soluble form (glucuronide) by glucuronosyl transferase, excreted into the bile, and converted tourobilinogen in the colon. Urobilinogen is mostly excreted in the stool; a small portion isreabsorbed and excreted by the kidney. Bilirubin can be filtered by the kidney only in itsconjugated form (measured as the direct fraction); thus increased direct serum bilirubin level isassociated with bilirubinuria. Increased bilirubin production and excretion (even withouthyperbilirubinemia, as in hemolysis) produce elevated urinary urobilinogen levels. There are nonormal 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 bilirubinfrom damaged hepatocytes or bile ducts). Mild rises in bilirubin may be caused by hemolysis andGilbert'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 neonatalhyperbilirubinaemia, where the newborn's liver is not able to properly process the bilirubincausing 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 areabnormal. 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


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(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 inserum 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 butwithout pigmentation of the sclera. Normally infants usually show a rise of bilirubin during thefirst day of life a case known as physiological jaundice. Unconjugated hyperbilirubinaemia in aneonate can lead to accumulation of bilirubin in certain brain regions, a phenomenon known askernicterus, with consequent irreversible damage to these areas manifesting as variousneurological 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 significantlyassociated 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 maynot be indicated unless the serum bilirubin level exceeds approximately 15 mg/dL, whereas inthe bottle-fed infant, such investigations may be indicated if the serum bilirubin exceedsapproximately 12 mg/dL. (18) (19)

Liver Serum markers

Viral markers

Hepatitis A : HAV Ab IgM: Positive result definesa recent HAV infection it may be negative in earlyinfection.

HAV Ab Total: Positive result indicates pastinfection 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 monthsindicates 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 andHBsAbnegative

HBeAg: Marker of active HBV replication, Marker of infectivity.

HBcAb Total: Indicates past infection with HBV, Usually persists for life.


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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 anti-

viral resistance. (20) (21) (22)

Hepatitis C: HCV Ab (Enzyme immunoassay) (EIA) : is the most commonly used method todetect antibody. May represent only evidence of HCV infection , Positive in acute or chronicinfection .

RIBA (Recombinant immunoblot) HCV Ab : This test is more specific than EIA test Conditionsgiving 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 measureof virus replication in the liver, assesses the infectivity of a patient (confirm active HCVinfection). (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 aredetected in significant titers (1:80 in adults and 1:40 in children), while ANA alone aredetected 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 characteristicserologic marker for the diagnosis of AIH-2

Antibodies against soluble liver antigens (anti-SLA): Autoantibodies to SLA are also known asanti-liver-pancreas antigen (anti-LP) antibodies. The anti - SLA auto-antibodies cannot bedetected by IIF on common substrate. A competitive ELISA or a radioimmunoassay usuallydetects 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, theonly conditions associated with extreme elevations greater than500 ng/ml. In both tumors it has


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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 bronchogeniccancers. 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 theleast sensitive to risk factors for HCC (such as cirrhosis, and hence the most useful in predictingHCC. It differentiates HCC from non-malignant liver diseases. Reference Interval: 0.0-7.4ng/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 expensiveand safest technique for creating images

Using trans-abdominal ultrasound, the examiner canmeasure 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 reflectchanges in the liver parenchyma, as in cases of hepatic steatosis and liver cirrhosis which showsdiffuse hyperechogenicity, and focal liver lesions which have different echogenicity from thesurrounding 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 isobstruction. Ultrasound also provides guidance when inserting a needle to obtain a tissue samplefor biopsy.

A type of ultrasound, called Doppler ultrasound, can show blood flow in the bloodvessels 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 ultrasoundcan 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 biliarytract; 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


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computer technology to produce cross-sectional images (often called slices), both horizontallyand vertically, of the body. CT scans may be done with or without contrast. Contrast is asubstance 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 theintroductionof helical or spiral CT scanning.

There is a risk for allergic reaction to the dye if the child is allergic to or sensitive tomedications, 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 andother lesions, injuries, bleeding, infections, abscesses, unexplained abdominal pain, obstructions,or other conditions, particularly when another type of examination, such as x-rays, physicalexamination, 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. 3-CT 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 CTscans of the liver and biliary tract is to provide guidance for biopsies and/or aspiration of tissuefrom the liver or gallbladder.

Magnetic Resonance imaging (MRI)

It is one of the newest diagnostic medical imaging technologies that uses strong magnetsand pulses of radio waves to manipulate the natural magnetic properties in the body to generate avisible 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 thanradiological methods, all of which depend on the differing physical properties of tissues. Thissensitivity 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 dostandard 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 somewhatcomplex 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 isthe potential for an interaction between the strong MRI magnet and metal objects that might beembedded in a patient's body. The force of magnetic attraction on certain types of metal objects


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(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 spotsin the pictures. Areas where the tracer collects in low amounts or does not show up are seen asdark 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 showthe 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 somecases, the child may develop soreness or swelling at the injection site. There is always a smallchance of damage to cells or tissue from being exposed to any radiation, even the low levelradioactive tracer used for this test. Normal amounts of the radioactive tracer are found in theliver. 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 becauseof 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 tumorsmay 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 theduodenum, the ampulla of Vater is identified, the

pancreatic and biliary ducts are cannulated, andradiographic contrast medium is injected. Thetechnique has an 80% success rate in skilled handsand 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 equivocalinformation being obtained.

The development of a prototype fiber-opticduodenoscope (7.5 mm in diameter) has improved thediagnostic yield in this group of patients. In general, thediagnostic value of this technique has been superseded bythat of MRI, which is noninvasive, but ERCP retains animportant role in therapy as removal of common bile duct
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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 magneticresonance imaging to visualize the biliary and pancreaticducts in a non-invasive manner. This procedure can beused to determine if gallstones arelodged in any of theducts surrounding the gallbladder. MRCP is a much lessinvasive investigation than ERCP. Although bothtechniques can image the ductal system in detail, MRCPalso allows imaging of the surrounding parenchyma. (33)

Percutaneous transhepaticcholangiography(PTC)

This technique is useful for identifying biliarydisease if the intrahepatic bile ducts are dilated secondaryto obstruction and ERCP is impossible or unsuccessful. Athin needle (Chiba) is passed through the liver, the bileducts or gallbladder is punctured and radiographic contrastmedium is injected. External drainage of the biliary tree,dilation of biliary strictures, and the insertion of biliarystents 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 isunder anaesthetic, the doctor will use an ultrasound scan to find the best place from which to takethe biopsy. When this has been locatated, a local anaesthetic injection will be used to numb thearea, 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 beclosed 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)


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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 alsohelps 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 anyfurther investigations or treatment. Your childs doctor will see you when you arrive at thehospital to explain the procedure in more detail, discuss any questions you may have and ask youto 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 haveany food or milk for six hours before the procedure, although he or she can have clear fluids upto three hours beforehand. Some children are at risk of low blood sugar levels when they do noteat or drink, so they will be given a glucose solution through a drip (intravenously). Before thetest 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 anti-inflammatory or NSAID. You must sign a consent form. Blood tests are sometimes done to testyour blood's ability to clot. You will be told not eat or drink anything for the 8 hours before thetest. (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 mayalso complain of a headache, sore throat and feeling dizzy. These side effects are usually shortlived. 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 fewhours of the biopsy, but can rarely happen up to 15 days after the procedure. It can also causeinjury to the lung, gallbladder or kidney. (35)


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(6) (British Medical Journal 30 March 1986)

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(18) Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M. (2008). "Bilirubin possesses powerfulimmunomodulatory activity and suppresses experimental autoimmune encephalomyelitis". J. Immunol.181 (3): 188797. PMID 18641326.

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How to Investigate a Case of Liver Disease

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