The classification of liver disorders is obscure because the etiology and pathogenetic mechanisms are often not clearly defined. This is based on anatomy, i.e., disease of hepatic parenchyma, disease of the hepatobiliary system, and disease of the hepatic vascular system. The focus of this presentation will concentrate on hepatitis, one of the classifications under parenchymal disease.

Viral Hepatitis

HEPATITIS A VIRUS (HAV). This virus is found primarily in feces and causes a transient viremia (virus found in the blood). The method of transmission is usually via fecal or oral pathway and in common in children and young adults in areas of poor sanitation or water contamination. The virus may be diagnosed using serosurveys with the antibody to hepatitis A (anti-HAV) as the marker. A short incubation occurs prior to the acute onset of symptoms leading to a complete recovery or death from acute liver failure (mortality under 1%).

HEPATITIS B VIRUS (HBV). This virus is found in greatest concentration in liver and less in blood. Transmission occurs through blood, blood products, or other body fluids. HBV has a carrier state with the highest carrier rates in Southeast Asia, China, Africa and Greenland. Symptoms follow a long incubation period (2-12 weeks) and present with insidious onset, with 10% of the cases continuing onto a chronic state. The most useful markers for acute infection are hepatitis B surface antigen (HBs Ag) and antibody to hepatitis B core antigen (anti-HBc). HBV has a strong epidemiological association with hepatocellular carcinoma.

NON-A/ NON-B HEPATITIS (NANB) (predominantly C). This disease process is thought to be two different conditions caused by two different viruses; the causative agent is possibly a retrovirus. At least 90% of post-transfusion hepatitis cases are due to NANB (HBV is uncommon since blood screening is able to detect contaminated blood). A long incubation period (2-26 weeks) is present before insidious onset of symptoms present (most without jaundice). The greatest risk is the progression to chronic liver disease. Chronic hepatitis C is diagnosed by the presence of blood of the antibody to HCV (anti-HCV). Liver enzymes show fluctuation in elevations with this disease.

DELTA AGENT (hepatitis D). This is the newest discovery in viral hepatitis; an ongoing infection of HBV is necessary before the Delta agent replicates. The Delta can coinfect with HBV, or superinfect an HBV carrier. The host ability to clear HBV determines the duration of the Delta infection. It is the HBV, not HBV replication that provides an environment conducive to Delta. (5) The transmission is similar to HBV found in chronic carriers or in persons infected simultaneously with HBsAg and Delta. The prognosis is very poor.

HEPATITIS E demonstrates the clinical characteristics of hepatitis A infection and is transmitted via the fecal-oral route. (12) It is found more frequently in water-borne epidemics in India.

CLINICAL FEATURES OF ACUTE VIRAL HEPATITIS. The patients may initially present with flu-like symptoms, loss of appetite, weakness, and headache. When the disease flourishes, abnormal liver enzymes (ALT and AST) and alkaline phosphatase are present. Bilirubin levels are variable.

PATHOLOGY OF VIRAL HEPATITIS. In acute viral hepatitis the pathologic changes are the same for Hepatitis A, B and C with hepatocyte injury and welling, necrosis, disarray of the heptic lobules, Kupfer cell hyperplasia, and inflammatory cells in the portal areas.

Approximately 5% of patients will go on to develop chronic hepatitis (disease lasts longer than six months). These patients will continue to have mild symptoms of fatigue and anorexia or may be asymptomatic. Chronic persistent hepatitis (CPH) does not progress to cirrhosis; it most cases it ultimately resolves. (5)

Patients with chronic active hepatitis (CAH) have hepatocellular necrosis and fibrosis. This is a serious progressive disorder that usually progresses to cirrhosis. Elevation of liver enzymes and globulin levels are apparent in the laboratory tests.

The liver is a very complex organ with interdependent metabolic, excretory, and defense functions. There is not one simple test that may be used to assess the overall liver function. The utilization of several tests, known as liver function tests, (or LFTs), improved the detection of hepatobiliary abnormalities, helps to differentiate the basis for clinically suspected disease, and may assist in determining the severity of the hepatic disease. The reader is referred to the summary table of clinical and laboratory values found at the end of this section.

Some of the most useful hepatic laboratory tests are serum bilirubin, alkaline phosphatase, and transaminase. Less valuable tests include cholesterol and LDH; while prothrombin time predicts the severity of hepatocellular disease.

Bilirubin. Hyperbilirubinemia results from increased bilirbuin production, decreased liver uptake or conjugation, or decreased biliary excretion. Increased bilirubine production or decreased liver uptake or conjugation causes unconjugated bilirubin in serum to increase. Decreased bile formation and excretion (cholestasis) elevates conjugated bilirubin in serum which later appears in the urine. (Urine bilirubin is normally absent except in the presence of hepatobiliary disease.)

Alkaline phosphatase. This enzyme normally comes from the liver and bone, and the placenta (during pregnancy). Alkaline phosphatase increases markedly in diseases that impair bile formation (cholestasis) and to a lesser extent in hepatocellular disease. These values increase up to four times normal in intrahepatic diseases (primary biliary cirrhosis, drug-induced liver disease, liver transplantation rejection) or from extrahepatic causes such as bile duct obstruction. In hepatocellular disease (hepatitis, cirrhosis, infiltrative abnormalities), the alkaline phosphatase levels tend to be slightly lower. Isolated elevations occur in granulomatous hepatitis or focal liver disease (abscess, neoplastic infiltration, partial bile duct obstruction).

Tranaminase. Aspartate transaminase (AST) and alanine aminotransferase (ALT) are sensitive indicators of liver injury. AST is also present in the heart, skeletal muscle, brain, and kidney. Thus, these organs may be the cause of AST elevation. Very high levels of AST indicate liver cell injury. ALT is found primarily in liver cells is reliable for routine screening for liver disease (hepatitis).

Lactic dehydrogenase. LDH may be high with liver tumors but is insensitive for hepatocellular injury.

Serum albumin. Serum albumin is decreased in chronic liver disease (cirrhosis and ascites) because of the increased volume of distribution.

Serum immunoglobulins. This value rises in most cases of chronic liver disease when the reticuloendothelial system is defective or bypassed by portal venous shunts. Serum globulin levels rise slightly in acute hepatitis and more markedly in chronic active hepatitis.

Alphafetoprotein (AFP). The AFP is synthesized by the fetal liver (and is normally elevated in the mother and newborn). High elevations are seen in primary hepatocellular carcinoma.

CLINICAL and LABORATORY VALUES
TEST	NORMAL VALUES	SIGNIFICANCE OF A CHANGE
Alkaline phosphatase	Adult: 13-39 IU/I	in liver disease
Ammonia	20-70 mEq/L	in liver disease in dibetes mellitus
Bile and Bilirubin	Direct < 0.5 mg/dl Indirect < 1.1 mg/dl	during obstruction of the bile ducts
Glucose	70-100 mg/100 ml (fasting)	in diabetes mellitus in liver disease
Hematocrit	Women: 38-47% Men: 40-54%	in cirrhosis of liver
Hemoglobin	Women: 12-16 g/100 ml Men: 13-18 g/100 ml	in cirrhosis of liver
Iron	50-150 ug/100 ml (can be higher in males)	in liver disease
Lactic dehydrogenase (LDH)	60-120 U/ml	in liver disease
Lipids-total   Cholestorol- total        HDL        LDL   Triglycerides   Phospholipids   Fatty acids	<180 mg/100ml 40-150 mg/100 ml	(cholesterol) in chronic hepatitis (cholesterol) in acute hepatitis
Platelet count	150,000-400,000 /mm3	in cirrhosis of liver
Transaminase	10-40 U/ml	in liver disease
Urea	25-35 g/day	in some liver diseases during obstruction of bile ducts

Plain radiograph of the abdomen. Radiography of the abdomen has limited usefulness in evaluating hepatobiliary disease unless calcifications in the liver or gallbladder, opaque gallstones, or air in the biliary tract is present. Evidence of hepatosplenomegaly and ascites may be noted on the x-ray.

Ultrasound. This modality is the most important investigative tool in screening for biliary tract abnormalities and mass lesions in the liver. Ultrasound is better in defining focal lesions than diffuse disease (fatty liver, cirrhosis); localization of lesions permits ultrasound guided aspiration and biopsy. Sonography is the least expensive, safest, and most sensitive technique for visualizing the biliary system. Gallstones cast echogenic foci with posterior shadowing and movement with gravity. The size of the stone may be determined more accurately than the number of stones (due to overlap along the dependent border). Acute cholecystitis includes a thickened gallbladder wall, pericholecystic fluid, an impacted stone in the gallbladder neck, and positive Murphy's sign. Polyps of the gallbladder wall may appear as immobile homogeneous structures without shadowing.

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Doppler Ultrasound. The use of Doppler within the abdomen measures the frequency change of a backscattered ultrasonic wave reflected from moving red blood cells. Thus the direction and velocity of blood flow may be determined when the transducer is parallel to the vessel. Doppler may show the patency of intrahepatic vessels and determine the direction of blood flow.

	Transverse view of the right upper quadrant shows the hepatic vasculature with B-flow, 3-D imaging, and color Doppler

Radionuclide Scanning. This nuclear medicine procedure involves the hepatic extraction of an injected radiopharmaceutical (usually technetium 99m) from the blood. Liver-spleen scanning uses technetrium 99m sulfur colloid (rapidly extracted from the blood by reticuloendothelial cells). A cold spot is produced when a focal lesion is present. If diffuse (hepatitis, cirrhosis) liver disease is found, there will be a decrease in liver uptake with an increase in uptake by the spleen and bone marrow.

The hepatobiliary excretory system may also be imaged with a derivative of technetium 99m.

Computed Tomography. Variations in density of different hepatic lesions and the addition of IV contrast helps to differentiate subtle differences between soft tissues and define the vascular structures and the biliary tract. CT does not have the problem of fat or intestinal gas interference that ultrasound may have.

Magnetic Resonance Imaging. Blood vessels may be identified without the use of contrast material in the liver. The identification of tumors and hepatic blood flow, as well as the biliary tract is obtained with this more exquisite, expensive imaging technique.

Endoscopic retrograde cholangiopancreatography (ERCP). This combines endoscopy (to identify and cannulate the ampulla of Vater in the second portion of the duodenum), radiography (injection of contrast agent into the biliary and pancreatic ducts), and most recently ultrasound (to image the pancreas, pancreatic duct, and biliary duct. It is especially effective in pancreaticobiliary disease and in assessing the biliary tract in patients with persistent jaundice. Ultrasound of the abdomen usually precedes the ERCP to obtain a baseline study of the upper abdomen.

Liver Biopsy Procedures. Once a lesion is located the tissue must be examined under the microscope to make a histologic diagnosis. In centers where liver biopsies are frequently performed, the mortality rate is approximately 1 in 1000. Morbidity is 1% with the following major complications: intra-abdominal bleeding, hematoma, hemothorax, puncture of the gallbladder, vagal shock, A-V fistula, or infection. Biopsy procedures are invasive and may be performed in any one of four ways.

Percutaneous Liver Biopsy. This technique is performed under local anesthesia, usually at the bedside or in the department. Guidance with ultrasound or CT is utilized to guide the needle into the exact area to be biopsied.

Transvenous Liver Biopsy. This procedure is performed by threading a needle through a catheter inserted into the right internal jugular vein and through the right atrium into the inferior vena cava and hepatic vein. The needle is then advanced through the hepatic vein into the liver. Hepatic vein and wedge pressures can also be obtained during the procedure.

Laparoscopic Biopsy. This is a directed needle biopsy of the liver (for surface lesions) and facilitates diathermy coagulation of the puncture site in patients with compromised coagulation status.

Open Liver Biopsy. This procedure is a wedge biopsy of the liver performed at open laparotomy; this technique is utilized as an accompaniment of surgery, not as a sole procedure.

Liver resection is a common surgical operative procedure to remove a malignant tumor from the liver. The success rate for removal with a five-year survival is as high as 60% when the tumor is confined to one of the lobes of the liver. Up to three-fourths of the liver can be safely removed and the existing liver liver (if normal) can regenerate itself to its preoperative size in 6-8 weeks.

A liver donor liver transplant is the replacement of a diseased liver due to chronic liver failure, acute liver failure, or tumor within the liver. The diseased liver is then replaced with a segment of the liver from a healthy human donor (usually a relative or close friend - the blood type of the donor must be the same as the recipient's and the donor must be in good physical and mental health.).

Ultrasound Evaluation. Ultrasound plays a significant role in the pre- and postoperative evaluation of the liver transplant patient. Prior to the surgery, a baseline study is performed to evaluate the liver parenchyma to identify the presence of hepatic lesions, determine the patency and size of the portal vein, hepatic veins, and IVC, and assess the biliary system for dilatation. In addition to the liver evaluation, the spleen and kidneys are also assessed for size.

In the post-operative period thrombosis of the hepatic artery is the most serious complication in the weeks following the surgery. Doppler and color flow analysis of the hepatic vascular structures have provided useful clinical information to determine the patency of the vessels. Normal patency patterns of the hepatic artery show a low-resistance arterial signal in the area of the porta hepatis. When thrombosis is present, the arterial signal is absent or significantly reduced.

Other complications following transplant surgery may include hepatic dysfunction, abscess, ascites, infarction, delayed biliary leak, or massive hepatic necrosis.

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Sagittal image of the transplanted liver with massive ascites.

Ultrasound has made a significant contribution to hepatobiliary disease. The ability to evaluate the texture, vascular patency, and determine hemodynamics with Doppler and color flow has consistently contributed to the diagnostic accuracy of managing the patient with diffuse liver disease. The evaluation of the patient with mild hepatitis may be obscure with sonography and other imaging procedures; as the disease process progresses, specific sonographic findings may be seen. Sensitive laboratory analysis and liver biopsy will provide the information necessary to classify the type of viral hepatitis present.

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