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While there are many causes of liver disease (Table 329-1), these disorders generally present clinically in a few distinct patterns and are usually classified as hepatocellular, cholestatic (obstructive), or mixed. In hepatocellular diseases (such as viral hepatitis and alcoholic liver disease), features of liver injury, inflammation, and necrosis predominate. In cholestatic diseases, such as gallstone or malignant obstruction, primary biliary cholangitis (previously referred to as primary biliary cirrhosis), and some drug-induced liver diseases, features of inhibition of bile flow predominate. In a mixed pattern, features of both hepatocellular and cholestatic injury are present (such as in cholestatic forms of viral hepatitis and many drug-induced liver diseases). The pattern of onset and prominence of symptoms can rapidly suggest a diagnosis, particularly if major risk factors are considered, such as the age and sex of the patient and a history of exposure or risk behaviors.
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Typical presenting symptoms of liver disease include jaundice, fatigue, itching, right-upper-quadrant pain, nausea, poor appetite, abdominal distention, and intestinal bleeding. At present, however, many patients are diagnosed with liver disease who have no symptoms and who have been found to have abnormalities in biochemical liver tests as a part of a routine physical examination or screening for blood donation or for insurance or employment. The wide availability of batteries of liver tests makes it relatively simple to demonstrate the presence of liver injury as well as to rule it out in someone in whom liver disease is suspected.
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Evaluation of patients with liver disease should be directed at (1) establishing the etiologic diagnosis, (2) estimating disease severity (grading), and (3) establishing the disease stage (staging). Diagnosis should focus on the category of disease (hepatocellular, cholestatic, or mixed injury) as well as on the specific etiologic diagnosis. Grading refers to assessment of the severity or activity of disease—active or inactive as well as mild, moderate, or severe. Staging refers to estimation of the point in the course of the natural history of the disease, whether early or late; or precirrhotic, cirrhotic, or end-stage. This chapter introduces general, salient concepts in the evaluation of patients with liver disease that help lead to the diagnoses discussed in subsequent chapters.
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The clinical history should focus on the symptoms of liver disease—their nature, patterns of onset, and progression—and on potential risk factors for liver disease. The manifestations of liver disease include constitutional symptoms such as fatigue, weakness, nausea, poor appetite, and malaise and the more liver-specific symptoms of jaundice, dark urine, light stools, itching, abdominal pain, and bloating. Symptoms can also suggest the presence of cirrhosis, end-stage liver disease, or complications of cirrhosis such as portal hypertension. Generally, the constellation of symptoms and their patterns of onset rather than a specific symptom points to an etiology.
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Fatigue is the most common and most characteristic symptom of liver disease. It is variously described as lethargy, weakness, listlessness, malaise, increased need for sleep, lack of stamina, and poor energy. The fatigue of liver disease typically arises after activity or exercise and is rarely present or severe after adequate rest; that is, it is “afternoon” rather than “morning” fatigue. Fatigue in liver disease is often intermittent and variable in severity from hour to hour and day to day. In some patients, it may not be clear whether fatigue is due to the liver disease or due to other problems such as stress, anxiety, sleep disturbance, or a concurrent illness.
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Nausea occurs with more severe liver disease and may accompany fatigue or be provoked by smelling food odors or eating fatty foods. Vomiting can occur but is rarely persistent or prominent. Poor appetite with weight loss occurs frequently in acute liver disease, but is rare in chronic disease except when cirrhosis is present and advanced. Diarrhea is uncommon in liver disease except with severe jaundice, in which a lack of bile acids reaching the intestine can lead to steatorrhea.
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Right-upper-quadrant discomfort or ache (“liver pain”) occurs in many liver diseases and is usually marked by tenderness over the liver area. The pain arises from stretching or irritation of Glisson’s capsule, which surrounds the liver and is rich in nerve endings. Severe pain is most typical of gallbladder disease, liver abscess, and severe sinusoidal obstruction syndrome (previously known as veno-occlusive disease) but is also an occasional accompaniment of acute hepatitis.
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Itching occurs with acute liver disease, appearing early in obstructive jaundice (from biliary obstruction or drug-induced cholestasis) and somewhat later in hepatocellular disease (acute hepatitis). Itching also occurs in chronic liver diseases—typically the cholestatic forms such as primary biliary cholangitis and sclerosing cholangitis, in which it is often the presenting symptom, preceding the onset of jaundice. However, itching can occur in any liver disease, particularly once cirrhosis develops.
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Jaundice is the hallmark symptom of liver disease and perhaps the most reliable marker of severity. Patients usually report darkening of the urine before they notice scleral icterus. Jaundice is rarely detectable with a bilirubin level <43 μmol/L (2.5 mg/dL). With severe cholestasis, there will also be lightening of the color of the stools and steatorrhea. Jaundice without dark urine usually indicates indirect (unconjugated) hyperbilirubinemia and is typical of hemolytic anemia and the genetic disorders of bilirubin conjugation, the common and benign form being Gilbert syndrome and the rare and severe form being Crigler-Najjar syndrome. Gilbert syndrome affects up to 5% of the general population; the jaundice in this condition is more noticeable after fasting and with stress.
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Major risk factors for liver disease that should be sought in the clinical history include details of alcohol use, medication use (including herbal compounds, birth control pills, and over-the-counter medications), personal habits, sexual activity, travel, exposure to jaundiced or other high-risk persons, injection drug use, recent surgery, remote or recent transfusion of blood or blood products, occupation, accidental exposure to blood or needlestick, and familial history of liver disease.
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For assessing the risk of viral hepatitis, a careful history of sexual activity is of particular importance and should include the number of lifetime sexual partners and, for men, a history of having sex with men. Sexual exposure is a common mode of spread of hepatitis B but is uncommon for hepatitis C. A family history of hepatitis, liver disease, and liver cancer is also important. Maternal-infant transmission occurs with both hepatitis B and C. Vertical spread of hepatitis B can now be prevented by passive and active immunization of the infant at birth, although addition of antiviral therapy during the third trimester of pregnancy is now recommended for mothers with levels of HBV DNA >200,000 IU/mL. Vertical spread of hepatitis C is uncommon, but there are no reliable means of prevention. Transmission is more common among HIV-co-infected mothers and is also linked to prolonged and difficult labor and delivery, early rupture of membranes, internal fetal monitoring, and a high viral load. A history of injection drug use, even in the remote past, is of great importance in assessing the risk for hepatitis B and C. Injection drug use is now the single most common risk factor for hepatitis C. Transfusion with blood or blood products is no longer an important risk factor for acute viral hepatitis. However, blood transfusions received before the introduction of sensitive enzyme immunoassays for antibody to hepatitis C virus in 1992 is an important risk factor for chronic hepatitis C. Blood transfusion before 1986, when screening for antibody to hepatitis B core antigen was introduced, is also a risk factor for hepatitis B. Travel to a developing area of the world, exposure to persons with jaundice, and exposure to young children in day-care centers are risk factors for hepatitis A. Tattooing and body piercing (for hepatitis B and C) and eating shellfish (for hepatitis A) are frequently mentioned but are actually types of exposure that quite rarely lead to the acquisition of hepatitis.
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Hepatitis E is one of the more common causes of jaundice in Asia and Africa but is uncommon in developed nations. In endemic areas transmission is usually through exposure to fecally contaminated water. Recently, non-travel-related (autochthonous) cases of hepatitis E have been described in developed countries, including the United States. These cases appear to be due to strains of hepatitis E virus that are endemic in swine and some wild animals (genotypes 3 and 4). While occasional cases are associated with eating raw or undercooked pork or game (deer and wild boars), most cases of hepatitis E occur without known exposure, predominantly in elderly men without typical risk factors for viral hepatitis. Hepatitis E infection can become chronic in immunosuppressed individuals (such as transplant recipients, patients receiving chemotherapy, or patients with HIV infection), in whom it presents with abnormal serum enzymes in the absence of markers of hepatitis B or C.
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A history of alcohol intake is important in assessing the cause of liver disease and also in planning management and recommendations. In the United States, for example, at least 70% of adults drink alcohol to some degree, but significant alcohol intake is less common; in population-based surveys, only 5% of individuals have more than two drinks per day, the average drink representing 11–15 g of alcohol. Alcohol consumption associated with an increased rate of alcoholic liver disease is probably more than two drinks (22–30 g) per day in women and three drinks (33–45 g) in men. Most patients with alcoholic cirrhosis have a much higher daily intake and have drunk excessively for ≥10 years before onset of liver disease. In assessing alcohol intake, the history should also focus on whether alcohol abuse or dependence is present. Alcoholism is usually defined by the behavioral patterns and consequences of alcohol intake, not by the amount. Abuse is defined by a repetitive pattern of drinking alcohol that has adverse effects on social, family, occupational, or health status. Dependence is defined by alcohol-seeking behavior, despite its adverse effects. Many alcoholics demonstrate both dependence and abuse, and dependence is considered the more serious and advanced form of alcoholism. A clinically helpful approach to diagnosis of alcohol dependence and abuse is the use of the CAGE questionnaire (Table 329-2), which is recommended for all medical history-taking.
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Family history can be helpful in assessing liver disease. Familial causes of liver disease include Wilson disease; hemochromatosis and α1 antitrypsin deficiency; and the more uncommon inherited pediatric liver diseases—that is, familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis, and Alagille syndrome. Onset of severe liver disease in childhood or adolescence in conjunction with a family history of liver disease or neuropsychiatric disturbance should lead to investigation for Wilson’s disease. A family history of cirrhosis, diabetes, or endocrine failure and the appearance of liver disease in adulthood suggests hemochromatosis and should prompt investigation of iron status. Abnormal iron studies in adult patients warrant genotyping of the HFE gene for the C282Y and H63D mutations typical of genetic hemochromatosis. In children and adolescents with iron overload, other non-HFE causes of hemochromatosis should be sought. A family history of emphysema should lead to investigation of α1 antitrypsin levels and, if levels are low, for protease inhibitor (Pi) genotype.
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The physical examination rarely uncovers evidence of liver dysfunction in a patient without symptoms or laboratory findings, nor are most signs of liver disease specific to one diagnosis. Thus, the physical examination complements rather than replaces the need for other diagnostic approaches. In many patients, the physical examination is normal unless the disease is acute or severe and advanced. Nevertheless, the physical examination is important in that it can yield the first evidence of hepatic failure, portal hypertension, and liver decompensation. In addition, the physical examination can reveal signs—related either to risk factors or to associated diseases or findings—that point to a specific diagnosis.
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Typical physical findings in liver disease are icterus, hepatomegaly, hepatic tenderness, splenomegaly, spider angiomata, palmar erythema, and skin excoriations. Signs of advanced disease include muscle wasting, ascites, edema, dilated abdominal veins, hepatic fetor, asterixis, mental confusion, stupor, and coma. In male patients with cirrhosis, particularly that related to alcohol use, signs of hyperestrogenemia such as gynecomastia, testicular atrophy, and loss of male-pattern hair distribution may be found.
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Icterus is best appreciated when the sclera is inspected under natural light. In fair-skinned individuals, a yellow tinge to the skin may be obvious. In dark-skinned individuals, examination of the mucous membranes below the tongue can demonstrate jaundice. Jaundice is rarely detectable if the serum bilirubin level is <43 μmol/L (2.5 mg/dL) but may remain detectable below this level during recovery from jaundice (because of protein and tissue binding of conjugated bilirubin).
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Spider angiomata and palmar erythema occur in both acute and chronic liver disease; these manifestations may be especially prominent in persons with cirrhosis but can develop in normal individuals and are frequently found during pregnancy. Spider angiomata are superficial, tortuous arterioles, and—unlike simple telangiectases—typically fill from the center outward. Spider angiomata occur only on the arms, face, and upper torso; they can be pulsatile and may be difficult to detect in dark-skinned individuals.
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Hepatomegaly is not a highly reliable sign of liver disease because of variability in the liver’s size and shape and the physical impediments to assessment of liver size by percussion and palpation. Marked hepatomegaly is typical of cirrhosis, sinusoidal obstruction syndrome, infiltrative disorders such as amyloidosis, metastatic, or primary cancers of the liver, and alcoholic hepatitis. Careful assessment of the liver edge may also reveal unusual firmness, irregularity of the surface, or frank nodules. Perhaps the most reliable physical finding in the liver examination is hepatic tenderness. Discomfort when the liver is touched or pressed upon should be carefully sought with percussive comparison of the right and left upper quadrants.
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Splenomegaly, which occurs in many medical conditions, can be a subtle but significant physical finding in liver disease. The availability of ultrasound (US) methods for assessment of the spleen allows confirmation of the physical finding.
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Signs of advanced liver disease include muscle wasting and weight loss as well as hepatomegaly, bruising, ascites, and edema. Ascites is best appreciated by attempts to detect shifting dullness by careful percussion. US examination will confirm the finding of ascites in equivocal cases. Peripheral edema can occur with or without ascites. In patients with advanced liver disease, other factors frequently contribute to edema formation, including hypoalbuminemia, venous insufficiency, heart failure, and medications.
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Hepatic failure is defined as the occurrence of signs or symptoms of hepatic encephalopathy in a person with severe acute or chronic liver disease. The first signs of hepatic encephalopathy can be subtle and nonspecific—change in sleep patterns, change in personality, irritability, and mental dullness. Thereafter, confusion, disorientation, stupor, and eventually coma supervene. In acute liver failure, excitability and mania may be present. Physical findings include asterixis and flapping tremors of the body and tongue. Fetor hepaticus refers to the slightly sweet, ammoniacal odor that can develop in patients with liver failure, particularly if there is portal-venous shunting of blood around the liver. Other causes of coma and disorientation should be excluded, mainly electrolyte imbalances, sedative use, and renal or respiratory failure. The appearance of hepatic encephalopathy during acute hepatitis is the major criterion for diagnosis of fulminant hepatitis and indicates a poor prognosis. In chronic liver disease, encephalopathy is usually triggered by a medical complication such as gastrointestinal bleeding, over-diuresis, uremia, dehydration, electrolyte imbalance, infection, constipation, or use of narcotic analgesics.
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A helpful measure of hepatic encephalopathy is a careful mental-status examination and use of the trail-making test, which consists of a series of 25 numbered circles that the patient is asked to connect as rapidly as possible using a pencil. The normal range for the connect-the-dot test is 15–30 sec; it is considerably longer in patients with early hepatic encephalopathy. Other tests include drawing of abstract objects or comparison of a signature to previous examples. More sophisticated testing—for example, with electroencephalography and visual evoked potentials—can detect mild forms of encephalopathy but are rarely clinically useful.
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Other signs of advanced liver disease include umbilical hernia from ascites, hydrothorax, prominent veins over the abdomen, and caput medusa, a condition that consists of collateral veins radiating from the umbilicus and results from recanulation of the umbilical vein. Widened pulse pressure and signs of a hyperdynamic circulation can occur in patients with cirrhosis as a result of fluid and sodium retention, increased cardiac output, and reduced peripheral resistance. Patients with long-standing cirrhosis and portal hypertension are prone to develop the hepatopulmonary syndrome, which is defined by the triad of liver disease, hypoxemia, and pulmonary arteriovenous shunting. The hepatopulmonary syndrome is characterized by platypnea and orthodeoxia: shortness of breath and oxygen desaturation that occur paradoxically upon the assumption of an upright position. Measurement of oxygen saturation by pulse oximetry is a reliable screening test for hepatopulmonary syndrome.
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Several skin disorders and changes are common in liver disease. Hyperpigmentation is typical of advanced chronic cholestatic diseases such as primary biliary cholangitis and sclerosing cholangitis. In these same conditions, xanthelasma and tendon xanthomata occur as a result of retention and high serum levels of lipids and cholesterol. Slate-gray pigmentation of the skin is also seen with hemochromatosis if iron levels are high for a prolonged period. Mucocutaneous vasculitis with palpable purpura, especially on the lower extremities, is typical of cryoglobulinemia of chronic hepatitis C but can also occur in chronic hepatitis B.
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Some physical signs point to specific liver diseases. Kayser-Fleischer rings occur in Wilson disease and consist of a golden-brown copper pigment deposited in Descemet’s membrane at the periphery of the cornea; they are best seen by slit-lamp examination. Dupuytren contracture and parotid enlargement are suggestive of chronic alcoholism and alcoholic liver disease. In metastatic liver disease or primary hepatocellular carcinoma, signs of cachexia and wasting as well as firm hepatomegaly and a hepatic bruit may be prominent.
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DIAGNOSIS OF LIVER DISEASE
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The major causes of liver disease and key diagnostic features are outlined in Table 329-3, and an algorithm for evaluation of the patient with suspected liver disease is shown in Fig. 329-1. Specifics of diagnosis are discussed in later chapters. The most common causes of acute liver disease are viral hepatitis (particularly hepatitis A, B, and C), drug-induced liver injury, cholangitis, and alcoholic liver disease. Liver biopsy usually is not needed in the diagnosis and management of acute liver disease, exceptions being situations where the diagnosis remains unclear despite thorough clinical and laboratory investigation. Liver biopsy can be helpful in diagnosing drug-induced liver disease and acute alcoholic hepatitis.
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The most common causes of chronic liver disease, in general order of frequency, are chronic hepatitis C, alcoholic liver disease, nonalcoholic steatohepatitis, chronic hepatitis B, autoimmune hepatitis, sclerosing cholangitis, primary biliary cholangitis, hemochromatosis, and Wilson disease. Hepatitis E virus is a rare cause of chronic hepatitis, with cases occurring mostly in persons who are immunosuppressed or immunodeficient. Strict diagnostic criteria have not been developed for most liver diseases, but liver biopsy plays an important role in the diagnosis of autoimmune hepatitis, primary biliary cholangitis, nonalcoholic and alcoholic steatohepatitis, and Wilson disease (with a quantitative hepatic copper level in the last instance).
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Diagnosis of liver disease is greatly aided by the availability of reliable and sensitive tests of liver injury and function. A typical battery of blood tests used for initial assessment of liver disease includes measurement of levels of serum alanine (ALT) and aspartate aminotransferases (AST), alkaline phosphatase (AlkP), direct and total serum bilirubin and albumin, and prothrombin time. The pattern of abnormalities generally points to hepatocellular versus cholestatic liver disease and helps determine whether the disease is acute or chronic and whether cirrhosis and hepatic failure are present. On the basis of these results, further testing over time may be necessary. Other laboratory tests may be helpful, such as γ-glutamyl transpeptidase (γGT) to define whether AlkP elevations are due to liver disease; hepatitis serology to define the type of viral hepatitis; and autoimmune markers to diagnose primary biliary cholangitis (antimitochondrial antibody), sclerosing cholangitis (peripheral antineutrophil cytoplasmic antibody), and autoimmune hepatitis (antinuclear, smooth-muscle, and liver-kidney microsomal antibody). A simple delineation of laboratory abnormalities and common liver diseases is given in Table 329-3.
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The use and interpretation of liver function tests are summarized in Chap. 330.
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Great advances have been made in hepatobiliary imaging, although no method is adequately accurate in demonstrating underlying cirrhosis in its early stages. Of the many modalities available for imaging the liver, US, computerized tomography (CT), and magnetic resonance imaging (MRI) are the most commonly employed and are complementary to one another. In general, US and CT are highly sensitive for detecting biliary duct dilation and are the first-line options for investigating cases of suspected obstructive jaundice. All three modalities can detect a fatty liver, which appears bright on imaging studies. Modifications of CT and MRI can be used to quantify liver fat, and this information may ultimately be valuable in monitoring therapy in patients with fatty liver disease. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) are the procedures of choice for visualization of the biliary tree. MRCP offers several advantages over ERCP: there is no need for contrast media or ionizing radiation, images can be acquired faster, the procedure is less operator dependent, and it carries no risk of pancreatitis. MRCP is superior to US and CT for detecting choledocholithiasis but is less specific. MRCP is useful in the diagnosis of bile duct obstruction and congenital biliary abnormalities, but ERCP is more valuable in evaluating ampullary lesions and primary sclerosing cholangitis. ERCP permits biopsy, direct visualization of the ampulla and common bile duct, and intraductal ultrasonography and brushings for cytological evaluation of malignancy. It also provides several therapeutic options in patients with obstructive jaundice, such as sphincterotomy, stone extraction, and placement of nasobiliary catheters and biliary stents. Doppler US and MRI are used to assess hepatic vasculature and hemodynamics and to monitor surgically or radiologically placed vascular shunts, including transjugular intrahepatic portosystemic shunts. Multidetector or spiral CT and MRI with contrast-enhancement are the procedures of choice for the identification and evaluation of hepatic masses, the staging of liver tumors, and preoperative assessment. With regard to mass lesions, the sensitivity of hepatic imaging continues to increase; unfortunately, specificity remains a problem, and often two and sometimes three studies are needed before a diagnosis can be reached. An emerging imaging modality for the investigation of hepatic lesions is contrast-enhanced US. This procedure permits enhancement of liver lesions in a similar fashion as contrast-enhanced, cross-sectional CT, or MR imaging. Major advantages are real-time assessment of liver perfusion throughout the vascular phases without risk of nephrotoxicity and radiation exposure. Other advantages are its widespread availability and lower cost. Limitations include body habitus of the patient and skill of the operator. US is the recommended modality for hepatocellular carcinoma screening. Contrast-enhanced US, CT, and MRI are appropriate for further investigation of lesions detected on screening US. The American College of Radiologists has developed a Liver Imaging Reporting and Data System (LI-RADS) to standardize the reporting and data collection of CT, MR, and contrast-enhanced US imaging for hepatocellular carcinoma (HCC). This system allows for more consistent reporting and reduces imaging interpretation variability and errors.
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Recently, US transient elastography has been approved for the measurement of hepatic stiffness—providing an indirect assessment of fibrosis and cirrhosis; this technique can eliminate the need for liver biopsy if the only indication is the assessment of disease stage. MR elastography is more sensitive than US elastography, but is also more expensive and requires advanced scheduling and special equipment. Studies are ongoing to determine whether hepatic elastography is an appropriate means of monitoring fibrosis and disease progression. Finally, interventional radiologic techniques allow the biopsy of solitary lesions, the radiofrequency ablation and chemoembolization of cancerous lesions, the insertion of drains into hepatic abscesses, the measurement of portal pressure, and the creation of vascular shunts in patients with portal hypertension. Which modality to use depends on factors such as availability, cost, and experience of the radiologist with each technique.
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Liver biopsy remains the gold standard in the evaluation of patients with liver disease, particularly chronic liver disease. Liver biopsy is necessary for diagnosis in selected instances but is more often useful for assessment of the severity (grade) and stage of liver damage, prediction of prognosis, and monitoring of the response to treatment. The size of the liver biopsy sample is an important determinant of reliability; a length of 1.5–2 cm is necessary for accurate assessment of fibrosis. Because liver biopsy is an invasive procedure and not without complications, it should be used only when it will contribute materially to decisions about management and therapy. In the future, noninvasive means of assessing disease activity (batteries of blood tests) and fibrosis (elastography and fibrosis markers) may replace liver biopsy for the staging and grading of disease.
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GRADING AND STAGING OF LIVER DISEASE
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Grading refers to an assessment of the severity or activity of liver disease, whether acute or chronic; active or inactive; and mild, moderate, or severe. Liver biopsy is the most accurate means of assessing severity, particularly in chronic liver disease. Serum aminotransferase levels serve as convenient and noninvasive markers for disease activity but do not always reliably reflect disease severity. Thus, normal serum aminotransferase levels in patients with hepatitis B surface antigen in serum may indicate the inactive carrier state or may reflect mild chronic hepatitis B or hepatitis B with fluctuating disease activity. Serum testing for hepatitis B e antigen and hepatitis B virus DNA can help sort out these different patterns, but these markers can also fluctuate and change over time. Similarly, in chronic hepatitis C, serum aminotransferase levels can be normal despite moderate disease activity. Finally, in both alcoholic and nonalcoholic steatohepatitis, aminotransferase levels are quite unreliable in reflecting severity. In these conditions, liver biopsy is helpful in guiding management and identifying appropriate therapy, particularly if treatment is difficult, prolonged, and expensive, as is often the case in chronic viral hepatitis. Of the several well-verified numerical scales for grading activity in chronic liver disease, the most commonly used are the METAVIR, histology activity index and the Ishak fibrosis scale.
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Liver biopsy is also the most accurate means of assessing stage of disease as early or advanced, precirrhotic, and cirrhotic. Staging of disease pertains largely to chronic liver diseases in which progression to cirrhosis and end-stage disease can occur but may require years or decades. Clinical features, biochemical tests, and hepatic imaging studies are helpful in assessing stage but generally become abnormal only in the middle to late stages of cirrhosis. Noninvasive tests that suggest advanced fibrosis include mild elevations of bilirubin, prolongation of prothrombin time, slight decreases in serum albumin, and mild thrombocytopenia (which is often the first indication of worsening fibrosis). Combinations of blood test results that include clinical features, routine laboratory tests, and special laboratory tests such as serum proteins or small molecules that are affected by or involved with fibrogenesis have been used to create models for predicting advanced liver disease, but these models are not reliable enough to use on a regular basis or for repeated measures and only separate advanced from early disease (Table 329-4). Recently, elastography and noninvasive breath tests using 13C-labeled compounds have been proposed as a means of detecting early stages of fibrosis and liver dysfunction, but their reliability and reproducibility remain to be proven. A major limitation of noninvasive markers is that they can be affected by disease activity. Even elastography is limited in this regard, in that it measures liver stiffness, not fibrosis per se, and can be affected by inflammation, edema, hepatocyte necrosis, and intrasinusoidal cellularity (inflammatory, malignant, or sickled cells). Thus, at present, mild to moderate stages of hepatic fibrosis are detectable only by liver biopsy. In the assessment of stage, the degree of fibrosis is usually used as the quantitative measure. The amount of fibrosis is generally staged on a scale of 0 to 4+ (METAVIR scale) or 0 to 6+ (Ishak scale). The importance of staging relates primarily to prognosis, recommendation of therapy and to optimal management of complications. Patients with cirrhosis are candidates for screening and surveillance for esophageal varices and hepatocellular carcinoma. Patients without advanced fibrosis need not undergo screening.
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Once cirrhosis develops, other scoring systems are employed to assess compensated versus decompensated disease and prognosis. The initial staging system used for this purpose was the modified Child-Pugh classification, with a scoring system of 5–15: scores of 5 and 6 represent Child-Pugh class A (consistent with “compensated cirrhosis”), scores of 7–9 represent class B, and scores of 10–15 represent class C (Table 329-5). This scoring system was initially devised to stratify patients with cirrhosis into risk groups before portal decompressive surgery. The Child-Pugh score is a reasonably reliable predictor of survival in many liver diseases and predicts the likelihood of major complications of cirrhosis, such as bleeding from varices and spontaneous bacterial peritonitis. This classification scheme was used to assess prognosis in cirrhosis and to provide standard criteria for listing a patient as a candidate for liver transplantation (Child-Pugh class B). More recently, the Child-Pugh system has been replaced by the Model for End-Stage Liver Disease (MELD) system for the latter purpose. The MELD score is a prospectively derived system designed to predict the prognosis of patients with liver disease and portal hypertension. Initially, this score was calculated from three noninvasive variables: the prothrombin time expressed as the international normalized ratio (INR), the serum bilirubin level, and the serum creatinine concentration. The ability of the MELD score to predict outcome after liver transplantation is regularly monitored and was modified to increase its accuracy and improve allocation of donated livers. These modifications include serum sodium concentration as a factor in the model and a reweighting of the MELD components. A separate scoring system pediatric end-stage liver disease (PELD) is used for children (<12 years of age). Transient elastography has also been used to stage cirrhosis and has been shown to be useful in predicting complications such as variceal hemorrhage, ascites development and liver-related death.
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The MELD system provides a more objective means of assessing disease severity and has less center-to-center variation than the Child-Pugh score as well as a wider range of values. The MELD and PELD systems are currently used to establish priority listing for liver transplantation in the United States. Convenient MELD and PELD calculators are available via the internet: (http://optn.transplant.hrsa.gov/resources/MeldPeldCalculator.asp?index=98).
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NONSPECIFIC ISSUES IN THE MANAGEMENT OF PATIENTS WITH LIVER DISEASE
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Specifics on the management of different forms of acute or chronic liver disease are supplied in subsequent chapters, but certain issues are applicable to any patient with liver disease. These issues include advice regarding alcohol use, medication use, vaccination, and surveillance for complications of liver disease. Alcohol should be used sparingly, if at all, by patients with liver disease. Abstinence from alcohol should be encouraged for all patients with alcohol-related liver disease, patients with cirrhosis, and patients receiving interferon-based therapy for hepatitis B and during antiviral therapy of hepatitis C. With regard to vaccinations, all patients with liver disease should receive hepatitis A vaccine, and those with risk factors should receive hepatitis B vaccine as well. Influenza and pneumococcal vaccination should also be encouraged, with adherence to the recommendations of the Centers for Disease Control and Prevention. Patients with liver disease should exercise caution in using any medications other than those that are most necessary. Drug-induced hepatotoxicity can mimic many forms of liver disease and can cause exacerbations of chronic hepatitis and cirrhosis; drugs should be suspected in any situation in which the cause of exacerbation is unknown. Finally, consideration should be given to surveillance for complications of chronic liver disease such as variceal hemorrhage and hepatocellular carcinoma. Cirrhosis warrants upper endoscopy to assess the presence of varices, and the patient should receive chronic therapy with beta blockers or should be offered endoscopic obliteration if large varices are found. Moreover, cirrhosis warrants screening and long-term surveillance for development of hepatocellular carcinoma. While the optimal regimen for such surveillance has not been established, an appropriate approach is US of the liver at 6- to 12-month intervals.