Approach to the Patient with Liver Disease

 Liver Disease
In most instances, a diagnosis of liver disease can be made accurately by a careful history, physical examination, and application of a few laboratory tests. In some circumstances, radiologic examinations are helpful or, indeed, diagnostic. Liver biopsy is considered the "gold standard" in evaluation of liver disease but is now needed less for diagnosis than for grading and staging disease. This chapter provides an introduction to diagnosis and management of liver disease, briefly reviewing the structure and function of the liver; the major clinical manifestations of liver disease; and the use of clinical history, physical examination, laboratory tests, imaging studies, and liver biopsy.

Liver Structure and Function
The liver is the largest organ of the body, weighing 1–1.5 kg and representing 1.5–2.5% of the lean body mass. The size and shape of the liver vary and generally match the general body shape—long and lean or squat and square. The liver is located in the right upper quadrant of the abdomen under the right lower rib cage against the diaphragm and projects for a variable extent into the left upper quadrant. The liver is held in place by ligamentous attachments to the diaphragm, peritoneum, great vessels, and upper gastrointestinal organs. It receives a dual blood supply; ~20% of the blood flow is oxygen-rich blood from the hepatic artery, and 80% is nutrient-rich blood from the portal vein arising from the stomach, intestines, pancreas, and spleen.
The majority of cells in the liver are hepatocytes, which constitute two-thirds of the mass of the liver. The remaining cell types are Kupffer cells (members of the reticuloendothelial system), stellate (Ito or fat-storing) cells, endothelial cells and blood vessels, bile ductular cells, and supporting structures. Viewed by light microscopy, the liver appears to be organized in lobules, with portal areas at the periphery and central veins in the center of each lobule. However, from a functional point of view, the liver is organized into acini, with both hepatic arterial and portal venous blood entering the acinus from the portal areas (zone 1) and then flowing through the sinusoids to the terminal hepatic veins (zone 3); the intervening hepatocytes constitute zone 2. The advantage of viewing the acinus as the physiologic unit of the liver is that it helps to explain the morphologic patterns and zonality of many vascular and biliary diseases not explained by the lobular arrangement.
Portal areas of the liver consist of small veins, arteries, bile ducts, and lymphatics organized in a loose stroma of supporting matrix and small amounts of collagen. Blood flowing into the portal areas is distributed through the sinusoids, passing from zone 1 to zone 3 of the acinus and draining into the terminal hepatic veins ("central veins"). Secreted bile flows in the opposite direction, in a countercurrent pattern from zone 3 to zone 1. The sinusoids are lined by unique endothelial cells that have prominent fenestrae of variable size, allowing the free flow of plasma but not cellular elements. The plasma is thus in direct contact with hepatocytes in the subendothelial space of Disse.
Hepatocytes have distinct polarity. The basolateral side of the hepatocyte lines the space of Disse and is richly lined with microvilli; it demonstrates endocytotic and pinocytotic activity, with passive and active uptake of nutrients, proteins, and other molecules. The apical pole of the hepatocyte forms the cannicular membranes through which bile components are secreted. The canniculi of hepatocytes form a fine network, which fuses into the bile ductular elements near the portal areas. Kupffer cells usually lie within the sinusoidal vascular space and represent the largest group of fixed macrophages in the body. The stellate cells are located in the space of Disse but are not usually prominent unless activated, when they produce collagen and matrix. Red blood cells stay in the sinusoidal space as blood flows through the lobules, but white blood cells can migrate through or around endothelial cells into the space of Disse and from there to portal areas, where they can return to the circulation through lymphatics.
Hepatocytes perform numerous and vital roles in maintaining homeostasis and health. These functions include the synthesis of most essential serum proteins (albumin, carrier proteins, coagulation factors, many hormonal and growth factors), the production of bile and its carriers (bile acids, cholesterol, lecithin, phospholipids), the regulation of nutrients (glucose, glycogen, lipids, cholesterol, amino acids), and metabolism and conjugation of lipophilic compounds (bilirubin, anions, cations, drugs) for excretion in the bile or urine. Measurement of these activities to assess liver function is complicated by the multiplicity and variability of these functions. The most commonly used liver "function" tests are measurements of serum bilirubin, albumin, and prothrombin time. The serum bilirubin level is a measure of hepatic conjugation and excretion, and the serum albumin level and prothrombin time are measures of protein synthesis. Abnormalities of bilirubin, albumin, and prothrombin time are typical of hepatic dysfunction. Frank liver failure is incompatible with life, and the functions of the liver are too complex and diverse to be subserved by a mechanical pump; dialysis membrane; or concoction of infused hormones, proteins, and growth factors.

Liver Diseases
While there are many causes of liver disease (Table 295-1), they generally present clinically in a few distinct patterns, usually classified as hepatocellular, cholestatic (obstructive), or mixed. In hepatocellular diseases (such as viral hepatitis or alcoholic liver disease), features of liver injury, inflammation, and necrosis predominate. In cholestatic diseases (such as gall stone or malignant obstruction, primary biliary cirrhosis, 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.

Table 295-1 Liver Diseases
Inherited hyperbilirubinemia
Gilbert syndrome
Crigler-Najjar syndrome, types I and II
Dubin-Johnson syndrome
Rotor syndrome
Viral hepatitis
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Hepatitis E
Others (mononucleosis, herpes, adenovirus hepatitis)
Cryptogenic hepatitis
Immune and autoimmune liver diseases
Primary biliary cirrhosis
Autoimmune hepatitis
Sclerosing cholangitis
Overlap syndromes
Graft-vs-host disease
Allograft rejection
Genetic liver diseases
1 Antitrypsin deficiency
Wilson disease
Benign recurrent intrahepatic cholestasis (BRIC)
Progressive familial intrahepatic cholestasis (PFIC), types I–III
Others (galactosemia, tyrosinemia, cystic fibrosis, Newman-Pick disease, Gaucher disease)
Alcoholic liver disease
Acute fatty liver
Acute alcoholic hepatitis
Laennec cirrhosis
Nonalcoholic fatty liver
Acute fatty liver of pregnancy
Liver involvement in systemic diseases
Glycogen storage diseases
Celiac disease
Mycobacterium avium intracellulare
Cholestatic syndromes
Benign postoperative cholestasis
Jaundice of sepsis
Total parenteral nutrition (TPN)–induced jaundice
Cholestasis of pregnancy
Cholangitis and cholecystitis
Extrahepatic biliary obstruction (stone, stricture, cancer)
Biliary atresia
Caroli disease
Drug-induced liver disease
Hepatocellular patterns (isoniazid, acetaminophen)
Cholestatic patterns (methyltestosterone)
Mixed patterns (sulfonamides, phenytoin)
Micro- and macrovesicular steatosis (methotrexate, fialuridine)
Vascular injury
Venoocclusive disease
Budd-Chiari syndrome
Ischemic hepatitis
Passive congestion
Portal vein thrombosis
Nodular regenerative hyperplasia
Mass lesions
Hepatocellular carcinoma
Focal nodular hyperplasia
Metastatic tumors

Typical presenting symptoms of liver disease include jaundice, fatigue, itching, right upper quadrant pain, 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 suspected of liver disease.
Evaluation of patients with liver disease should be directed at (1) establishing the etiologic diagnosis, (2) estimating the disease severity (grading), and (3) establishing the disease stage (staging). Diagnosis should focus on the category of disease, such as hepatocellular, cholestatic, or mixed injury, as well as on the specific etiologic diagnosis. Grading refers to assessing the severity or activity of disease—active or inactive, and mild, moderate, or severe. Staging refers to estimating the place in the course of the natural history of the disease, whether acute or chronic; early or late; precirrhotic, cirrhotic, or end-stage.
The goal of this chapter is to introduce general, salient concepts in the evaluation of patients with liver disease that help lead to the diagnoses discussed in subsequent chapters.

Clinical History
The clinical history should focus on the symptoms of liver disease—their nature, pattern of onset, and progression—and on potential risk factors for liver disease. The symptoms 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 pattern of onset rather than a specific symptom points to an etiology.
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 in the morning after adequate rest (afternoon vs. 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 to other problems such as stress, anxiety, sleep disturbance, or a concurrent illness.
Nausea occurs with more severe liver disease and may accompany fatigue or be provoked by odors of food or eating fatty foods. Vomiting can occur but is rarely persistent or prominent. Poor appetite with weight loss occurs commonly in acute liver diseases but is rare in chronic disease, except when cirrhosis is present and advanced. Diarrhea is uncommon in liver disease, except with severe jaundice, where lack of bile acids reaching the intestine can lead to steatorrhea.
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 gall bladder disease, liver abscess, and severe venoocclusive disease but is an occasional accompaniment of acute hepatitis.
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 cirrhosis and sclerosing cholangitis where it is often the presenting symptom, occurring before the onset of jaundice. However, itching can occur in any liver disease, particularly once cirrhosis is present.
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 less more 43 mol/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 population; the jaundice is more noticeable after fasting and with stress.
Major risk factors for liver disease that should be sought in the clinical history include details of alcohol use, medications (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 with blood and blood products, occupation, accidental exposure to blood or needlestick, and familial history of liver disease.
For assessing the risk of viral hepatitis, a careful history of sexual activity is of particular importance and should include number of life-time 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 rare 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. Vertical spread of hepatitis C is uncommon, but there are no reliable means of prevention. Transmission is more common in HIV-co-infected mothers and is also linked to prolonged and difficult labor and delivery, early rupture of membranes, and internal fetal monitoring. 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 (anti-HCV) in 1992 is an important risk factor for chronic hepatitis C. Blood transfusion before 1986, when screening for antibody to hepatitis B core antigen (anti-HBc) was introduced, is also a risk factor for hepatitis B. Travel to an underdeveloped area of the world, exposure to persons with jaundice, and exposure to young children in day-care centers are risk factors for hepatitis A. Hepatitis E is uncommon in the United States; however, it is one of the more common causes of jaundice in Asia and Africa. Tattooing and body piercing (for hepatitis B and C) and eating shellfish (for hepatitis A) are frequently mentioned but are actually quite rare types of exposure for acquiring hepatitis.
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% have more than two drinks per day, the average drink representing 11–15 g 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 upon whether alcohol abuse or dependence is present. Alcoholism is usually defined on the behavioral patterns and consequences of alcohol intake, not on the basis of the amount of alcohol intake. 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 295-2), which is recommended in all medical history taking.
Table 295-2 CAGE Questionsa
Have you ever felt you ought to Cut down on your drinking?
Have people Annoyed you by criticizing your drinking?
Have you ever felt Guilty or bad about your drinking?
Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (Eyeopener)?

aOne "yes" response should raise suspicion of an alcohol use problem, and more than one is a strong indication that abuse or dependence exists.

Family history can be helpful in assessing liver disease. Familial causes of liver disease include Wilson disease; hemochromatosis and 1 antitrypsin (1AT) deficiency; and the more uncommon inherited pediatric liver diseases of familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis, and Alagille syndrome. Onset of severe liver disease in childhood or adolescence with a family history of liver disease or neuropsychiatric disturbance should lead to investigation for Wilson disease. A family history of cirrhosis, diabetes, or endocrine failure and the appearance of liver disease in adulthood should suggest hemochromatosis and lead to investigation of iron status. Patients with abnormal iron studies warrant genotyping of the HFE gene for the C282Y and H63D mutations typical of genetic hemochromatosis. A family history of emphysema should provoke investigation of 1AT levels and, if low, for Pi genotype.

Physical Examination
The physical examination rarely demonstrates 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 usually 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 be the first evidence for the presence of hepatic failure, portal hypertension, and liver decompensation. In addition, the physical examination can reveal signs that point to a specific diagnosis, either in risk factors or in associated diseases or findings.
Typical physical findings in liver disease are icterus, hepatomegaly, hepatic tenderness, splenomegaly, spider angiomata, palmar erythema, and excoriations. Signs of advanced disease include muscle-wasting, ascites, edema, dilated abdominal veins, hepatic fetor, asterixis, mental confusion, stupor, and coma. In males with cirrhosis, particularly when related to alcohol, signs of hyperestrogenemia such as gynecomastia, testicular atrophy, and loss of male-pattern hair distribution may be found.
Icterus is best appreciated by inspecting the sclera under natural light. In fair-skinned individuals, a yellow color of the skin may be obvious. In dark-skinned individuals, the mucous membranes below the tongue can demonstrate jaundice. Jaundice is rarely detectable if the serum bilirubin level is less than 43 mol/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).
Spider angiomata and palmar erythema occur in both acute and chronic liver disease and may be especially prominent in persons with cirrhosis, but they can occur in normal individuals and are frequently present during pregnancy. Spider angiomata are superficial, tortuous arterioles and, unlike simple telangiectases, typically fill from the center outwards. 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.
Hepatomegaly is not a very reliable sign of liver disease, because of the variability of the size and shape of the liver and the physical impediments to assessing liver size by percussion and palpation. Marked hepatomegaly is typical of cirrhosis, venoocclusive disease, infiltrative disorders such as amyloidosis, metastatic or primary cancers of the liver, and alcoholic hepatitis. Careful assessment of the liver edge may also demonstrate unusual firmness, irregularity of the surface, or frank nodules. Perhaps the most reliable physical finding in examining the liver is hepatic tenderness. Discomfort on touching or pressing on the liver should be carefully sought with percussive comparison of the right and left upper quadrants.
Splenomegaly occurs in many medical conditions but can be a subtle but significant physical finding in liver disease. The availability of ultrasound (US) assessment of the spleen allows for confirmation of the physical finding.
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.
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 occur in patients with liver failure, particularly if there is portal-venous shunting of blood around the liver. Other causes of coma and confusion 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.
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 s; it is considerably delayed in patients with early hepatic encephalopathy. Other tests include drawing abstract objects or comparison of a signature to previous examples. More sophisticated testing such as with electroencephalography and visual evoked potentials can detect mild forms of encephalopathy, but are rarely clinically useful.
Other signs of advanced liver disease include umbilical hernia from ascites, hydrothorax, prominent veins over the abdomen, and caput medusa, which consists of collateral veins seen radiating from the umbilicus and resulting from the 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, defined by the triad of liver disease, hypoxemia, and pulmonary arteriovenous shunting. The hepatopulmonary syndrome is characterized by platypnea and orthodeoxia, representing shortness of breath and oxygen desaturation that occur paradoxically upon assuming an upright position.
Several skin disorders and changes occur commonly in liver disease. Hyperpigmentation is typical of advanced chronic cholestatic diseases such as primary biliary cirrhosis 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. A slate-gray pigmentation to the skin also occurs 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.
Some physical signs point to specific liver diseases. Kayser-Fleischer rings occur in Wilson's 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 may be prominent, as well as firm hepatomegaly and a hepatic bruit.

Laboratory Testing
Diagnosis in 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 measuring levels of serum alanine and aspartate aminotransferases (ALT and AST), alkaline phosphatase, direct and total serum bilirubin, and albumin and assessing prothrombin time. The pattern of abnormalities generally points to hepatocellular versus cholestatic liver disease and will help to decide whether the disease is acute or chronic and whether cirrhosis and hepatic failure are present. Based on these results, further testing over time may be necessary. Other laboratory tests may be helpful, such as -glutamyl transpeptidase (GGT) to define whether alkaline phosphatase elevations are due to liver disease; hepatitis serology to define the type of viral hepatitis; and autoimmune markers to diagnose primary biliary cirrhosis (antimitochondrial antibody; AMA), sclerosing cholangitis (peripheral antineutrophil cytoplasmic antibody; P-ANCA), 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 295-3. The use and interpretation of liver function tests.

Table 295-3 Important Diagnostic Tests in Common Liver Diseases
Diagnostic Test
Hepatitis A
Anti-HAV IgM
Hepatitis B
HBsAg and anti-HBc IgM
HBsAg and HBeAg and/or HBV DNA
Hepatitis C
Anti-HCV and HCV RNA
Hepatitis D (delta)
HBsAg and anti-HDV
Hepatitis E
Autoimmune hepatitis
ANA or SMA, elevated IgG levels, and compatible histology
Primary biliary cirrhosis
Mitochondrial antibody, elevated IgM levels, and compatible histology
Primary sclerosing cholangitis
P-ANCA, cholangiography
Drug-induced liver disease
History of drug ingestion
Alcoholic liver disease
History of excessive alcohol intake and compatible histology
Nonalcoholic steatohepatitis
Ultrasound or CT evidence of fatty liver and compatible histology
1 Antitrypsin disease
Reduced 1 antitrypsin levels, phenotypes PiZZ or PiSZ
Wilson disease
Decreased serum ceruloplasmin and increased urinary copper; increased hepatic copper level
Elevated iron saturation and serum ferritin; genetic testing for HFE gene mutations
Hepatocellular cancer
Elevated -fetoprotein level  more than 500; ultrasound or CT image of mass

Note: HAV, HBV, HCV, HDV, HEV: hepatitis A, B, C, D, or E virus; HBsAg, hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core (antigen); HBeAg, hepatitis e antigen; ANA, antinuclear antibodies; SMA, smooth-muscle antibody; P-ANCA, peripheral antineutrophil cytoplasmic antibody.

Diagnostic Imaging
There have been great advances made in hepatic imaging, although no method is suitably accurate in demonstrating underlying cirrhosis. There are many modalities available for imaging the liver. US, CT, and MRI are the most commonly employed and are complementary to each other. In general, US and CT have a high sensitivity for detecting biliary duct dilatation and are the first-line options for investigating the patient with suspected obstructive jaundice. Both US and CT can detect a fatty liver, which appears bright on both studies.
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, it is less operator dependent, and it carries no risk of pancreatitis. MRCP is superior to US and CT for detecting choledocholithiasis but less specific. It 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 allows for biopsy, direct visualization of the ampulla and common bile duct, and intraductal ultrasonography. 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 such as transjugular intrahepatic portosystemic shunts. CT and MRI are indicated for the identification and evaluation of hepatic masses, staging of liver tumors, and preoperative assessment. With regard to mass lesions, 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. Recently, methods using elastrography have been developed to measure hepatic stiffness as a means of assessing hepatic fibrosis. US elastrography is now undergoing evaluation for its ability to detect different degrees of hepatic fibrosis and to obviate the need for liver biopsy in assessing disease stage. If found to be reliable, hepatic elastrography may be an appropriate means of monitoring fibrosis and disease progression. Finally, interventional radiologic techniques allow the biopsy of solitary lesions, insertion of drains into hepatic abscesses, measurement of portal pressure, and 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.

Liver Biopsy
Liver biopsy remains the gold standard in the evaluation of patients with liver disease, particularly in patients with chronic liver diseases. In selected instances, liver biopsy is necessary for diagnosis but is more often useful in assessing the severity (grade) and stage of liver damage, in predicting prognosis, and in monitoring response to treatment. The size of the liver biopsy is an important determinant of its reliability; a length of 1.5–2 cm being necessary for accurate assessment of fibrosis. In the future, noninvasive means of assessing disease activity (batteries of blood tests) and fibrosis (elastrography and fibrosis markers) may replace liver biopsy in assessing stage and grade of disease.

Diagnosis of Liver Disease
The major causes of liver disease and key diagnostic features are outlined in Table 295-3, and an algorithm for evaluation of the patient with suspected liver disease is given in Fig. 295-1. 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 is usually 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 the diagnosis of drug-induced liver disease and in establishing the diagnosis of acute alcoholic hepatitis.
Figure 295-1
Algorithm for evaluation of abnormal liver tests. For patients with suspected liver disease, an appropriate approach to evaluation is initial testing for routine liver tests such as bilirubin, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AlkP). These results (sometimes complemented by testing of -glutamyl transpeptidase; GGT) will establish whether the pattern of abnormalities is hepatic, cholestatic, or mixed. In addition, the duration of symptoms or abnormalities will show whether the disease is acute or chronic. If the disease is acute and if history, laboratory tests, and imaging studies do not reveal a diagnosis, liver biopsy is appropriate to help to establish the diagnosis. If the disease is chronic, liver biopsy can be helpful not only for diagnosis but also to grade the activity and stage the progression of disease. This approach is largely applicable to patients without immune deficiency. In patients with HIV infection or after bone marrow or solid organ transplantation, diagnostic evaluation should also include evaluation of opportunistic infections (adenovirus, cytomegalovirus, coccidioidomycosis, etc.) as well as vascular and immunologic conditions (venoocclusive disease, graft-vs-host disease). HAV, HCV: hepatitis A or C virus; HBsAg, hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core (antigen); ANA, antinuclear antibodies; SMA, smooth-muscle antibody; MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatography; 1AT, 1 antitrypsin; AMA; antimitochondrial antibody; P-ANCA, peripheral antineutrophil cytoplasmic antibody.

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 cirrhosis, hemochromatosis, and Wilson disease. 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 cirrhosis, nonalcoholic and alcoholic steatohepatitis, and Wilson disease (with a quantitative hepatic copper level).

Grading and Staging of Liver Disease
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 are used as a convenient and noninvasive means to follow disease activity, but aminotransferase levels are not always reliable in reflecting disease severity. Thus, normal serum aminotransferase levels in patients with hepatitis B surface antigen (HBsAg) in serum may indicate the inactive HBsAg 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 resolve 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 activity of disease. 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 recommending therapy, particularly if therapy is difficult, prolonged, and expensive as is often the case in chronic viral hepatitis. There are several well-verified numerical scales for grading activity in chronic liver disease, the most common being the histology activity index and the Ishak histology scale.
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 liver disease can occur, but which may require years or decades to develop. 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 have been used to create models for predicting advanced liver disease, but these are not reliable enough to use on a regular basis and they only separate advanced from early disease. Recently, elastrography has been proposed as a means of detecting early stages of fibrosis, but its reliability and reproducibility remain to be proven. Thus, at present early stages of fibrosis are detectable only by liver biopsy. In assessing stage, the degree of fibrosis is usually used as its quantitative measure. The amount of fibrosis is generally staged on a 0 to 4+ (histology activity index) or 0 to 6+ scale (Ishak scale). The importance of staging relates primarily to prognosis and to guiding 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.
Cirrhosis can also be staged clinically. A reliable staging system is the modified Child-Pugh classification with a scoring system of 5–15: scores of 5 and 6 being Child-Pugh class A (consistent with "compensated cirrhosis"), scores of 7–9 indicating class B, and 10–15 class C (Table 295-4). This scoring system was initially devised to stratify patients into risk groups prior to undergoing 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. It was used to assess prognosis in cirrhosis and to provide the standard criteria for listing for liver transplantation (Child-Pugh class B). Recently the Child-Pugh system has been replaced by the model for end-stage liver disease (MELD) score for assessing the need for liver transplantation. The MELD score is a prospectively derived scoring system designed to predict prognosis of patients with liver disease and portal hypertension. It is calculated using three noninvasive variables—the prothrombin time expressed as international normalized ratio (INR), serum bilirubin, and serum creatinine
Table 295-4 Child-Pugh Classification of Cirrhosis
Serum bilirubin
Less than 34
Less than 2.0
More than 51
More than 3.0
Serum albumin
More than 35
More than 3.5
Less than 30
Less than 3.0
Prothrombin time
seconds prolonged
Less than 1.7
More than 6
More than 2.3
Easily controlled
Poorly controlled
Hepatic encephalopathy

Note: The Child-Pugh score is calculated by adding the scores of the five factors and can range from 5–15. Child-Pugh class is either A (a score of 5–6), B (7–9), or C (10 or above). Decompensation indicates cirrhosis with a Child-Pugh score of 7 or more (class B). This level has been the accepted criterion for listing for liver transplantation.

MELD provides a more objective means of assessing disease severity and has less center-to-center variation than the Child-Pugh score and has a wider range of values. MELD is currently used to establish priority listing for liver transplantation in the United States. A similar system using bilirubin, INR, serum albumin, age, and nutritional status is used for children below the age of 12 (PELD).
Thus, liver biopsy is helpful not only in diagnosis but also in management of chronic liver disease and assessment of prognosis. Because liver biopsy is an invasive procedure and not without complications, it should be used only when it will contribute materially to management and therapeutic decisions.

Nonspecific Issues in Management of Patients with Liver Disease
Specifics on management of different forms of acute or chronic liver disease are given in subsequent chapters, but certain issues are applicable to any patient with liver disease. These include advice regarding alcohol use, medications, 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 and in patients with cirrhosis and those receiving interferon-based therapy for hepatitis B or C. Regarding vaccinations, all patients with liver disease should receive hepatitis A vaccine and those with risk factors should receive hepatitis B vaccination as well. Influenza and pneumococcal vaccination should also be encouraged. Patients with liver disease should be careful in use of any medications, other than the 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 where 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. Patients with cirrhosis warrant upper endoscopy to assess the presence of varices and should be given chronic therapy with beta blockers or offered endoscopic obliteration if large varices are found. Patients with cirrhosis also warrant 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.

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