While there are many causes of liver disease (Table 301-1), 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 gallstone 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.
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 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.
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 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 patterns 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 versus 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 gallbladder 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 <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's syndrome and the rare and severe form being Crigler-Najjar syndrome. Gilbert's 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 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 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 one of the more common causes of jaundice in Asia and Africa but is uncommon in developed nations, although mild cases have been associated with eating raw or undercooked pork or game (deer and wild boars). 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 on whether alcohol abuse or dependence is present. Alcoholism is usually defined by 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 301-2), which is recommended in all medical history-taking.
Table 301-2 CAGE Questions* |Favorite Table|Download (.pdf)
Table 301-2 CAGE Questions*
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)?
Family history can be helpful in assessing liver disease. Familial causes of liver disease include Wilson's disease; hemochromatosis and α1 antitrypsin (α1AT) 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's 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. Adult patients with abnormal iron studies 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 provoke investigation of α1AT levels and, if low, for Pi genotype.
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 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 <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).
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 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.
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 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.
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 seconds; 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. Measurement of oxygen saturation by pulse oximetry is a reliable screening test for the presence of hepatopulmonary syndrome.
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.
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 (AlkP), 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 γ-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 301-3.
Table 301-3 Important Diagnostic Tests in Common Liver Diseases |Favorite Table|Download (.pdf)
Table 301-3 Important Diagnostic Tests in Common Liver Diseases
HBsAg and anti-HBc IgM
HBsAg and HBeAg and/or HBV DNA
Anti-HCV and HCV RNA
Hepatitis D (delta)
HBsAg and anti-HDV
ANA or SMA, elevated IgG levels, and compatible histology
Primary biliary cirrhosis
Mitochondrial antibody, elevated IgM levels, and compatible histology
Primary sclerosing cholangitis
Drug-induced liver disease
History of drug ingestion
Alcoholic liver disease
History of excessive alcohol intake and compatible histology
Ultrasound or CT evidence of fatty liver and compatible histology
α1 Antitrypsin disease
Reduced α1 antitrypsin levels, phenotypes PiZZ or PiSZ
Decreased serum ceruloplasmin and increased urinary copper; increased hepatic copper level
Elevated iron saturation and serum ferritin; genetic testing for HFE gene mutations
Elevated α-fetoprotein level >500; US or CT image of mass
The use and interpretation of liver function tests is summarized in Chap. 302.
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. 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, which 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, 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 elastography have been developed to measure hepatic stiffness as a means of assessing hepatic fibrosis. US and MR elastrography are now undergoing evaluation for their 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 elastography may be an appropriate means of monitoring fibrosis and disease progression. Finally, interventional radiologic techniques allow the biopsy of solitary lesions, performance of radiofrequency ablation and chemoembolization of cancerous 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.