Because of the liver's complexity, liver disease is often reflected by abnormalities of different hepatic "systems" - i.e., hepatocytes (hepatocellular dysfunction), the biliary excretory apparatus (cholestasis) and the vascular system (portal hypertension). In addition, the liver often is involved in systemic disease by virtue of its rich metabolic and reticuloendothelial activity and its large blood supply.

Patterns of disproportionate involvement often provide an important clue to the underlying disorder. For example, viral hepatitis characteristically produces predominant hepatocellular dysfunction; primary biliary cirrhosis, predominant cholestasis; cryptogenic cirrhosis, predominant portal hypertension; and alcoholic liver disease, variably predominant dysfunction of any of these three systems. The clinician can usually take advantage of these general patterns to help establish a diagnosis, though overlap and exceptions are frequent.

 

2.1 Clinical Features of Liver Disease

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Table 1 lists the most important clinical manifestations of liver disease. Most can be seen in both acute and chronic hepatic disorders; features marked by an asterisk usually denote chronicity. This distinction can be of diagnostic value at the bedside. For example, a clinical diagnosis of acute hepatitis should be reconsidered if physical examination reveals spider nevi and palmar erythema.

Nondescript anorexia, malaise and fatigue are common manifestations of both acute and chronic liver disease. An abrupt onset often reflects acute viral or drug-induced hepatitis, whereas insidious development typifies alcoholic liver disease, chronic active hepatitis and other chronic disorders.

Fever is another nonspecific feature of some liver conditions, especially the prodromal phase of acute viral hepatitis, severe alcoholic hepatitis and (sometimes) malignancy. However, frank rigors and chills are rare in these conditions, and instead strongly suggest acute cholangitis, usually secondary to common duct stone.

Patients with advanced chronic liver disease, especially alcoholic cirrhosis, often develop deterioration of general health, weight loss and a characteristic "cirrhotic habitus" in which wasted extremities and shoulder girdle contrast with a bloated belly from ascites.

Generalized pruritus is a hallmark of cholestatic disorders, especially if chronic. When cholestasis is prolonged -for example, in primary biliary cirrhosis -this may be accompanied by cutaneous lipid deposits (xanthelasma, xanthomas) and by features of malabsorption.

This cardinal feature of liver disease indicates hyperbilirubinemia. Bilirubin arises primarily from the physiologic breakdown of senescent red blood cells, with a minor contribution from other heme sources. It is not water-soluble and is therefore transported in plasma loosely attached to albumin. This form of the pigment is called unconjugated or indirect-reacting bilirubin. The molecule is then taken up by hepatocytes and conjugated in microsomes with glucuronic acid to form bilirubin diglucuronide; the reaction is catalyzed by the enzyme glucuronyl transferase. Other minor conjugates are also formed; their clinical significance is unknown.

Transformed bilirubin is then secreted into the bile canaliculus along with the other constituents of bile. A small amount normally enters the blood as conjugated or direct-reacting bilirubin. In contrast to unconjugated bilirubin, this form of the pigment is water-soluble and is therefore excreted into urine, though a portion becomes tightly bound to circulating albumin (the so-called albumin-bound fraction of conjugated bilirubin).

After reaching the gut through the biliary tree, bilirubin is transformed by intestinal bacteria into pigmented breakdown products collectively called urobilinogen; these impart the normal brown color to stool. With impairment of biliary secretion (cholestasis) the stools are therefore often pale, but this is a relatively crude and unreliable diagnostic feature. Some urobilinogen is absorbed from the intestine and recycled through the liver (the enterohepatic circulation), with a portion escaping into the urine.

Various derangements in the above metabolic steps can result in jaundice. An increased bilirubin load from hemolysis may overwhelm the liver's conjugating capacity, resulting in unconjugated hyperbilirubinemia. This is invariably mild, however, unless there is also concomitant hepatic dysfunction. Isolated unconjugated hyperbilirubinemia also occurs in some specific defects of bilirubin metabolism, though these are rare except for Gilbert's syndrome (see Section 3 below).

In the vast majority of cases, jaundice is due to either hepatocellular disease or biliary obstruction. Both produce multiple defects in the pathway of bilirubin metabolism, including impaired hepatocellular uptake and transport, defective conjugation, decreased canalicular secretion, and "leakage" of conjugated bilirubin into the circulation. The resultant hyperbilirubinemia is a mixture of unconjugated and conjugated pigment; usually the latter predominates, but the exact proportion varies widely and has no specific diagnostic value.

Clinically, mild jaundice can usually be detected when serum bilirubin is about twice the upper limit of normal, and is best diagnosed by inspecting the patient's sclerae in natural daylight. More advanced cases are often apparent at a glance. Patients with severe long-standing jaundice sometimes have a generalized muddy-yellow appearance.

A readily palpable liver is not necessarily enlarged, for it may merely be low lying -as, for example, in emphysema. Thus the upper border should be percussed when the edge is palpable.

The "quality" or feel of the liver is at least as important diagnostically as its size. For example, the liver usually retains its rubbery, relatively sharp edge when enlargement is due to fatty infiltration, acute hepatitis or passive congestion, whereas chronic fibrosis typically produces a blunt, indurated edge. Individual cirrhotic nodules are rarely detectable clinically. Palpable lumpiness instead favors malignant infiltration. It is important to remember that major liver disease - including a high proportion of cirrhosis - may not be associated with hepatomegaly.

Abdominal pain is common in biliary or pancreatic disease that might secondarily affect the liver -for example, common duct stone or pancreatic carcinoma -but pain is relatively uncommon in primary hepatic disorders. True hepatic pain is usually due to distention of the liver capsule, typically felt as a deep-seated right upper quadrant ache. This is often accompanied by hepatic tenderness on physical examination, best elicited by compression of the rib cage or fist percussion over the liver. The commonest causes are acute hepatitis, passive congestion from cardiac failure, and malignancy. Pain from malignancy is sometimes pleuritic in character and may be accompanied by a hepatic friction rub or bruit on auscultation. Some individuals claim some discomfort when the liver edge is palpated; this has no special significance and should not be interpreted as hepatic tenderness.

These findings as listed in Table 1 are important clues to chronic liver disease. Their pathogenesis is still poorly understood, but altered metabolism of sex hormones by the diseased liver appears important. The abnormalities may be seen in any chronic hepatic disorder, but are especially prevalent in alcoholic liver disease; this probably relates in part to a direct toxic effect of ethanol on gonadal function.

The liver synthesizes most clotting factors, including vitamin K-dependent factors II, VII, IX and X. Severe hepatocellular dysfunction is therefore often accompanied by an enhanced bruising and bleeding tendency and by abnormal coagulation studies, particularly an increased INR/prothrombin time. Malabsorption of the fat-soluble vitamin K in prolonged cholestasis can also produce an abnormal INR/prothrombin time.

Thrombocytopenia is common in patients with cirrhosis, primarily as a result of portal hypertension with hypersplenism, but usually the platelet counts are not low enough to induce clinical bleeding. In patients with alcoholic liver disease, thrombocytopenia may also be due to direct marrow suppression by alcohol and/or nutritional folate deficiency.

Dysfibrinogenemia also sometimes contributes to coagulopathy in cases of severe hepatic dysfunction.

A hyperdynamic circulation and relatively low blood pressure are sometimes seen in patients with severe liver disease, especially fulminant hepatitis and advanced cirrhosis. The mechanism may relate to the accumulation of vasoactive agents normally cleared by the liver, which reduce tone. Occasional patients with cirrhosis develop intrapulmonary A-V shunting, with resultant arterial desaturation and (rarely) clubbing (hepatopulmonary syndrome).

A number of topics will be discussed in later sections, including portal hypertension (Section 11), fluid derangements (Section 12 and Section 14) and hepatic encephalopathy (Section 13).

No single test can assess overall hepatic function, as the liver is a complex organ with interdependent metabolic, excretory and defense functions. Thus a number of laboratory tests are usually combined to detect hepatobiliary abnormalities and to assess their severity, follow the course of the disease, and help establish an etiology. Diagnosis is often based on patterns of abnormality that help distinguish hepatocellular dysfunction from excretory impairment (cholestasis), though overlap is great. In only a minority of cases does a specific laboratory test establish the diagnosis.

Radiologic imaging techniques and liver biopsy often provide essential diagnostic information, but their use should be tailored to the specific clinical circumstances.

2.2.1.1 Bilirubin

This is a relatively insensitive indicator of liver disease, but it provides a clue to the overall assessment of hepatic function. The degree of bilirubin elevation often correlates poorly with clinical severity, but serial values are useful for following the course of the illness. Direct/indirect (conjugated/unconjugated) fractionation is not of diagnostic value in most cases of jaundice, and cannot distinguish hepatocellular disease from biliary obstruction. Measuring the presence of unconjugated hyperbilirubinemia is useful only in cases of mild, isolated bilirubin elevation to corroborate hemolysis or Gilbert's syndrome.

Urine bilirubin has little diagnostic value except in early hepatitis, when bilirubinuria precedes clinical jaundice, and in isolated unconjugated hyperbilirubinemia, when bilirubinuria is absent despite jaundice. (Unconjugated bilirubin is not cleared into urine.) Otherwise bilirubinuria is commonly present in hepatobiliary jaundice of any cause.

These liver enzymes include alanine aminotransferase (ALT), found primarily in liver cytosol, and aspartate aminotransferase (AST), also found in several other tissues, most notably skeletal and cardiac muscle. Both are exquisitely sensitive indicators of hepatocellular injury and provide the best guide to hepatocellular necrosis/inflammation.

The magnitude of elevation covers a very wide range. Levels <100 IU are common and nonspecific, and often have no clinical significance; levels of 100-300 IU are seen in numerous mild/moderate inflammatory processes. In acute viral or drug hepatitis aminotransferase levels are typically in the 500-1,500 IU range, but in alcoholic hepatitis they are usually <300 IU, even if the disease is severe. Values >3,000 IU usually are seen only in acute toxic necrosis or severe hypoxia ("shock liver," "ischemic hepatitis"); in both disorders levels typically plummet within two to three days, whereas values fall more slowly in viral hepatitis. Aminotransferase levels are variable in biliary obstruction but usually remain <200 IU, except with acute passage of common duct stone, characterized by a sudden rise to hepatitic levels and a rapid fall over the next one to two days.

The AST to ALT ratio is usually <1 in most circumstances, but is typically >1.5 in alcoholic liver disease; though not absolute, this is diagnostically helpful for alcoholic injury. Alcohol consumption lessens the ALT rise as a result of deficiency of a coenzyme needed for ALT synthesis.

The level of this bile canalicular enzyme is disproportionately increased in impaired bile excretion, and therefore an elevated level of ALP is a hallmark of cholestasis. An elevation in its level is due to enhanced synthesis rather than hepatocytic leakage; thus, the level usually rises slowly over days or weeks rather than abruptly. A disproportionately elevated ALP may be seen in infiltrative disorders, especially malignancy.

ALP isoenzymes also are present in bone and placenta. If the source of an isolated increase in ALP is not clinically clear, a concomitant elevation of g-glutamyl transpeptidase (GGT) indicates a hepatobiliary origin. A form of ALP specific to the liver is 5'-nucleotidase (5'NT).

Levels of GGT usually parallel ALP, but this microsomal enzyme is also easily inducible - for example, by ethanol and numerous drugs. Thus, GGT is often disproportionately elevated in alcoholic liver disease, although this is too nonspecific for diagnostic reliability.

2.2.1.5.1 Albumin

Synthesized by the liver, albumin is the major contributor to oncotic pressure in the serum. Decreased levels usually develop only in severe hepatic dysfunction - most often in advanced cirrhosis - and therefore imply a relatively poor prognosis. Albumin usually remains normal in acute hepatitis; falling values in this setting imply an unusually severe course.

Nonspecific diffuse elevation is common in chronic liver disease, and of no consequence. Sometimes there is disproportionate elevation of IgG in autoimmune hepatitis, of IgM in primary biliary cirrhosis, and of IgA in alcoholic liver disease.

The INR/prothrombin time is a valuable index of the liver's ability to synthesize vitamin K-dependent clotting factors - a true "function" test. Increasing INR/PT implies relatively severe dysfunction, analogous to low serum albumin, and is especially worrisome in acute hepatitis. An abnormal value may be found in chronic cholestasis due to vitamin K malabsorption rather than impaired hepatic synthesis of clotting factors. Improvement after parenteral administration of vitamin K therefore favors a diagnosis of cholestasis over hepatocellular failure, but there are too many exceptions for diagnostic reliability.

Complex lipoprotein derangements are common in liver disease, though usually not routinely studied. Cholesterol is often low in acute or chronic liver failure, whereas hypercholesterolemia is associated with prolonged cholestasis. Striking triglyceride elevations occasionally occur in alcoholic liver disease ("alcoholic lipemia").

2.2.2.1 Hepatitis serology

Serology is crucial for the specific diagnosis of hepatitis A, B, C and D. See Section 4 for details.

This is actually a complex series of antibodies directed against dehydrogenase components of mitochondrial membranes of various tissues. Nevertheless, it serves as a valuable marker for primary biliary cirrhosis, as it is present in >90% of cases. Antimitochondrial antibody is uncommon in other disorders, though there is some overlap with autoimmune hepatitis.

Such nonspecific immune markers are seen relatively commonly in autoimmune hepatitis; they are infrequent in other hepatic diseases.

This normal hepatic fetal protein disappears soon after birth. Detection therefore reflects hepatic dedifferentiation. Levels >250 ng/mL serve as a relatively specific marker for hepatocellular carcinoma, though they are also seen occasionally in other tumors. Values <100 ng/mL are nonspecifically seen in hepatic regeneration - e.g., recovering from hepatitis.

In general, radiologic imaging is essential for the accurate diagnosis of biliary disease, important for focal liver disease (e.g., tumor), but overused and of relatively little value for diffuse hepatocellular disease (e.g., hepatitis, cirrhosis).

Ultrasound is now the most widely used imaging procedure. Highly reliable for diagnosis of gallstones (>95% sensitivity), it has replaced oral cholecystography. US is less accurate in detecting common bile duct stones (<40% sensitivity), but reliably establishes the presence of a dilated biliary tree, which implies mechanical obstruction. It is therefore the primary initial tool to distinguish intrahepatic from extrahepatic cholestasis. It also detects focal hepatic lesions (e.g., tumor, cysts), sometimes with characteristic diagnostic features. It is less useful in detecting diffuse hepatocellular disease, as features are usually nonspecific. Abdominal ultrasound can be useful in the detection of fatty liver (steatosis), which results in a diffuse increase in echogenicity.

Ultrasonography can also provide important ancillary information relevant to hepatobiliary disease - e.g., splenomegaly or pancreatic mass. Doppler US is valuable in establishing the patency of hepatic vessels, especially the portal vein.

An expensive alternative to US, CT sometimes provides additional hepatic information. Generally less valuable than US for biliary disease, CT has proven more valuable for assessing the pancreas.

2.2.3.3.1 Endoscopic retrograde cholangiopancreatography (ERCP)

Upper endoscopy allows direct cannulation of the common bile duct and/or pancreatic duct; the injection of contrast agent yields excellent definition of ductal anatomy. ERCP permits definitive visualization of the biliary tree for common duct stone, sclerosing cholangitis and other conditions. It also allows therapeutic intervention - e.g., removal of common duct stones via endoscopic papillotomy or stenting a stricture.

In PTC, direct contrast visualization of the biliary tree is obtained via percutaneous needle puncture of liver. This is done less often than ERCP, but is especially useful if there is high biliary obstruction - e.g., a tumor at the bifurcation of the hepatic ducts. It also permits therapeutic intervention such as stent insertion to bypass a ductal malignancy.

ERCP and PTC require considerable technical expertise and have significant risks. They should not be undertaken lightly, but are highly valuable in selected cholestatic situations and often obviate laparotomy.

A liver-spleen scan using 99mTc-sulfur colloid can reveal space-occupying lesions and diffuse parenchymal disease, but such scans are much less sensitive than US or CT; therefore, their use has rapidly waned. A 99mTc-labeled RBC scan can visualize suspected vascular lesions, especially hemangiomas. Cholescintigraphy using 99mTc-iminodiacetic acid derivatives (termed HIDA scan) can reveal cystic duct obstruction, especially in acute cholecystitis. The HIDA scan also assesses biliary excretion/patency and anatomy, but results often are less than ideal or misleading. Occasionally 67Ga-citrate scans are used to help detect liver abscess or tumor.

NMR is an expensive but valuable imaging technique, not yet widely available. It can detect some lesions poorly seen by US or CT and sometimes can better clarify the nature of focal defects. NMR can also show the biliary tree, though in less detail than ERCP, and in selected instances of biliary obstruction may serve as a noninvasive alternative to ERCP.

Percutaneous liver biopsy provides important diagnostic information at relatively low risk, but is needed in only a minority of cases of hepatic dysfunction. A small core of liver tissue is obtained at the bedside by needle aspiration under local anesthesia. This usually provides a surprisingly reliable reflection of the underlying disorder, though sampling error can occur in focal disease and some cases of cirrhosis.

The major indications are shown in Table 2. Transient right upper quadrant pain is not uncommon after biopsy, but significant hemorrhage, bile peritonitis or other major complications are rare if cases are properly selected.

Relative contraindications include a clinical bleeding tendency, INR > 1.5 or prothrombin time more than three seconds greater than control, severe thrombocytopenia, marked ascites, and high-grade biliary tract obstruction. A transjugular approach can be used with relative safety in cases of coagulopathy or severe ascites.

Fine-needle aspiration of specific hepatic lesions can be obtained under US or CT guidance. This provides a cytologic sample, but is usually inadequate for full histologic assessment. Ultrasound guidance can be used to obtain a "core biopsy" from the liver.

When faced with a patient with known or suspected liver disease, the physician should attempt to answer several central questions: (1) Is the disorder acute or chronic? (2) Is it primarily a hepatocellular problem (e.g., hepatitis), a disorder of hepatobiliary secretion (cholestasis) or a vascular problem (e.g., portal hypertension)? (3) If hepatocellular, is alcohol, a virus or a drug responsible? If cholestatic, is it an intrahepatic problem or due to mechanical biliary obstruction? If vascular, is it due to cirrhosis or to a less common cause? (4) Is this actually a systemic disorder involving the liver rather than a primary hepatic problem? (5) Are there complications that require specific treatment? These and other pertinent questions are approached by bedside clinical judgment coupled with ancillary tests.

Broadly speaking, the most important diagnostic tool is a complete history and physical examination. Laboratory tests, imaging techniques and liver biopsy are valuable and sometimes essential for diagnosis, but in most cases clinical acumen provides the most important diagnostic information. Moreover, clinical judgment determines what additional studies should be undertaken and how to interpret the results. Diagnostic errors most often arise from an inadequate history and physical examination with undue reliance on ancillary tests.

The clinical assessment should emphasize aspects discussed above in Section 2.1. Inquire about ethanol, drugs (prescribed, over-the-counter and illicit) and epidemiologic factors relevant to viral hepatitis, especially in cases of suspected hepatocellular injury. In addition, pursuit of systemic illness is often necessary. A positive family history may also be obtained from patients with certain metabolic diseases found in children such as Wilson's disease, a₁-antitrypsin deficiency and autoimmune liver disease. If a cholestatic disorder is suspected, clues to a possible extrahepatic cause should also be sought -e.g., biliary or pancreatic pain, rigors and chills or weight loss. The physical examination may provide valuable information on the size and nature of the liver, presence or absence of signs of chronic liver injury, and complications such as portal hypertension, fluid retention or encephalopathy (see Section 2.1).

The extent and nature of laboratory investigations are guided by the initial clinical evaluation. Broadly speaking, a minimal initial study will include CBC plus bilirubin, AST and/or ALT, and ALP. These few simple tests usually clarify whether the problem is primarily a hepatocellular injury (disproportionate aminotransferase elevations) or an excretory problem (predominant ALP elevation). If the former is clinically apparent but the etiology is not, viral hepatitis markers may help, especially if the disorder is acute. If a cholestatic problem seems most likely, early US (or CT) should help distinguish intrahepatic from extrahepatic causation. If US indicates extrahepatic obstruction, direct biliary visualization by ERCP (or PTC) should be considered, whereas liver biopsy may be warranted if the process appears intrahepatic.

As yet there is no reliable biochemical marker of liver fibrosis. Thus laboratory indicators of hepatic dysfunction are often normal or only mildly deranged in cases of inactive cirrhosis; this is a common circumstance. It is well to remember that alcoholic liver disease is the commonest cause of chronic hepatocellular injury, even in patients who initially deny heavy ingestion.

With appropriate evaluation, a diagnosis can readily be established in the large majority of patients with hepatobiliary dysfunction. In many circumstances, however, especially if the hepatic abnormalities are minor, the wisest approach is simply to follow the patient's progress with periodic clinical and laboratory assessments.