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Assessment of Liver Dysfunction



      As discussed in the previous section, liver injury from a variety of causes can lead to very similar clinical symptoms, a common endpoint being hepatocyte damage and scar formation. However, a thorough history and physical examination can reveal clues to the potential etiologies of liver disease. Laboratory studies can help establish the pattern of injury, the functional status of the liver, and the specific causes of disease. Finally, liver biopsy is a safe procedure that can provide valuable information about the patterns and etiologies of liver injury.



Objectives



These objectives will focus your attention on expected learning outcomes. After you complete this section, you should be able to:



1. Describe important clinical symptoms and physical examination findings that aid in the recognition and diagnosis of liver disease.



2. Identify patterns of liver chemistry abnormalities that are clues to specific categories of liver disease.



3. Identify tests that assess specific hepatic functions.



4. Describe auxiliary laboratory studies that help diagnose specific liver diseases such as viral hepatitis.



5. Describe the technique, risks, and potential uses of liver biopsy.



6. Define the various terms used to describe the histologic appearance of biopsy specimens.





Key Concepts

1. A patient's medical history can reveal risk factors (family history, behavioral exposure) and symptoms (weight loss, fatigue, jaundice, bleeding, etc.) of liver disease.

2. Physical examination can reveal important signs of liver disease, such as jaundice, spider angiomas, ascites, and liver enlargement and tenderness.



3. Marked increase in aminotransferases (ALT/AST) implies hepatocellular damage; increased alkaline phosphatase and bilirubin occurs with cholestasis.



4. Serum albumin levels and prothrombin time assess the functional status of the liver, specifically its synthetic function.



5. Blood tests for viral proteins or antiviral antibodies can confirm viral infection; blood tests can also be used to investigate autoimmune or metabolic diseases.



6. Liver biopsy is a safe outpatient procedure that may be useful in establishing the cause, stage of disease, and monitoring response to therapy.



7. Microscopic examination of a liver biopsy specimen can reveal characteristic patterns of inflammation, necrosis, and fibrosis.





History and Physical Examination

When patients present to physicians with suspected hepatic disease, a complete oral history is the first step in investigating potential causes. Physical findings on examination may provide additional clues both to the etiology and extent of disease.

1. History. Physicians can use the following questions to help diagnose suspected liver disease.



Family history of liver disease? Some liver diseases are inherited and therefore may be present in close relatives. Examples include genetic hemochromatosis and Wilson's disease.



Toxin exposure? Many medications can cause liver injury. Patients should provide a complete list of medications, including over-the-counter hepatotoxins such as aspirin, acetaminophen, and vitamin A. Also, alcohol use and potential environmental (e.g., wild mushrooms) and industrial (e.g., solvents) exposure should be discussed.



Risks for viral hepatitis? Contaminated water (or shellfish), personal contact with infected persons, or exposure via day-care centers or travel can lead to hepatitis A infection. Blood transfusions, accidental needle sticks (for health care workers), intravenous drug use, and sexual contact with infected persons are risks for hepatitis B and C infection, but wt to 40% of patients with hepatitis B or C do not have known risk factors.



Other systemic diseases? Certain diseases, such as severe heart failure and autoimmune disease, can affect the liver.



Weight loss or severe fatigue? Many patients with liver disease complain of fatigue, but weight loss may occur with cancer. An example would be the development of hepatocellular carcinoma in a patient with cirrhosis.



Pruritus or jaundice?



These usually occur with long-standing cholestasis and may be associated with dark urine and light stools. Examples include cancers of the pancreas and bile ducts (often painless) or impacted gallstones (painful).



Bleeding from the nose, gums, skin, or gut? Patients with severe liver disease develop bleeding problems and may report previous history of variceal bleeding (signifying portal hypertension).



Confusion or poor sleep? These are clues to hepatic encephalopathy, which may occur in patients with hepatic dysfunction and portosystemic shunting.



Abdominal distention? This may be caused by the development of ascites.



2. Physical Examination. Careful examination of the patient may provide clues to the potential cause of liver dysfunction. Many findings, such as an enlarged liver, suggest the presence of hepatic disease even when it is not initially suspected. Additionally, a physical exam may reveal signs of portal hypertension, such as ascites, that help the physician assess disease severity. Particular findings associated with liver disease are described below.



a. Skin. Some common skin signs of liver dysfunction are apparent even to the untrained eye, and many prompt the patient to seek medical attention.



Jaundice. Jaundice (yellow discoloration of the skin and whites of the eyes) is due to the deposition of excess bilirubin. It is also called icterus. As described previously, jaundice usually suggests hepatocellular damage or bile duct obstruction. Scratch marks on the skin suggest pruritus (itching), a symptom that often accompanies hyperbilirubinemia.



Spider angiomas. Spider angiomas are red tufts of fine blood vessels, which blanch with pressure, oriented in a spider pattern on the trunk, face, forearms, and hands. They are often present in patients with cirrhosis and are possibly due to increased levels of circulating estrogens (decreased clearance and breakdown by the liver).



Palmar erythema. This refers to reddening of the palms of the hands and finger tips; it is most frequently associated with alcoholic liver disease.



Edema. Edema is fluid accumulation, commonly in the subcutaneous tissues of the lower legs, due to salt and water retention in patients with cirrhosis.



b. Abdomen. Abdominal signs of liver dysfunction range from obvious to subtle.



Ascites. Ascites is fluid accumulation in the abdomen that results in abdominal distention and bulging flanks. Its presence signifies severe liver disease, usually cirrhosis.



Liver abnormalities. These may give important clues to the type and extent of disease. The liver may be abnormally enlarged (hepatomegaly); firm, nodular, and small (cirrhotic); large and tender (acute hepatitis); or rock hard (cancer). It is important to assess and document liver size on physical exam, but the presence of ascites may make this difficult.



Spleen enlargement. Spleen enlargement (splenomegaly) is present whenever one can feel the spleen protruding beneath the left rib cage. This is generally due to portal hypertension and congestion of the splenic vein.



Caput medusae. Caput medusae are dilated veins in the abdominal wall, radiating from the umbilicus (navel), that develop as portosystemic collateral vessels due to portal hypertension associated with cirrhosis.



c. Eyes. Two distinctive signs of liver dysfunction concern the eyes: jaundice and Kayser-Fleischer rings. Jaundice is apparent in the whites of the eyes of patients with hyperbilirubinemia, as noted above. Kayser-Fleischer rings are golden-brown rings within the cornea of the eye (seen over the iris) that result from the deposition of copper in patients with Wilson's disease.



d. Other findings. Manifestations of liver disease may also be apparent in the hands (clubbing or nail changes), testicles, and breasts. Asterixis and fetor hepaticus are changes associated with hepatic encephalopathy.



Clubbing. Clubbing, or bulbous enlargement of the fingertips, may develop in patients with cirrhosis; it is also present in many other conditions.



Nail changes. Nail changes such as "whitening" of the nail beds may occur in cirrhotic patients.



Testicular atrophy (shrunken testicles) / gynecomastia (painful swelling of the breasts). These are most commonly associated with alcoholic liver disease and may be due to increased levels of circulating estrogens.



Asterixis. Asterixis, also called "liver flap," is a forward flapping of the hand when the arm is extended and the hand is flexed backward. It is associated with hepatic encephalopathy.



Fetor hepaticus. This is a musty, sweetish breath odor that may develop in patients with severely advanced liver disease or encephalopathic coma.





Laboratory Tests of Liver Function

Laboratory studies serve three general purposes in investigating liver disease. First, specific patterns of laboratory values can help assess hepatic inflammation and distinguish hepatocyte necrosis from cholestasis. Tests that measure proteins synthesized by the liver or liver enzymes provide functional parameters. Finally, specific tests, such as viral markers, can be used to confirm certain diseases such as viral hepatitis.

1. Liver Cell Injury / Necrosis. Aminotransferases (also called transaminases ) are enzymes that catalyze protein transformations within hepatocytes. Aspartate transaminase (AST, also called SGOT) is found in liver, muscle, kidney, and brain, whereas alanine transaminase (ALT, also called SGPT) is found predominantly in the liver. A measurable increase in these enzymes in the blood signifies hepatocyte damage or death (hepatocellular necrosis) from such causes as viral hepatitis, toxin-induced hepatic necrosis, and ischemia.



Normal serum levels are 10 to 40 U/L (units per liter), but this range varies by lab. The ratio of these enzyme levels is also useful, since the selective toxic effect of alcohol typically results in greater elevations of AST relative to ALT.



2. Bile Formation and Flow. Obstruction of bile flow (cholestasis) results in increased alkaline phosphatase and bilirubin levels more than aminotransferases. Alkaline phosphatase is an enzyme in the membrane of biliary ductular cells, but it is also found in other tissues, such as bone. Normal values range from 36 to 92 U/L (varies by lab). Bilirubin is a breakdown pigment of red blood cells; its normal value is less than 1.2 mg/dL.



A marked increase in alkaline phosphatase, with normal or mildly increased bilirubin and AST/ALT levels, occurs when the liver is infiltrated by cancers, fungi, or other invaders. Marked increase in both alkaline phosphatase and bilirubin, with normal or a mild increase in AST and ALT levels, suggests cholestasis.



3. Protein Synthesis. Serum albumin and prothrombin time reflect the true "functional" status, or synthetic function, of the liver.



Serum albumin transports substances in the blood and helps hold water within blood vessels. Normal range is 3.1 to 4.3 g/dL, and half-life (time for a measurable 50% decrease) is about 20 days. Therefore, decreases in albumin levels occur over weeks, not days.



Prothrombin time (PT) is a standardized test that measures the ability of blood to clot, measured in seconds (normal range: 8.8 to 11.6 seconds). An increase in PT reflects poor clotting, due to fewer circulating clotting factors. The half-life of coagulation factors is short, generally hours.



4. Other Tests. Many other laboratory studies target specific etiologies of acute or chronic liver disease, including viral infections, autoimmune diseases, and inherited metabolic diseases.



a. Tests for viral infection. Antibodies against hepatitis A, B, and C detected in the blood generally reflect infection by these viruses. For HAV and HBV, detectable antibody signifies recovery and immunity to reinfection. However, current assays for anti-HCV antibodies do not correlate with the course of disease or immunity. For viruses for which vaccines are available, antiviral antibodies may indicate vaccination rather than natural infection.



Tests can also detect viral proteins, such as the hepatitis B surface antigen (HBsAg), which is present during acute and active infection. Further, it is now possible to test for HBV and HCV by measuring viral DNA.



Seroconversion refers to the transition from an antibody-negative to an antibody-positive state and usually implies recovery from infection. For example, during acute infection with hepatitis B, a test for HBsAg in the blood is positive, indicating circulating virus. With recovery, the test for surface antigen changes from positive to negative, and the test for antibody to the surface antigen from negative to positive, indicating elimination of virus due to a successful immune response. These patients are then immune to reinfection with HBV.



b. Tests for autoimmune diseases. Autoimmune diseases are usually charancterized by the presence of antibodies directed against self-antigens. Examples of such antibodies are:



?antinuclear antibodies directed against nuclear proteins of cells; may be present in autoimmune hepatitis ?antimitochondrial antibodies directed against a cell component called mitochondria; present in over 90% of patients with primary biliary cirrhosis



?antibodies directed against liver-kidney microsomes (anti-LKM) are found in certain types of autoimmune liver diseases and high titers of anti-LKM in these conditions may be predictive of responsiveness to treatment with glucocorticoids.



c. Tests for inherited metabolic diseases. Genetic disorders such as hemochromatosis, Wilson's disease, and alpha 1 - antitrypsin deficiency can be detected by laboratory measurement of the affected substance or associated protein.



?iron: patients can be screened for hemochromatosis by measuring blood iron levels; if levels are elevated, confirmation can be obtained by liver biopsy to quantify the liver iron content



?alpha 1 - antitrypsin: levels are decreased in alpha 1 -antitrypsin deficiency



?ceruloplasmin: this copper carrier protein is usually decreased in patients with Wilson's disease; low levels can be confirmed by liver biopsy to assess liver copper content