Demystifying the liver and its diseases

Hepatitis C virus (red) is an RNA virus that is transmitted through bodily fluids.
Hepatitis C virus (red) is an RNA virus that is transmitted through bodily fluids.

At a glance

  • Functions of the liver include protein synthesis, detoxification, and metabolic processes.

  • Liver problems are often discovered incidentally through routine laboratory testing or screening blood tests.

  • Liver disease can have either an infectious or noninfectious etiology, such as hepatitis, nonalcoholic fatty liver disorders, and drug-induced injury.

  • Patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis whose liver enzymes normalize after modificaiton of risk factors can be monitored conservatively and may avoid a liver biopsy.

  • Imaging is becoming more sensitive to fatty infiltration in the liver. Both ultrasonography and MRI can be useful.

The liver has a multitude of functions, including protein synthesis, detoxification, and metabolic processes. Problems in the liver are often discovered incidentally through routine lab testing or screening blood tests that include liver enzyme determinations. Abnormal results can make any practitioner nervous. Liver disease is like a puzzle: You need to put the pieces together to see the whole picture. 


Liver function tests


A more descriptively accurate term for liver function tests (LFTs) might be "liver injury tests." Some tests in the hepatic profile can tell you how well the liver is functioning. The most common determinations are those for bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin and alkaline phosphatase levels.

When an abnormal result is found, the clinician must figure out its origin. One of the most common reasons for referral to a hepatologist is elevated results on the LFTs. The tests most often found to have abnormal results include those for AST and ALT. 


Hepatocyte injury. For AST and ALT to become elevated, there must be injury to the hepatic tissues rich in these enzymes. The injury results in changes in cell permeability and leakage of AST and ALT into the blood. The more damage there is to the hepatocytes, the greater the leakage. ALT is more specific for liver injury than AST. Elevations in AST can also be the result of cardiac and muscle disease. 


Cholestasis. Patients with cholestasis will have elevations in their bilirubin, alkaline phosphatase (AP), and γ-glutamyltranspeptidase (GGT) levels. These elevations indicate damage to the bile ducts. AP is associated with the biliary tract but not specific to it. Elevations in AP can also be attributed to bone, placental and intestinal sources.

In the liver, AP is located in the hepatocyte membrane bordering the bile canaliculi. When this membrane is damaged, the enzyme is shed and AP levels in the blood become elevated. To help determine the etiology of an elevated AP level, the test can be fractionated into its various sources. This test will provide the concentration of AP attributable to each source as well as its percentage of the total. Depending on the laboratory, a normal AP level is usually <120 units/L. 


GGT, like AP, is not specific to the liver. Alcohol intake can also cause elevations in the GGT. Sometimes the GGT can help differentiate the AP level with a hepatic etiology from other sources. 


Bilirubin is a major breakdown product of hemoglobin and is derived from RBCs that have died and been removed by the spleen. During the degradation process, heme is separated out and the globin protein is transferred to the liver, where it is metabolized further in a process called conjugation.

Bilirubin that has gone to the liver and undergone further metabolic process is called conjugated bilirubin. This form of bilirubin is water-soluble and goes into the bile. The bilirubin that does not undergo this process is called unconjugated or indirect bilirubin.

On laboratory reports, the most commonly reported level is the total bilirubin. A patient who develops jaundice will typically have a total bilirubin level that is at least two to three times the upper limit of normal (normal level being <1.0 mg/dL). The total bilirubin level must be fractionated to further differentiate the causes of any abnormality. 


Synthetic function. The tests of synthetic function in the liver include prothrombin time (PT)/international normalized ratio (INR), platelet count and albumin level. Abnormal results indicate disease that has caused loss of proteins or inability to synthesize proteins. If a patient presents with hypoalbuminemia, thrombocytopenia (platelet count <150,000/µL) 
and/or an elevated INR, the clinician should add advanced liver disease or cirrhosis to the list of differentials. 


Other liver disorders. The last two liver tests worthy of mention are miscellaneous assays of the ammonia and the α-fetoprotein (AFP) levels. An ammonia level is usually measured when a patient presents with acute changes in mental status because ammonia can cross the blood-brain barrier and become toxic to the brain. In liver disease, ammonia may build up because the liver cannot process it quickly enough or because an enzyme that breaks down the ammonia is absent or is present only in insufficient quantities. This can lead to hepatic encephalopathy in the patient with cirrhosis.

Ammonia levels, while useful, are primarily measured to rule out causes of changes in mental status. Ammonia levels are not always measured in hepatology practices. If the patient is mentating well, an elevated ammonia level may not mean anything. To use an old cliché, treat the patient, not the laboratory results. 


AFP is a tumor marker for hepatocellular carcinoma (HCC) in patients with liver disease. The normal AFP level is <20 ng/mL. Most patients with hepatitis C have AFP levels that are <100 ng/mL. Any elevation in AFP warrants further investigation. Most concerning are elevated levels that continue to climb or levels found to be significantly elevated on first screening (i.e., in the several thousand range). The latest guidelines from the American Association for the Study of Liver Diseases do not recommend using AFP alone as a screening or diagnostic tool for HCC.1,2

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