Friday, September 6, 2013

Interpreting and Correlating Abnormal Laboratory Values : Liver Function Tests

The most common liver test abnormalities can be summarized to a set of six conditions as in Table 1. The principles for these patterns are explained as follows.
  
1.   
All acute injuries and/or necrotic lesions in the liver primarily cause a marked rise in the levels of the aminotransferases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Cell injury and necrosis also cause the rise of other enzymes such as lactate dehydrogenase (LD). These include acute hepatitis
(e.g., infectious and chemically induced), infarction, and trauma. The biliary tract is always affected so that direct bilirubin rises from interference with bile flow. Because of biliary tract injury, the enzyme alkaline phosphatase rises along with gamma-glutamyl transferase (GGT) and 5′-nucleotidase (5′-N). Hepatocyte injury causes loss of conjugation of transported bilirubin, so that indirect (unconjugated) bilirubin also rises. Because, generally, in hepatitis, much less than 80% of the liver is destroyed, total regeneration will occur and enough tissue is present to enable adequate levels of protein synthesis and ammonia fixation as urea. Therefore, the total protein and albumin and ammonia levels remain normal. These typical results are summarized in condition 1 of Table 1.
  
2.   
Cirrhosis of the liver is characterized by two cardinal features: fibrosis, preventing regeneration of liver tissue wherever this has occurred and nodules of regenerating liver tissue, which are the only source of any kind of hepatocytic function. Thus, in cirrhosis, almost the reverse pattern occurs from the one seen in condition 1 in Table 8-5 for hepatitis. Because, in panhepatic cirrhosis, there is destruction of >80% of liver tissue, with no regeneration of damaged liver tissue, the AST/ALT aminotransferases and LD levels (all from the regenerating nodules) tend to be normal or low or occasionally mildly elevated. However, the total protein and albumin are both abnormally low. The ammonia levels are elevated. Because there is insufficient viable liver tissue remaining, and because fibrosis destroys the cholangioles, both indirect and direct bilirubin tend to be elevated. These findings are summarized in condition 2 of Table 1.
  
3.   
Acute biliary obstruction caused by stones in the biliary tree or by neoplasms that block bile excretion, results in elevations in direct bilirubin and biliary tract alkaline phosphatase, along with the enzymes, GGT and 5′-N (see above). All other liver function test results are normal. For simple biliary obstruction, therefore, the pattern is as shown in condition 3 of Table 1.
  
4.   
Space-occupying lesions of the liver are characterized, for reasons that are not well understood, by isolated elevations of the enzymes, alkaline phosphatase and LD. This pattern is shown in condition 4 of Table 1. The most common cause of this condition is metastatic carcinoma to the liver.
  
5.   
Passive congestion of the liver is characterized by a mild elevation of aminotransferases (AST/ALT) and LD and, in more severe cases, elevations of total bilirubin and alkaline phosphatase. This pattern is also seen in infectious mononucleosis, where the rise in bilirubin may be marked. The general passive congestion pattern is shown in condition 5 of Table 1.
  
6.   
Acute fulminant hepatic failure from a variety of causes which include Reye's syndrome and hepatitis C. This condition is total liver failure. The overall pattern is shown in condition 6 of Table 1. It appears as a combination of hepatitis and cirrhosis. Here AST and ALT reach exceptionally high values, often in excess of 10 000 IU/L. At the same time, total protein and albumin are markedly reduced, and the ammonia levels are abnormally elevated, causing hepatic encephalopathy. LD, alkaline phosphatase and bilirubin are also elevated. Besides the marked rise in AST and ALT, combined with hyperammonemia, there is a characteristic disproportional rise of AST over ALT, further confirming the diagnosis. It is vital to recognize this pattern because the underlying condition is a medical emergency which must be treated promptly.

Table 1 : Six Fundamental Patterns of Liver Function Tests
Condition
AST
ALT
LD
ALP
TP
Albumin
Bilirubin
Ammonia
1. Hepatitis
H
H
H
H
N
N
H
N
2. Cirrhosis
N
N
N
N–sl H
L
L
H
H
3. Biliary obstruction
N
N
N
H
N
N
H
N
4. Space-occupying lesion
N or H
N or H
H
H
N
N
N–H
N
5. Passive congestion
Sl H
sl H
sl H
N–sl H
N
N
N–sl H
N
6. Fulminant failure
Very H
H
H
H
L
L
H
H

H = high; N = normal; L = low; sl = slightly; AST = aspartate aminotransferase; ALT = alanine aminotransferase; LD = lactate dehydrogenase; ALP = alkaline phosphatase; TP = total protein.

Correlations of Liver Function Test Results with Other Laboratory Findings

In severe liver failure, secondary to cirrhosis or to fulminant hepatic failure, it is not uncommon to find electrolyte abnormalities and abnormalities in renal function tests, and in the coagulation profile. Patients with either conditions 2 or 6 in Table 1, often have ascites, with marked third space fluid loss. This results in increased levels of both ADH and aldosterone to retain intravascular water. Depending on which levels ‘win out,’ the patient may become hypo- or hypernatremic.

Severe liver failure can also cause the hepatorenal syndrome, i.e., renal dysfunction secondary to hepatic failure. This disease is characterized by the typical patterns shown in conditions 2 and 6 in Table 1. As discussed in the renal section above, renal failure results in elevations in BUN and creatinine with a 10-20:1 ratio, indicative of renal failure. The Uosm/Posm ratio is < 1.2:1, indicating tubular dysfunction.

Severe coagulopathies with elevated APTTs and PTs may be seen due to the absence of production of coagulation factors. Not infrequently, DIC will accompany the liver failure. This condition must be distinguished from low coagulation factor production combined with hepatosplenomegaly due to portal hypertension as in cirrhosis. The splenomegaly may result in sequestration of platelets, so that the overall pattern may resemble DIC but not be true DIC. To clinch the diagnosis of DIC, there should be elevations of both D-dimer and fibrin split products (FSP) levels. Also, in severe liver failure, abnormal red cell forms, called target cells, may be seen in the peripheral blood smear.

Patients with cirrhosis and acute fulminant hepatic failure tend to be immunocompromised. Many of these patients have defective T cell function but produce an excess of (ineffective) immunoglobulin. Thus these patients tend to have low serum albumin levels from diminished albumin synthesis but elevated serum immunoglobulins.


(Source: McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods,21st ed.)
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