Liver Enzymes

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There are multiple biochemical tests commonly referred to as liver enzymes, but for the purposes of this chapter we will discuss only those that are readily available and used in routine clinical practice. Biochemical liver tests can be summarized as those that reflect injury and those that reflect synthetic or excretory function. This text will refer to liver function tests (LFTs) as those tests that reflect the latter, and will not refer to the enzymes that generally reflect injury, the aminotransferases. The most commonly used liver tests are bilirubin, alkaline phosphatase, and the aminotrans-

ferases. other less commonly used but useful tests are y-glutamyl transpeptidase (GGT), 5'-nucleotidase (5'NT), albumin, and prothrombin time (PT). Aminotransferase tests are for aspartate aminotransferase (AST), formerly serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT), formerly serum glutamic pyruvic transaminase, both of which participate in hepatic glu-coneogenesis. Leakage of these enzymes into serum occurs with hepatocyte injury and death. Whereas ALT is quite liver specific, AST is not and is also commonly found in skeletal and cardiac muscle tissue. A more complete description of each is given in Tables 104-1 and 104-2.

The aminotransferases are generally reflective of parenchymal liver injury, such as that seen with viral hepatitis, medication or toxin-induced injury, autoimmune hepatitis, and several infiltrative disorders, such as hemochromatosis, Wilson's disease, a-1-antitrypsin deficiency, and fatty liver disease. Of course, in some of these conditions, alkaline phosphatase and GGT can be elevated to some extent as well, but bilirubin is not elevated unless there is obstruction to bile flow or significant liver dysfunction or injury.

Alkaline phosphatase is a ubiquitous enzyme often elevated in disorders of the biliary tract, but can also be mildly elevated in various liver diseases primarily involving the parenchyma, possibly as a result of injury to small bile ducts. It can also be elevated as a result of normal physiology in pregnancy and childhood, and in pathologic bone conditions. Interestingly, alkaline phosphatase does not always rise immediately with bile duct obstruction. Elevations are not simply a "backwash" of the enzyme into the serum, but rather require upregulation of messenger ribonucleic acid for increased production of alkaline phos-phatase in response to bile duct epithelial injury.

GGT is an ubiquitous enzyme found in many organs including brain, intestine, heart, kidney, and the liver, but importantly not found in bone. Hence, its elevation suggests alkaline phosphatase elevation is not of bone origin. A more specific, but rarely used test is for 5'NT, which is also found in several organs but only released into plasma by the liver when injured. Hence, its elevation is very specific to the liver.

Bilirubin can be elevated for a myriad of reasons, some attributable to liver excretory dysfunction or significant

TABLE 104-1. Enzymes Reflecting Liver Injury

Lab Test

Physiologic Function

Source

Commonly Associated

Of Note

Pitfalls

Liver Abnormalities

AST

Catalyzes transfer of aminogroup

Liver, heart, kidney,

Viral hepatitis,

AST/ALT ratio > 2 typically

May be normal viral

from aspartic acid to ketoglutaric

pancreas,brain,

alcohol liver injury,

due to alcohol injury.

hepatitis or with

acid to produce oxaloacetic acid

RBC, WBC

ischemichepatic injury,

AST/ALT > 1 also seen

advancing fibrosis.

drug induced hepatitis,

in cirrhosis. ALT rarely

Falsely low with dialysis.

ALT

Catalyzes transfer of amino group

Liver

fatty liver disease,

> 300 U/L in chronic

Poor correlation with

from alanine acid to ketoglutaric

Wilson's disease,

conditions.

degree of liver necrosis in

acid to ketoglutaric produce

celiac disease,

acute setting.

pyruvic acid

a-1-Antitrypsin deficiency

LDH

Catalyzes interconversion

Heart, liver, kidney, Several isoenzymes which can be measured.

of lactate and pyruvate

muscle, brain, blood Poor specificity for liver disease,

cells, lungs, necrotic and not useful overall.

conditions, infiltrative

disorders, hemolysis,

muscle injury,

malignancies

ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase; RBC = red blood cells; WBC = white blood cells.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase; RBC = red blood cells; WBC = white blood cells.

liver injury, and at other times, not related to the liver at all. The most important reasons for bilirubin elevation are obstructive disorders of bile flow and hepatic dysfunction, which may be mild or indicative of liver failure. The latter is generally accompanied by other signs, including cognitive and psychomotor dysfunction and coagulation disorders. Liver related disorders such as congenital hyperbilirubinemias (Tables 104-2 and 104-3) are characterized by bilirubin abnormalities due to enzyme deficiencies but are not reflective of liver failure or synthetic dysfunction per se.

A general scheme of the proper workup and diagnosis of disorders associated with patterns of liver disease is outlined in Figure 104-1. Although this is simplified, it does reflect the thought process one should have when assessing elevated enzymes. The old axiom of rechecking abnormal enzymes to confirm chronicity holds true, but enzymes are rarely spuriously elevated without some underlying pathology, even if the pathology is transient, such as idiosyncratic medication-induced injury. Occasionally enzymes may be elevated with systemic disease and not reflect underlying liver disease, but these situations are generally understood because of other

AST/ALT

Bilirubin alone

Alkaline phos ± bilirubin

Mixed

Fractionate bilirubin

Conjugated

Ultrasonography

Ultrasonography

Biliary tract dilation

History specific tests/serology

Unconjugated

Evaluate for hemolysis

Normal

Check AMA

Biliary tract dilation

ERCP

Mass

Liver biopsy.

CT/MRI

FIGURE 104-1. A general scheme of the proper workup and diagnosis of disorders associated with patterns of liver disease. ALT = alanine aminotransferase; AST = aspartate aminotransferase; CA = cancer antigen; CEA = carcinoembryonic antigen; CT = computed tomography; ERCP = endoscopic retrograde cholangiography; MRI = magnetic resonance imaging.

TABLE 104-2. Liver Tests Reflecting Cholestasis and Biliary Tract Disorders

Laboratory

Physiologic Function

Source

Commonly Associated

Of Note

Pitfalls

Test

Liver Abnormalities

Bilirubin,

Bilirubin glucoronide,

Liver

Liver necrosis, PBC/PSC,

Prognostically useful

Value of conjugated

conjugated

results from conjugation

cirrhosis,

in alcohol liver disease,

bilirubin may be

of bilirubin in the liver.

intrahepatic cholestasis

PSC, PBC; Renally

overestimated with diazo

Water soluble.

due to drugs or genetic

excreted, so rarely

method of measurement;

abnormality, sepsis,

> 30 mg/dL with

Often elevated in sepsis

bilary tract obstruction

normal renal function

or postoperative

situations in setting

of no liver disease

Bilirubin,

Organic anion from

RBC

Hemolysis

Sustained hemolysis will not

unconjugated

hemoglobin degradation.

breakdown

Physiologic

result in value > 5 mg/dL

Lipid soluble

Defects in

jaundice of newborn

in setting of normal liver

hepatic conjugation

Inherited defects of

function

or uptake

bilirubin uptake

Alkaline

Group of glycoprotein

Liver, bone,

Cholestatic liver diseases

Coded by four genes

Multiple sources; Exact

hosphatase

isoenzymes that catalyze

kidney, intestines,

Obstruction of bile flow

Immunologically distinct

physiologic function not

hydrolysis of phosphate esters

placenta, cancers,

Infiltrative disorders of liver

Found on plasma membranes

clear; Degree of elevation

WBCs

Malignancies

Elevations due primarily to

often does not correlate

increased synthesis in

with clinical finding

obstructive liver disease, not

impairedexcretion in bile

GGT

Catalyzes transfer of y-glutamyl

Liver, spleen,

Cholestatic liver disease,

Membrane associated and found Found in many tissues

groups of peptides to other

kidney, brain,

alcohol injury, biliary tract

in biliary tree; Catalyzes

Sometimes not elevated

amino acids

heart, lung,

disease

metabolism of glutathione

with alkaline phosphatase

pancreas, seminal

conjugates with some

in liver disease

vesicles

xenobiotics

Elevated with alcohol

use in some patients and

with certain medications

5'NT

Catalyzes hydrolysis of

Liver, intestines,

Cholestatic disease

Physiologic significance not

Not readily available

nucleotides by releasing

brain, heart,

where alkaline phosphatase

known; Although found in

through all laboratories

phosphate from pentose ring

vascular tissue,

is elevated

several tissues, only released

pancreas

from plasma membranes of

hepatobiliary tissue with injury

GGT = y-glutamyl transpeptidases; 5'NT = 5' nucleotidase; PBC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis; RBC = red blood cell; WBC = white blood cells.

GGT = y-glutamyl transpeptidases; 5'NT = 5' nucleotidase; PBC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis; RBC = red blood cell; WBC = white blood cells.

TABLE 104-3. Liver Disorders and Associated Laboratory Test Abnormalities

Conjugated Bilirubin

Unconjugated Bilirubin

Alkaline Phosphatase

Aminotransferase

Hepatitis, cirrhosis, biliary Hemolysis, tract obstruction, Dubin-Johnson syndrome, Rotor's syndrome, intrahepatic cholestasis

Physiologic (pregnancy, childhood), Hepatobiliary disorders, Viral hepatitis, medications, physiologic jaundice of newborn, Gilbert's syndrome, Crigler-Najjar syndromes, medications biliary tract disease, infiltrative disease, malignancy, bone disorders pancreatitis, alcohol, renal disease, medications herbs/supplements, alcohol, autoimmune hepatitis, hemochromatosis, wilson disease, a-1-antitrypsin deficiency, endocrinologic disorders, celiac disease

GGT = y-glutamyl transpeptidases.

circumstances. In other words, enzymes should be evaluated in conjunction with a careful history and examination of the patient, the information from which is invaluable to making sense of the enzyme abnormalities. For example, in a patient with elevated aminotransferases and a history of intravenous drug use, HC is a common finding. Rechecking the enzymes several months later to see if the abnormality persists is not necessary prior to checking viral hepatitis serologies, because the risk factor for enzyme elevation has been assessed. Likewise, in an individual with newly elevated enzymes soon after beginning therapy with a known potential hepatotoxin, such as a nonsteroidal anti-inflammatory drug (NSAID) or lipid-lowering agent, the diagnosis becomes slanted in favor of drug hepatotoxicity.

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