Laboratory Tests And Diagnostic Procedures in

Hepatobiliary Disease
Patricia Liu, M.D.

Liver function tests are best utilized in concert with the clinical situation and in conjunction with
serial determinations to ascertain the cause or evolution of the hepatic disorder. In addition, stool
and urine tests, radionuclide imaging, contrast cholangiography (transhepatic cholangiography and
endoscopic retrograde cholangiopancreatography), and histological assessment (liver biopsy) are
often utilized to delineate the nature of the liver disease.

Serum Enzymes (Serum Aminotransferase Transaminases)

Serum glutamic oxaloacetic transaminase, also referred to as aspartate aminotransferase, and

serum glutamic pyruvic transaminase, also called alanine aminotransferase (AST and ALT) are
commonly employed to ascertain liver function. Striking elevations in the serum levels of these
two enzymes are encountered in acute viral hepatitis, acute drug- or toxin-induced liver damage,
and ischemic hepatitis. In addition, levels exceeding 500 IU/L and, on rare occasions, 1,000 IU/L
can also be seen in patients with severe chronic active hepatitis, transiently in patients with
common bile duct stones, and in patients with Budd-Chiari and veno-occlusive disease.

There are a number of important hepatic disorders in which the serum AST and ALT are normal
or minimally elevated . These include idiopathic genetic hemochromatosis, methotrexate-induced
liver injury, liver dysfunction due to amiodarone, the liver disease associated with jejunal ileal
bypass surgery, and patients with chronic hepatitis C virus infection.

The ratio of AST and ALT is also sometimes of value in clinical practice. A ratio greater than 2
with both AST and ALT being less than 300 IU/L is characteristic of alcoholic liver disease.

On rare occasions, if both the AST and ALT are elevated, patients are subjected to a liver biopsy
after a very thorough serologic workup only to find that the liver histology is completely normal.
It is very important to exclude a primary muscle disorder in such patients since not only the AST
but also the ALT can be elevated in patients with muscle disorders.

Serum Alkaline Phosphatase

The sources of serum alkaline phosphatase include liver, bone, small intestine, placenta, and, on
rare occasions, tumors capable of producing alkaline phosphatase.

In general, patients with cholestasis have increased levels. However, the level of serum alkaline
phosphatase is not helpful in distinguishing intrahepatic from extrahepatic cholestasis. Rarely,
patients with hypernephroma and Hodgkin's disease have elevated levels in the absence of liver
involvement. Also, patients with Wilson's disease often have normal values.
On rare occasions, patients with a variety of malignant tumors have elevations in the serum
alkaline phosphatase level that are not caused by liver or bony metastases. This isoenzyme,
referred to as Regan isoenzyme, is biochemically and immunologically indistinguishable from
placental alkaline phosphatase, and in addition to being present in serum, can also be present in
tumor tissue or in malignant effusion fluids.

In normal children with active bone growth, influx of enzyme from osteoid tissue may result in a
threefold elevation above normal in alkaline phosphatase values. In the third trimester of
pregnancy, the serum level may double as a consequence of the contribution of placental alkaline
phosphatase, making interpretation of results of this test difficult during the latter stage of
pregnancy. Also, persons over the age of 50 years may normally have one and a half times normal
values. Subjects with blood groups O and B, who are ABH secretors and Lewis antigen-positive,
may have a significant amount of intestinal alkaline phosphatase in their serum, especially after
ingestion of a fatty meal. Thus, unlike other enzymes in the serum, the activity of alkaline
phosphatase can be noticeably affected by eating; hence, it is recommended that alkaline
phosphatase activity be assayed in the fasting state.

Although an elevation of the serum alkaline phosphatase level may be the first clue to
hepatobiliary disease, the alkaline phosphatase level is normal on rare occasions despite extensive
metastatic hepatic deposits or complete bile duct obstruction.

Patients with stage I or II Hodgkin's disease, hypernephroma, congestive heart failure, myeloid
metaplasia, peritonitis, diabetes, subacute thyroiditis, or uncomplicated gastric ulcer have been
reported to have mild elevations in serum alkaline phosphatase levels that are of probable liver
origin in the absence of overt liver involvement. Recently, twofold to fourfold elevations in serum
alkaline phosphatase levels were reported in several members of a family. No bone or hepatic
disorder was present in this family, who demonstrated the enzyme elevation in a pattern
suggesting autosomal dominant inheritance. In this context, the elevation of the serum alkaline
phosphatase level may be no more specific than that of an elevated sedimentation rate, and the
routine use of automated biochemical tests has indeed increased awareness of this phenomenon.

The most reliable method of determining the tissue origin of an elevated alkaline phosphatase level
is polyacrylamide gel electrophoresis. Since this is not routinely available in most clinical
laboratories and since methods using urea denaturation or heat inactivation are quite unreliable, it
is common practice to measure serum 5'-nucleotidase, or gamma glutamyl transpeptidase, when
dealing with an isolated or disproportionately elevated serum alkaline phosphatase level. In such
instances, elevations of the levels of any of these two enzymes generally imply that the source of
the elevated alkaline phosphatase level is hapatobiliary and not bony. 5'-nucleotidase levels may
increase in normal pregnancy, whereas gamma glutamyl transpeptidase levels do not. However,
commonly used drugs such as barbiturates, phenytoin, and alcohol may cause induction of hepatic
microsomal gamma glutamyl transpeptidase; therefore, an elevated serum level of this enzyme
does not necessarily imply frank liver cell injury. A disproportionately elevated serum gamma
glutamyl transpeptidase level for several days often follows moderate alcohol ingestion. This
finding is used by many physicians to detect alcohol abuse in patients who underestimate or deny
the ingestion of alcohol.
Serum Bilirubin

Most clinical laboratories use spectrophotometry to measure serum bilirubin. The normal value
for total bilirubin is less than 1 mg/dl. Two fractions - a conjugated or direct fraction (normally
less than 0.25 mg/dl) and an unconjugated or indirect fraction are obtained fairly routinely. It is
useful to classify hyperbilirubinemia into conjugated and unconjugated categories. Patients are
considered to have conjugated hyperbilirubinemia if greater than 50 percent of the elevated total
bilirubin level is conjugated, and categorized as having unconjugated hyperbilirubinemia if greater
than 80 percent of the total bilirubin level is unconjugated or indirect-reacting. Mild unconjugated
hyperbilirubinemia (total bilirubin level less than 5 mg/dl) is seen in Gilbert's disease
uncomplicated hemolytic disorders, and congestive heart failure. Mild conjugated
hyperbilirubinemia is a constant finding in the Dubin-Johnson and Rotor syndromes. Conjugated
hyperbilirubinemia of varying intensity is seen in a variety of liver disorders including acute viral,
drug-induced, and toxin-induced hepatitis, shock liver, and metastatic disease to the liver. Even in
fulminant hepatitis, the liver is capable of conjugating the bilirubin.

The height of the serum bilirubin level has no discriminative value in distinguishing intrahepatic
cholestasis from extrahepatic obstruction. Indeed, fairly marked elevations in total serum bilirubin
levels have been reported in patients with non-biliary tract sepsis. Although patients with
fulminant hepatitis may be anicteric, the level of serum bilirubin is of prognostic import in certain
conditions such as alcoholic hepatitis, primary biliary cirrhosis, and halothane hepatitis. In primary
biliary cirrhosis, persistent elevations of greater than 2.0 mg/dl in the serum total bilirubin level
usually occur late in the course of the disease and imply a poor prognosis. Bilirubin levels greater
than 10 mg/dl have been associated with a 60 percent mortality in patients with halothane
hepatitis.

Urine Bilirubin

The presence of bilirubin in the urine implies that it is direct bilirubin that is present, as indirect
bilirubin is tightly bound to albumin and hence not filtered by the normal kidney. This inexpensive
and sensitive test serves several functions: a positive result can rapidly confirm clinically suspected
hyperbilirubinemia; it implies hepatobiliary disease and excludes hemolysis; and it may provide an
early clue to the presence of hepatobiliary dysfunction, as presence of urine bilirubin often
antedates overt icterus.

Urine Urobilinogen

Urobilinogen results from the breakdown of conjugated bilirubin by intestinal bacteria. Normal
excretion in stool averages 100 mg per day. About 10 to 20 percent is absorbed into the portal
circulation, from where most of it undergoes entero-hepatic circulation. A small amount, usually
less than 2 mg per day, is excreted in the urine. Although urinary estimation is dependent upon
several factors including urine pH, rate of urine production, timing of collection (there is a diurnal
variation), and method employed, complete absence of urinary urobilinogen implies absence of
bilirubin in the intestine and strongly suggests complete bile duct obstruction. The passage of
clay-colored stools by the patient is equally meaningful. Increased urinary urobilinogen suggests
hemolysis or hepatic dysfunction.

Serum Lactate Dehydrogenase

Serum lactate dehydrogenase activity may arise from myocardium, liver, skeletal muscle, brain or
kidney tissue, and red blood cells. Therefore, an elevated serum 1actate dehydrogenase value is a
nonspecific finding. The hepatic origin (1aerate dehydrogenase 5) of serum lactate dehydrogenase
can be verified by isoenzyme determination. Increased lactate dehydrogenase levels are seen in
patients with a variety of hepatobiliary disorders including acute viral or drug hepatitis, congestive
heart failure, cirrhosis, and extrahepatic obstruction. Striking elevations in serum lactate
dehydrogenase and alkaline phosphatase levels are highly suggestive of metastatic disease to the
liver.

Serum Albumin and Globulin

Albumin is synthesized exclusively by hepatic parenchymal cells and has a serum half-life of about
20 days. Decreased levels in the serum can occur as a consequence of decreased synthesis or
excessive losses. The former occurs in patients with malnutrition or significant liver disease.
Hypoalbuminemia secondary to excessive loss of albumin is seen in patients with nephrotic
syndrome or protein-losing enteropathy.

A fall in the serum albumin level and a rise in levels of globulins, primarily gamma globulins, are
frequently seen in patients with chronic hepatitis or cirrhosis. Elevations in IgA levels are common
in alcoholic cirrhosis, and elevations in IgG levels are common in chronic active hepatitis.
Elevations in IgM levels are frequently seen in primary biliary cirrhosis; of the immunoglobulins,
only an elevation of the IgM fraction on immunoelectrophoresis has any significant specificity.

Diminished levels of alpha-l-globulins due to deficient alpha-1-antitrypsin activity can be

associated with chronic active hepatitis and cirrhosis in children and adults.

Coagulation Factors

All the clotting factors are synthesized by the liver, with the exception of factor VIII, which is
synthesized by reticuloendothelial cells and vascular endothelial cells. The half-life of these
coagulation factors is short, ranging from six hours for factor VII to five days for fibrinogen.
Therefore, acute liver injury often results in a prolongation of the prothrombin time, which is
dependent upon the activity of factors II, V, VII, and X. Factor VIII levels may be normal or
increased in severe hepatic injury; hence, assessment of factor VIII levels may help distinguish the
coagulopathy of liver disease from that secondary to disseminated intravascular coagulation where
factor VIII levels are generally decreased. Vitamin K-dependent factors include factors II, VII,
IX, and X. A prolongation of the prothrombin time beyond four seconds that of control despite
vitamin K administration (5 to 10 mg parenteral vitamin K; prothrombin time measurement
repeated 24 hours later) signifies fairly advanced liver disease. The prognostic significance of a
markedly elevated prothrombin time is exemplified by the 100 percent mortality reported in a
study of patients with halothane hepatitis who had a prothrombin time greater than 20 seconds.
Other clinically relevant aspects of abnormalities in coagulation include the necessity to correct
these factor deficiencies in patients with significant bleeding and the fact that certain procedures
such as percutaneous liver biopsy are contraindicated in patients with a significant coagulopathy.

Alpha Fetoprotein

Alpha fetoprotein is a unique alpha-l-globulin normally synthesized in large amounts by embryonic

liver cells and in trace amounts by fetal yolk sac cells and the fetal gastrointestinal tract. High
serum concentrations (greater than 500 ng/ml by radioimmunoassay) are present in 70 percent of
patients with primary hepatocellular carcinoma in the United States. Concentrations of this protein
fall dramatically in patients in whom partial curative hepatectomy is carried out. Serial
determinations aid in monitoring the response to therapy or detecting early recurrence.

Patients with yolk sac tumors with germ cell elements may also have high concentrations of alpha
fetoprotein. Modest elevations may be seen occasionally with other tumors, notably
gastrointestinal malignancies metastatic to the liver. Levels up to 500 ng/ml are seen during
pregnancy. High levels indicate multiple pregnancy, significant fetal neural tube defects, fetal
distress, or fetal death.

Serum Ferritin

Serum ferritin levels accurately reflect hepatic and total-body iron stores. However, the serum
ferritin can be elevated in a number of conditions, including idiopathic genetic hemochromatosis,
hepatocellular necrosis of any etiology (alcoholic liver disease, acute and chronic viral hepatitis,
drug-induced liver injury, obesity-related liver dysfunction), Hodgkin's disease, leukemia,
hyperthyroidism, uremia, and rheumatoid arthritis.

Measurement of serum iron concentration, percent transferrin saturation, and serum ferritin level
is the screening regimen currently recommended for idiopathic genetic hemochromatosis.

Serum Ceruloplasmin

Ceruloplasmin, a blue copper-containing glycoprotein is an acute-phase reactant. 95 percent of

patients with Wilson's disease have serum ceruloplasmin concentrations below 20 mg/dl. The
serum ceruloplasmin can be normal in 10 percent of patients with Wilson's and chronic active
hepatitis. It is also low in 10 percent of heterozygotes with Wilson's and low levels can also be
encountered in patients with nephrotic syndrome and protein-losing enteropathy.

Antimitochondrial Antibody

This autoantibody can be detected in the serum by a variety of methods including

immunofluorescence, double immunodiffusion, complement fixation, radioimmunoassay, and
enzyme-linked immunoassay. Mitochondrial antibodies are found in 0.8 to 1.6 percent of the
general population, 6 percent of patients with chronic active hepatitis, and 85 to 90 percent of
patients with primary biliary cirrhosis. Antimitochondrial antibodies are also found in a significant
number of asymptomatic relatives of patients with primary biliary cirrhosis and chronic active
hepatitis. Although the antibody titer has no discriminative value in distinguishing patients with
primary biliary cirrhosis from patients with a variety of other hepatobiliary disorders or
autoimmune conditions, recent studies suggest that the mitochondrial antibodies seen in disorders
other than primary biliary cirrhosis can be differentiated from those that appear to be specific for
primary biliary cirrhosis on the basis of characteristic immunofluorescent patterns that they
mediate in rat and human tissues or the effects of trypsin pretreatment of such tissue sections on
immunofluorescent staining. Mitochondrial antibodies directed against a purported specific
primary biliary cirrhosis antigen are believed to have high diagnostic relevance, and it has been
stated that when such antibodies are not detected in the serum, a diagnosis of primary biliary
cirrhosis should be made with caution and only after a careful period of clinical follow-up.
Mitochondrial antibodies appear to play no part in the pathogenesis of primary biliary cirrhosis
and provide no useful prognostic insight in this disorder.

Bile Acids

Serum levels of bile acids can be measured by sensitive chromatography techniques and
radioimmunoassays. Measurements can be made in the fasting state, two hours postprandially, and
following intravenous isotopic administration (bile acid tolerance test). The cost of the test and
the need for appropriate facilities in the laboratory limit the usefulness of these tests, which
currently appear to be not significantly superior to more routine and readily available tests. In
addition, an abnormal test result does not discriminate between hepatocellular and cholestatic liver
disease.

Blood Ammonia

Ammonia arises from bacterial degradation of nitrogenous contents (dietary protein, blood) in the
intestine. Although the blood and cerebrospinal fluid ammonia levels are elevated in most patients
with hepatic coma, there is a poor correlation between blood ammonia level and the degree of
hepatic encephalopathy. The correlation is better with arterial ammonia as compared with venous
ammonia, which may be increased by muscular exercise, seizure activity, or even clenching the
fist. Serial values of arterial ammonia are occasionally helpful in following individual patients.
Elevations in arterial blood ammonia levels have also been recognized in patients with
portosystemic shunting or inborn disorders of urea metabolism, and in patients following
ureteroileostomy. Blood ammonia measurements are of limited utility in the evaluation of most
patients with known hepatobiliary disease. Its greatest usefulness may be in evaluating patients
with coma or altered mental status of unclear cause. In such patients, an elevated arterial ammonia
concentration would suggest hepatocellular dysfunction as an important contributing factor.

Serum Lipids and Lipoproteins

Patients with cholestatic disorders (both intrahepatic and extrahepatic) frequently have an
elevation in the concentration of serum phospholipids and unesterified cholesterol, skin xanthomas
commonly appear if the total serum cholesterol level exceeds 450 mg/dl for longer than three
months. The major component of unesterified cholesterol is an abnormal low-density lipoprotein
designated lipoprotein X. Contrary to earlier claims, quantitation of serum lipoprotein X levels is
not helpful in distinguishing intrahepatic cholestasis from extrahepatic obstruction. Patients
with cirrhosis or malignant biliary obstruction who are malnourished may have low total serum
cholesterol levels.

Breath Tests

Several radiolabeled compounds have been used to assess hepatic function in humans. Most
studies have employed 14C aminopyrine. The test is inexpensive and entails minimal radioactive
exposure to patients (generally, less than 0.5 µCi per test) but should not be performed in children
or pregnant women. Studies in humans suggest that the aminopyrine test (14CO2 - a metabolic
product of the methyl group of aminopyrine - is measured) is an indirect measure of mixed-
function oxidase mass. Although not yet widely available, breath tests may emerge as excellent
non-invasive screening tests for detecting liver disease or prove useful in the periodic follow-up of
patients in whom liver biopsy is contraindicated.

Hepatic Scintiscanning

Technetium-99m sulfur colloid is taken up selectively by the reticuloendothelial cells and is used
occasionally in clinical practice. It often provides useful information regarding the size and shape
of the liver, although on occasion virtually no hepatic uptake of colloid is present in patients with
severe or far-advanced liver disease. Heterogeneous uptake of colloid by the liver with "shift" of
colloid to the spleen and vertebral bone marrow is characteristic but not specific for cirrhosis of
the liver. Focal defects of the liver are seen in many conditions, including hepatic cysts,
hemangiomas, abscesses, tumors, amyloidosis and "regenerative" cirrhotic nodules, and peliosis
hepatis. Lesions smaller than 2 cm in size and present deep within the hepatic parenchyma may
escape detection on liver scanning.

Hepatic scintiscanning may aid in the distinction between focal nodular hyperplasia and hepatic
adenoma, as scanning usually shows normal findings in the former condition, whereas a cold
defect is usually present in patients with a hepatic adenoma. Avid uptake by an enlarged caudate
lobe is characteristic of Budd-Chiari syndrome. In this condition, there is occlusion of the major
right and left hepatic veins. The caudate lobe has a separate arterial supply and venous drainage
and hence characteristically undergoes compensatory hypertrophy.

Hepatic scintiscanning is also useful in the evaluation of hepatic or splenic trauma (currently CT is
more often employed) and in the detection of remnant or accessory splenic tissue in patients who
have undergone splenectomy.

Hepatobiliary Scanning (Hida Scan)

Agents being used with increasing frequency for biliary scanning are technetium-99m-labeled
acetanilide iminodiacetic acid derivatives (dimethyl, paraisopropyl, and diisopropyl iminodiacetic
acids). These agents are rapidly taken up by functioning hepatocytes and excreted into the bile.
These radiopharmaceuticals are superior to Rose-Bengal as biliary scanners. In a broad sense,
they evaluate hepatic excretory function and the patency of the biliary tree. Adequate visualization
is often obtained in patients with serum bilirubin levels between 5 and 10 mg/dl. Nonvisualization
of the gallbladder within two hours with good visualization of the common bile duct is highly
suggestive of cystic duct obstruction or calculous cholecystitis. Caution in interpretation must be
exercised in those patients with concomitant hepatocellular dysfunction who' exhibit poor hepatic
uptake and concentration of the isotope. Dimethyl iminodiacetic acid scanning is thus most useful
in excluding cystic duct obstruction and acute cholecystitis if the gallbladder is clearly visualized.
Dimethyl iminodiacetic acid scanning has been used to demonstrate the gallbladder as the site of
the defect observed on the inferior border of the liver on technetium-99m sulfur colloid scanning.
Dimethyl iminodiacetic acid can also be used to diagnose choledochal cysts and demonstrate
biliary leaks or assess the patency of biliary-enteric shunts.

Angiography

Selective celiac, superior mesenteric, and hepatic angiography is employed in the evaluation of
selected patients with liver disease. Enlargement of the hepatic arteries, neovascularity,
arteriovenous shunting, and portal vein thrombosis are frequently encountered in patients with
primary hepatocellular carcinoma. However, differentiation from other primary hepatic lesions
such as focal nodular hyperplasia or angiosarcoma and from vascular metastatic tumors such as
hypernephroma, carcinoid, and choriocarcinoma is not always possible. Angiography may be
useful in defining the extent of tumor and delineating the anatomic vascular supply in preparation
for hepatic lobectomy. Angiography has been routinely performed prior to elective shunt surgery
for patients with variceal bleeding in order to define anatomy. Magnetic resonance angiography
may prove to be an adequate option in the future.

Ultrasonography

Ultrasound examination of the abdomen is a useful test in the evaluation of liver disease. It is
available in most hospitals, is inexpensive, and entails no radiation exposure to patients. Thus, it is
particularly applicable in the evaluation of liver and biliary tract disease in children and pregnant
women. Marked obesity and excessive intestinal gas can be limiting factors in obtaining good
resolution of the images. Ultrasound examination of the liver will often identify mass lesions 1 to
2 cm in size in the hepatic parenchyma and do this independent of hepatic function. The nature of
defects seen on technetium-99m sulfur colloid scanning - solid or cystic - can readily be
ascertained and it can facilitate guided aspiration of cysts or biopsy specimens of lesions.
Ultrasonography is an appropriate procedure for detecting gallstones and confirming the presence
of ascites; study in the fasting state is important. It is often used as the first test in the evaluation
of patients with cholestatic jaundice. Dilated bile ducts can be readily seen on ultrasound
examination in patients with mechanical extrahepatic biliary tract obstruction. Dilation of the bile
ducts may not be evident if the obstruction is incomplete or intermittent or if it has been present
for a short duration. Serial ultrasound examinations may provide valuable information in these
circumstances. The common bile duct is frequently dilated following cholecystectomy. Therefore,
an enlarged duct in this situation does not necessarily signify ongoing biliary tract obstruction.
Computed Tomographic Scanning

This modality is useful in detecting mass lesions (cysts, tumors, abscesses) within the liver, and
computed tomographic scanning with contrast enhancement can often accurately predict the
nature of the lesion identified. It has an advantage over ultrasound in obese patients and those
with excessive gas, but its widespread use is limited by the high cost; an additional consideration
is radiation exposure to patients. In patients with cholestatic jaundice, computed tomographic
scanning can distinguish intrahepatic cholestasis from mechanical extrahepatic obstruction with an
accuracy rate of 90 per cent. Computed tomographic scanning after intravenous injection of
iodinated contrast material has been reported to demonstrate hypertrophy of the caudate lobe,
stagnation of contrast material at the periphery of the liver, narrowing of the inferior vena cava in
its intrahepatic section, and failure of opacification of the major hepatic veins in patients with
Budd-Chiari syndrome. This constellation of findings appears to be specific for Budd-Chiari
syndrome, although further confirmatory experience is necessary before this diagnosis can be
confidently made in the absence of liver biopsy or venography.

Hepatic computed tomography has also been used to evaluate iron overload in the liver. It
appears to be moderately sensitive and highly specific for this purpose. However, liver biopsy with
quantitation of liver iron content remains the "gold test" in the diagnosis of hemochromatosis.

Computed tomographic scanning can also be useful in assessing liver fat content. Monoenergetic
computed tomographic scanning has been shown to accurately (good agreement with histologic
and chemical liver fat determination) predict liver fat content in patients with alcoholic liver
disease.

Magnetic Resonance Imaging (MRI)

This modality is useful in evaluating the extent of hepatic metastases. It is also of value in
assessing the patency of hepatic and portal veins and, hence, is a useful test in patients with
suspected Budd-Chiari syndrome and in patients with portal vein thrombosis. Hemangiomas of
the liver also have a characteristic MRI appearance. In patients with iron overload, a characteristic
black or hypointense liver is often encountered.

Percutaneous Transhepatic Cholangiography

Percutaneous transhepatic cholangiography using a "skinny" Chiba needle is performed in most

institutions by skilled radiologists. The success rate with multiple passes approaches 90 to 95
percent in patients with extrahepatic biliary tract obstruction and 70 percent in patients with
intrahepatic cholestasis and normal-sized bile ducts. Percutaneous transhepatic cholangiography
may be preferred over endoscopic retrograde cholangiopancreatography in patients with surgically
distorted gastroduodenal anatomy such as following hemigastrectomy and Billroth II anastomosis.
Marked ascites and irreversible coagulopathy are contraindications to this procedure. Serious
complications occur in about 5 percent of patients and include cholangitis, hemorrhage, bile
peritonitis, pneumothorax, and drug reaction, and are responsible for a 0.5 percent attendant
mortality.
Endoscopic Retrograde Cholangiopancreatography (ERCP)

This procedure is usually performed by a gastroenterologist and has a success rate of 80 to 90

percent in skilled hands. Serious complications occur in about 5 percent of patients and include
pancreatitis, instrumental injury, cholangitis, sepsis, and aspiration pneumonia. Endoscopic
retrograde cholangiopancreatography would appear to be the procedure of choice if
periampullary carcinoma, common duct stone, or postcholecystectomy biliary tract disease is
strongly suspected on clinical grounds. In patients with common duct stones, endoscopic
papillotomy can provide definitive therapeutic benefit.

Needle Biopsy of the Liver

Percutaneous needle biopsy of the liver is a commonly utilized and safe procedure that can be
performed at the bedside. It often provides precise and accurate tissue diagnosis without resorting
to general anesthesia and laparotomy, and most agree that it can be performed as an outpatient
procedure provided facilities are available for short-term observation and hospitalization should
the need arise. Accepted indications for liver biopsy include hepatocellular disease of uncertain
cause, unexplained hepatomegaly and/or splenomegaly, hepatic filling defects demonstrated by
radionuclide scanning, ultrasound examination, or computed tomographic scanning, chronic
hepatitis, fever of unknown origin, and staging of malignant lymphoma. Liver biopsy is often
helpful in the evaluation of patients with clinically suspected alcoholic liver disease to confirm the
diagnosis and ascertain the severity of damage to the liver and in the evaluation of patients with
portal hypertension. Liver biopsy is the single best "liver function test" (the gold standard) in
documenting hemochromatosis, Wilson's disease, certain varieties of glycogen storage disease and
type I Crigler-Najjar syndrome. Liver biopsy is not particularly helpful in distinguishing
intrahepatic from extrahepatic obstruction. Although liver biopsy is not apparently associated
with an excessive risk of complications in patients with extrahepatic obstruction, the
pathognomonic features of extrahepatic obstruction - a bile infarct with feathery degeneration of
surrounding hepatocytes - are not invariably present. Additionally, it provides no information
regarding the site or nature of the obstructing lesion. With the advent of imaging modalities to
visualize the extrahepatic biliary tree, needle biopsy of the liver is rarely performed today when
extrahepatic obstruction is suspected.

Contraindications for percutaneous needle biopsy of the liver include uncooperative or comatose
patients, hydatid cyst disease, hemangioma or angiosarcoma of the liver, right pleural disease or
local infection at the proposed biopsy site, and significant coagulopathy. Arbitrarily employed
contraindications include a prolongation of the prothrombin time greater than four seconds over
control, a partial thromboplastin time greater than 15 seconds over control, and a platelet count
less than 75,000/mm3. A bleeding time should be obtained in patients with borderline clotting
abnormalities or uremia, and in those taking antiplatelet drugs. In patients with a severe
coagulopathy, the transvenous (transjugular) approach may be used. In this technique, a catheter
is placed in the jugular vein and manipulated into a hepatic vein. If bleeding occurs, it occurs
within the vascular system itself.
Percutaneous needle biopsy of the liver is not contraindicated in amyloidosis unless the liver is
massively enlarged or there is an associated bleeding tendency. Tense ascites and severe anemia
are relative contraindications. Complications are numerous but rare and the overall mortality rate
is less than 0.02 percent. The incidence of complications appears to increase significantly if
multiple passes (greater than four using the percutaneous route) are employed. The most common
untoward effect is pain at the biopsy site or right shoulder. Moderate to severe pain with or
without hypotension usually manifests within the first three hours of the procedure. Serious
bleeding occurs in less than 0.3 percent of patients, although asymptomatic subcapsular or
intrahepatic hematomas are probably considerably more common. Extremely rare serious sequelae
include pneumothorax, hemothorax, hemobilia, arteriovenous fistula formation, and perforation of
colon or gallbladder. If suspicion for highly vascular tumors such as carcinoid is high, angiography
or nuclear medicine flow scanning should be performed before percutaneous biopsy. Suspected
primary hepatocellular carcinoma is not a contraindication to biopsy.

Liver biopsy in unsuspected echinococcal cyst disease can be followed by dissemination of

daughter scoleces or fatal anaphylaxis.

Peritoneoscopy and Laparotomy

Peritoneoscopy may be performed using local anesthesia and mild sedation. It permits adequate
visualization of the anterior surface of the liver, gallbladder, and stomach as well as parts of the
small intestine and colon. It has proved useful in the diagnosis by direct visual inspection and
directed needle biopsy of a variety of hepatic disorders including cirrhosis, hepatomegaly, hepatic
malignancy, and portal hypertension. Peritoneoscopy has helped in determining the cause of
ascites and in the staging of Hodgkin's disease. Contraindications include tense ascites, an
uncooperative patient, marked obesity, surgical abdominal scars, and severe coagulopathy.
Serious complications occur in 1 to 2 percent of patients and include air embolism, subcutaneous
emphysema, ascites leak, bowel perforation, and hemorrhage. The overall mortality rate is
approximately 0.03 percent.

Laparotomy is now seldom performed for the express purpose of diagnosing hepatobiliary
disease. On occasion, however, it is necessary to undertake this procedure to obtain biopsy and
culture material and perform operative cholangiography.

The increasing availability of and familiarity with the vast array of both noninvasive (eg,
ultrasonography, computed tomographic scanning, dimethyl iminodiacetic acid scanning, etc.) and
invasive (eg, skinny needle transhepatic cholangiography, endoscopic retrograde
cholangiopancreatography, angiography, liver biopsy, etc.) hepatic tests have resulted in the
infrequent use of peritoneoscopy and laparotomy for the evaluation of hepatobiliary disease.

References

1. Chopra S, Griffin PH: Laboratory tests and diagnostic procedures in evaluation of liver
disease. Am J Med 1985;79:221-230.
2. Kaplan MM: Alkaline phosphatase. N Engl J Med 1972; 286:200-202.

3. Schapiro JM, Smith H, Schaffner F: Serum bilirubin, a prognostic factor in primary

biliary cirrhosis. Gut 1979;20:137-140.

4. Blanckaert N, Kabra PM, Farina FA, Stafford BE, Marton LJ, Schmid R: Measurement
of bilirubin and its mono- and di-conjugates in human serum by alkaline methanolysis and
high performance liquid chromatography. J Lab Clin Med 1980;96:198-212.

5. Klion FM, Schaffner F, Popper H: Hepatitis after exposure to halothane. Ann Intern Med
1969; 71:467-477.

6. Howard JM, Ghent CN, Carey LS, Flanagan PR, Valberg LS: Diagnostic efficacy of
hepatic computed tomography in the detection of body iron overload. Gastroenterology
1983;84:209-215.

7. Elias E, Hamlyn AW, Jain S, et al: A randomized trial of percutaneous transhepatic

cholangiography with the Chiba needle versus endoscopic retrograde cholangiography
for bile duct visualization in jaundice. Gastroenterology 1976;71:439-443.

8. Mueller PR, Van Sonnenberg E, Simeone JF: Fine-needle transhepatic cholangiography:

indications and usefulness. Ann Intern Med 1982; 97:567-572.

9. Knauer MC: Percutaneous biopsy of the liver as a procedure for outpatients.

Gastroenterology 1978; 74:101-102.

10. Rösch J, Lakin PC, Antonovic R, Dotter CT: Transjugular approach to liver biopsy and
transhepatic cholangiography. N Engl J Med 1973; 289:227-231.

11. Perrault J, McGill DB, Ott BJ, Taylor WF: Liver biopsy: complications in 1000 inpatients
and outpatients. Gastroenterology 1978; 74:103-106.

12. Losowsky MS: Needle biopsy of the liver. A review. J R Soc Med 1982; 75:736-741.

13. Kaplan MM: Evaluation of hepatobiliary diseases. In: Stein JH, ed. and chief. Internal
Medicine,4th ed. Mosby-Yearbook, 1994; 544-552.

14. Bernardino ME, Galambos JT: Computed tomography and magnetic resonance imaging of
the liver. Sem Liv Dis 1989; 9:32-49.

15. Johnson CD: Magnetic resonance imaging of the liver: current clinical applications. Mayo
Clin Proc 1993; 68:147-156.

16. Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med
1997;126:137-145.