2547Approach to the Patient with Liver Disease CHAPTER 336

Portal areas of the liver consist of small veins, arteries, bile ducts, and

lymphatics organized in a loose stroma of supporting matrix and small

amounts of collagen. Blood flowing into the portal areas is distributed

through the sinusoids, passing from zone 1 to zone 3 of the acinus and

draining into the terminal hepatic veins (“central veins”). Secreted bile

flows in the opposite direction—that is, in a countercurrent pattern

from zone 3 to zone 1. The sinusoids are lined by unique endothelial

cells that have prominent fenestrae of variable sizes, allowing the free

flow of plasma but not of cellular elements. The plasma is thus in direct

contact with hepatocytes in the subendothelial space of Disse.

Hepatocytes have distinct polarity. The basolateral side of the hepatocyte lines the space of Disse and is richly lined with microvilli; it

exhibits endocytotic and pinocytotic activity, with passive and active

uptake of nutrients, proteins, and other molecules. The apical pole of

the hepatocyte forms the canalicular membranes through which bile

components are secreted. The canaliculi of hepatocytes form a fine

network, which fuses into the bile ductular elements near the portal

areas. Kupffer cells usually lie within the sinusoidal vascular space and

represent the largest group of fixed macrophages in the body. The stellate cells are located in the space of Disse but are not usually prominent

unless activated, when they produce collagen and matrix. Red blood

cells stay in the sinusoidal space as blood flows through the lobules,

but white blood cells can migrate through or around endothelial cells

into the space of Disse and from there to portal areas, where they can

return to the circulation through lymphatics.

Hepatocytes perform numerous and vital roles in maintaining

homeostasis and health. These functions include the synthesis of

most essential serum proteins (albumin, carrier proteins, coagulation

factors, many hormonal and growth factors), the production of bile

and its carriers (bile acids, cholesterol, lecithin, phospholipids), the

regulation of nutrients (glucose, glycogen, lipids, cholesterol, amino

acids), and the metabolism and conjugation of lipophilic compounds

(bilirubin, anions, cations, drugs) for excretion in the bile or urine.

Measurement of these activities to assess liver function is complicated

by the multiplicity and variability of these functions. The most commonly used liver “function” tests are measurements of serum bilirubin,

serum albumin, and prothrombin time. The serum bilirubin level is

a measure of hepatic conjugation and excretion; the serum albumin

level and prothrombin time are measures of protein synthesis. Abnormalities of bilirubin, albumin, and prothrombin time are typical of

hepatic dysfunction. Frank liver failure is incompatible with life, and

the functions of the liver are too complex and diverse to be subserved

by a mechanical pump; a dialysis membrane; or a concoction of infused

hormones, proteins, and growth factors.

LIVER DISEASES

While there are many causes of liver disease (Table 336-1), these

disorders generally present clinically in a few distinct patterns and are

usually classified as hepatocellular, cholestatic (obstructive), or mixed.

In hepatocellular diseases (such as viral hepatitis and alcoholic liver

disease), features of liver injury, inflammation, and necrosis predominate. In cholestatic diseases, such as gallstone or malignant obstruction,

primary biliary cholangitis (previously referred to as primary biliary

cirrhosis), and some drug-induced liver diseases, features of inhibition

of bile flow predominate. In a mixed pattern, features of both hepatocellular and cholestatic injury are present (such as in cholestatic forms

of viral hepatitis and many drug-induced liver diseases). The pattern

of onset and prominence of symptoms can rapidly suggest a diagnosis,

particularly if major risk factors are considered, such as the age and sex

of the patient and a history of exposure or risk behaviors.

Typical presenting symptoms of liver disease include jaundice,

fatigue, itching, right-upper-quadrant pain, nausea, poor appetite,

abdominal distention, and intestinal bleeding. At present, however,

many patients are diagnosed with liver disease who have no symptoms and who have been found to have abnormalities in biochemical

liver tests as a part of a routine physical examination or screening for

blood donation or for insurance or employment. The wide availability

of batteries of liver tests makes it relatively simple to demonstrate the

presence of liver injury as well as to rule it out in someone in whom

liver disease is suspected.

Evaluation of patients with liver disease should be directed at (1)

establishing the etiologic diagnosis, (2) estimating disease severity

(grading), and (3) establishing the disease stage (staging). Diagnosis

should focus on the category of disease (hepatocellular, cholestatic, or

mixed injury) as well as on the specific etiologic diagnosis. Grading refers

to assessment of the severity or activity of disease—active or inactive

as well as mild, moderate, or severe. Staging refers to estimation of the

point in the course of the natural history of the disease, whether early

or late; or precirrhotic, cirrhotic, or end-stage. This chapter introduces

general, salient concepts in the evaluation of patients with liver disease

that help lead to the diagnoses discussed in subsequent chapters.

■ CLINICAL HISTORY

The clinical history should focus on the symptoms of liver disease—

their nature, patterns of onset, and progression—and on potential risk

factors for liver disease. The manifestations of liver disease include

TABLE 336-1 Liver Diseases

Inherited hyperbilirubinemia

Gilbert syndrome

 Crigler-Najjar syndrome, types I

and II

Dubin-Johnson syndrome

Rotor syndrome

Viral hepatitis

Hepatitis A

Hepatitis B

Hepatitis C

Hepatitis D

Hepatitis E

 Others (Epstein-Barr virus

[mononucleosis] herpesvirus,

cytomegalovirus, adenovirus

hepatitis)

Cryptogenic hepatitis

Immune and autoimmune liver

diseases

Primary biliary cholangitis

Autoimmune hepatitis

Sclerosing cholangitis

Overlap syndromes

Graft-versus-host disease

Allograft rejection

Genetic liver diseases

α1

 Antitrypsin deficiency

Hemochromatosis

Wilson disease

 Benign recurrent intrahepatic

cholestasis

 Progressive familial intrahepatic

cholestasis, types I–III

 Others (galactosemia, tyrosinemia,

cystic fibrosis, Niemann-Pickdisease, Gaucher’s disease)

Alcoholic liver disease

Acute fatty liver

Acute alcoholic hepatitis

Laënnec cirrhosis

Nonalcoholic fatty liver

Steatosis

Steatohepatitis

Acute fatty liver of pregnancy

Liver involvement in systemic

diseases

Sarcoidosis

Amyloidosis

Glycogen storage diseases

Celiac disease

Tuberculosis

 Mycobacterium avium-intracellulare

infection

Cholestatic syndromes

Benign postoperative cholestasis

Jaundice of sepsis

 Total parenteral nutrition–induced

jaundice

Cholestasis of pregnancy

Cholangitis and cholecystitis

 Extrahepatic biliary obstruction

(stone, stricture, cancer)

Biliary atresia

Caroli disease

Cryptosporidiosis

Drug-induced liver disease

 Hepatocellular patterns (isoniazid,

acetaminophen)

 Cholestatic patterns

(methyltestosterone)

 Mixed patterns (sulfonamides,

phenytoin)

 Micro- and macrovesicular steatosis

(methotrexate, fialuridine)

Vascular injury

Sinusoidal obstruction syndrome

Budd-Chiari syndrome

Ischemic hepatitis

Passive congestion

Portal vein thrombosis

Nodular regenerative hyperplasia

Mass lesions

Hepatocellular carcinoma

Cholangiocarcinoma

Adenoma

Focal nodular hyperplasia

Metastatic tumors

Abscess

Cysts

Hemangioma

2548 PART 10 Disorders of the Gastrointestinal System

constitutional symptoms such as fatigue, weakness, nausea, poor appetite, and malaise and the more liver-specific symptoms of jaundice,

dark urine, light stools, itching, abdominal pain, and bloating. Symptoms can also suggest the presence of cirrhosis, end-stage liver disease,

or complications of cirrhosis such as portal hypertension. Generally,

the constellation of symptoms and their patterns of onset, rather than

a specific symptom, point to an etiology.

Fatigue is the most common and most characteristic symptom of

liver disease. It is variously described as lethargy, weakness, listlessness,

malaise, increased need for sleep, lack of stamina, and poor energy.

The fatigue of liver disease typically arises after activity or exercise and

is rarely present or severe after adequate rest; that is, it is “afternoon”

rather than “morning” fatigue. Fatigue in liver disease is often intermittent and variable in severity from hour to hour and day to day. In some

patients, it may not be clear whether fatigue is due to the liver disease

or due to other problems such as stress, anxiety, sleep disturbance, or

a concurrent illness.

Nausea occurs with more severe liver disease and may accompany

fatigue or be provoked by smelling food odors or eating fatty foods.

Vomiting can occur but is rarely persistent or prominent. Poor appetite

with weight loss occurs frequently in acute liver disease but is rare

in chronic disease except when cirrhosis is present and advanced.

Diarrhea is uncommon in liver disease except with severe jaundice, in

which a lack of bile acids reaching the intestine can lead to steatorrhea.

Right-upper-quadrant discomfort or ache (“liver pain”) occurs in

many liver diseases and is usually marked by tenderness over the liver

area. The pain arises from stretching or irritation of Glisson’s capsule,

which surrounds the liver and is rich in nerve endings. Severe pain is

most typical of gallbladder disease, liver abscess, and severe sinusoidal

obstruction syndrome (previously known as veno-occlusive disease)

but is also an occasional accompaniment of acute hepatitis.

Itching occurs with acute liver disease, appearing early in obstructive jaundice (from biliary obstruction) or drug-induced cholestasis

and somewhat later in hepatocellular disease (acute hepatitis). Itching

also occurs in chronic liver diseases—typically the cholestatic forms

such as primary biliary cholangitis and sclerosing cholangitis, in which

it is often the presenting symptom, preceding the onset of jaundice.

However, itching can occur in any liver disease, particularly once cirrhosis develops.

Jaundice is the hallmark symptom of liver disease and perhaps the

most reliable marker of severity. Patients usually report darkening of

the urine before they notice scleral icterus. Jaundice is rarely detectable

with a bilirubin level <43 μmol/L (2.5 mg/dL). With severe cholestasis,

there will also be lightening of the color of the stools and steatorrhea.

Jaundice without dark urine usually indicates indirect (unconjugated)

hyperbilirubinemia and is typical of hemolytic anemia and the genetic

disorders of bilirubin conjugation, the common and benign form being

Gilbert syndrome and the rare and severe form being Crigler-Najjar

syndrome. Gilbert syndrome affects up to 5% of the general population; the jaundice in this condition is more noticeable after fasting and

with stress.

Major risk factors for liver disease that should be sought in the clinical history include details of alcohol use, medication use (including

herbal compounds, birth control pills, and over-the-counter medications), personal habits, sexual activity, travel, exposure to jaundiced or

other high-risk persons, injection drug use, recent surgery, remote or

recent transfusion of blood or blood products, occupation, accidental

exposure to blood or needlestick, and familial history of liver disease.

For assessing the risk of viral hepatitis, a careful history of sexual

activity is of particular importance and should include the number

of lifetime sexual partners and, for men, a history of having sex with

men. Sexual exposure is a common mode of spread of hepatitis B and

D but is uncommon for hepatitis C. A family history of hepatitis, liver

disease, and liver cancer is also important. Maternal-infant transmission occurs with both hepatitis B and C. Vertical spread of hepatitis B

can now be prevented by passive and active immunization of the infant

at birth. Additionally, antiviral therapy during the third trimester of

pregnancy is now recommended for mothers with levels of HBV DNA

>200,000 IU/mL. Vertical spread of hepatitis C is uncommon, but there

are no reliable means of prevention. Transmission is more common

among HIV-co-infected mothers and is also linked to prolonged and

difficult labor and delivery, early rupture of membranes, internal fetal

monitoring, and a high maternal viral load. A history of injection drug

use, even in the remote past, is of great importance in assessing the

risk for hepatitis B and C. Injection drug use is now the single most

common risk factor for hepatitis C. Transfusion with blood or blood

products is no longer an important risk factor for acute viral hepatitis.

However, blood transfusions received before the introduction of sensitive enzyme immunoassays for antibody to hepatitis C virus in 1992

is an important risk factor for chronic hepatitis C. Blood transfusion

before 1986, when screening for antibody to hepatitis B core antigen

was introduced, is also a risk factor for hepatitis B. Travel to a developing area of the world, exposure to persons with jaundice, and exposure

to young children in day-care centers are risk factors for hepatitis A.

Tattooing and body piercing (for hepatitis B and C) and eating shellfish (for hepatitis A) are frequently mentioned but are actually types of

exposure that rarely lead to the acquisition of hepatitis.

Hepatitis E is one of the more common causes of jaundice in Asia

and Africa but is uncommon in developed nations. In endemic areas,

transmission is usually through exposure to fecally contaminated water.

Recently, non-travel-related (autochthonous) cases of hepatitis E have

been described in developed countries, including the United States.

These cases appear to be due to strains of hepatitis E virus that are

endemic in swine and some wild animals (genotypes 3 and 4). While

occasional cases are associated with eating raw or undercooked pork

or game (deer and wild boars), most cases of hepatitis E occur without

known exposure, predominantly in elderly men without typical risk

factors for viral hepatitis. Hepatitis E infection can become chronic in

immunosuppressed individuals (such as transplant recipients, patients

receiving chemotherapy, or patients with HIV infection), in whom it

presents with abnormal serum enzymes in the absence of markers of

hepatitis B or C.

A history of alcohol intake is important in assessing the cause of

liver disease and in planning management and recommendations. In

the United States, for example, at least 70% of adults drink alcohol to some degree, but significant alcohol intake is less common; in

population-based surveys, only 5% of individuals have more than two

drinks per day, the average drink representing 11–15 g of alcohol. Alcohol

consumption associated with an increased rate of alcoholic liver disease

is probably more than two drinks (22–30 g) per day in women and

three drinks (33–45 g) in men. Most patients with alcoholic cirrhosis

have a much higher daily intake and have drunk excessively for

≥10 years before onset of liver disease. In assessing alcohol intake, the

history should also focus on whether alcohol abuse or dependence is

present. Alcoholism is usually defined by the behavioral patterns and

consequences of alcohol intake, not by the amount. Abuse is defined

by a repetitive pattern of drinking alcohol that has adverse effects on

social, family, occupational, or health status. Dependence is defined by

alcohol-seeking behavior, despite its adverse effects. Many alcoholics

demonstrate both dependence and abuse, and dependence is considered the more serious and advanced form of alcoholism. A clinically

helpful approach to diagnosis of alcohol dependence and abuse is the

use of the CAGE questionnaire (Table 336-2), which is recommended

for all medical history-taking.

Family history can be helpful in assessing liver disease. Familial

causes of liver disease include Wilson disease; hemochromatosis and

TABLE 336-2 CAGE Questionsa

ACRONYM QUESTION

C Have you ever felt you ought to cut down on your drinking?

A Have people annoyed you by criticizing your drinking?

G Have you ever felt guilty or bad about your drinking?

E Have you ever had a drink first thing in the morning to steady

your nerves or get rid of a hangover (eye-opener)?

a

One “yes” response should raise suspicion of an alcohol use problem, and more

than one is a strong indication of abuse or dependence.

2549Approach to the Patient with Liver Disease CHAPTER 336

α1

 antitrypsin deficiency; and the less common inherited pediatric

liver diseases—that is, familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis, and Alagille syndrome. Onset of severe

liver disease in childhood or adolescence in conjunction with a family

history of liver disease or neuropsychiatric disturbance should lead to

investigation for Wilson disease. A family history of cirrhosis, diabetes,

or endocrine failure and the appearance of liver disease in adulthood

suggest hemochromatosis and should prompt investigation of iron

status. Abnormal iron studies in adult patients warrant genotyping of

the HFE gene for the C282Y and H63D mutations typical of genetic

hemochromatosis. In children and adolescents with iron overload,

other non-HFE causes of hemochromatosis should be sought. A family

history of emphysema should lead to investigation of α1

 antitrypsin

levels and, if levels are low, for protease inhibitor (Pi) genotype.

■ PHYSICAL EXAMINATION

The physical examination rarely uncovers evidence of liver dysfunction in a patient without symptoms or laboratory findings, nor are

most signs of liver disease specific to one diagnosis. Thus, the physical

examination complements rather than replaces the need for other

diagnostic approaches. In many patients, the physical examination is

normal unless the disease is acute or severe and advanced. Nevertheless, the physical examination is important in that it can yield the first

evidence of hepatic failure, portal hypertension, and liver decompensation. In addition, the physical examination can reveal signs—related

either to risk factors or to associated diseases or findings—that point

to a specific diagnosis.

Typical physical findings in liver disease are icterus, hepatomegaly,

hepatic tenderness, splenomegaly, spider angiomata, palmar erythema,

and skin excoriations. Signs of advanced disease include muscle wasting, ascites, edema, dilated abdominal veins, hepatic fetor, asterixis,

mental confusion, stupor, and coma. In male patients with cirrhosis,

particularly that related to alcohol use, signs of hyperestrogenemia

such as gynecomastia, testicular atrophy, and loss of male-pattern hair

distribution may be found.

Icterus is best appreciated when the sclera is inspected under natural light. In fair-skinned individuals, a yellow tinge to the skin may

be obvious. In dark-skinned individuals, examination of the mucous

membranes below the tongue can demonstrate jaundice. Jaundice is

rarely detectable if the serum bilirubin level is <43 μmol/L (2.5 mg/dL)

but may remain detectable below this level during recovery from jaundice (because of protein and tissue binding of conjugated bilirubin).

Spider angiomata and palmar erythema occur in both acute and

chronic liver disease; these manifestations may be especially prominent

in persons with cirrhosis but can develop in normal individuals and are

frequently found during pregnancy. Spider angiomata are superficial,

tortuous arterioles, and—unlike simple telangiectasias—typically fill

from the center outward. Spider angiomata occur only on the arms,

face, and upper torso; they can be pulsatile and may be difficult to

detect in dark-skinned individuals.

Hepatomegaly is not a very reliable sign of liver disease because of

variability in the liver’s size and shape and the physical impediments

to assessment of liver size by percussion and palpation. Marked

hepatomegaly is typical of cirrhosis, sinusoidal obstruction syndrome,

infiltrative disorders such as amyloidosis, metastatic or primary cancers of the liver, and alcoholic hepatitis. Careful assessment of the

liver edge may also reveal unusual firmness, irregularity of the surface,

or frank nodules. Perhaps the most reliable physical finding in the

liver examination is hepatic tenderness. Discomfort when the liver is

touched or pressed upon should be carefully sought with percussive

comparison of the right and left upper quadrants.

Splenomegaly, which occurs in many medical conditions, can be a

subtle but significant physical finding in liver disease. The availability

of ultrasound (US) methods for assessment of the spleen allows confirmation of the physical finding.

Signs of advanced liver disease include muscle wasting and weight

loss as well as hepatomegaly, bruising, ascites, and edema. Ascites

is best appreciated by attempts to detect shifting dullness by careful

percussion. US examination will confirm the finding of ascites in

equivocal cases. Peripheral edema can occur with or without ascites. In

patients with advanced liver disease, other factors frequently contribute

to edema formation, including hypoalbuminemia, venous insufficiency, heart failure, and medications.

Hepatic failure is defined as the occurrence of signs or symptoms of

hepatic encephalopathy in a person with severe acute or chronic liver

disease. The first signs of hepatic encephalopathy can be subtle and

nonspecific—change in sleep patterns, change in personality, irritability, and mental dullness. Thereafter, confusion, disorientation, stupor,

and eventually coma supervene. In acute liver failure, excitability and

mania may be present. Physical findings include asterixis and flapping

tremors of the body and tongue. Fetor hepaticus refers to the slightly

sweet, ammoniacal odor that can develop in patients with liver failure,

particularly if there is portal-venous shunting of blood around the liver.

Other causes of coma and disorientation should be excluded, mainly

electrolyte imbalances, sedative use, and renal or respiratory failure.

The appearance of hepatic encephalopathy during acute hepatitis is

the major criterion for diagnosis of fulminant hepatitis and indicates

a poor prognosis. In chronic liver disease, encephalopathy is usually

triggered by a medical complication such as gastrointestinal bleeding,

overdiuresis, uremia, dehydration, electrolyte imbalance, infection,

constipation, or use of narcotic analgesics.

A helpful measure of hepatic encephalopathy is a careful mental

status examination and use of the trail-making test, which consists of

a series of 25 numbered circles that the patient is asked to connect as

rapidly as possible using a pencil. The normal range for the connectthe-dot test is 15–30 s; it is considerably longer in patients with early

hepatic encephalopathy. Other tests include drawing of abstract objects

or comparison of a signature to previous examples. More sophisticated

testing—for example, with electroencephalography and visual evoked

potentials—can detect mild forms of encephalopathy but are rarely

clinically useful.

Other signs of advanced liver disease include umbilical hernia from

ascites, hydrothorax, prominent veins over the abdomen, and caput

medusa, a condition that consists of collateral veins radiating from the

umbilicus and results from recanulation of the umbilical vein. Widened pulse pressure and signs of a hyperdynamic circulation can occur

in patients with cirrhosis as a result of fluid and sodium retention,

increased cardiac output, and reduced peripheral resistance. Patients

with long-standing cirrhosis and portal hypertension are prone to

develop the hepatopulmonary syndrome, which is defined by the triad

of liver disease, hypoxemia, and pulmonary arteriovenous shunting.

The hepatopulmonary syndrome is characterized by platypnea and

orthodeoxia: shortness of breath and oxygen desaturation that occur

paradoxically upon the assumption of an upright position. Measurement of oxygen saturation by pulse oximetry is a reliable screening test

for hepatopulmonary syndrome.

Several skin disorders and changes are common in liver disease.

Hyperpigmentation is typical of advanced chronic cholestatic diseases

such as primary biliary cholangitis and sclerosing cholangitis. In these

same conditions, xanthelasma and tendon xanthomata occur as a result

of retention and high serum levels of lipids and cholesterol. Slate-gray

pigmentation of the skin is also seen with hemochromatosis if iron

levels are high for a prolonged period. Mucocutaneous vasculitis with

palpable purpura, especially on the lower extremities, is typical of

cryoglobulinemia of chronic hepatitis C but can also occur in chronic

hepatitis B.

Some physical signs point to specific liver diseases. Kayser-Fleischer

rings occur in Wilson disease and consist of a golden-brown copper

pigment deposited in Descemet’s membrane at the periphery of the

cornea; they are best seen by slit-lamp examination. Dupuytren contracture and parotid enlargement are suggestive of chronic alcoholism

and alcoholic liver disease. In metastatic liver disease or primary

hepatocellular carcinoma, signs of cachexia and wasting as well as firm

hepatomegaly and a hepatic bruit may be prominent.

■ DIAGNOSIS OF LIVER DISEASE

The key diagnostic tests of major causes of acute and chronic liver

disease are outlined in Table 336-3, and an algorithm for evaluation of

2550 PART 10 Disorders of the Gastrointestinal System

the patient with suspected liver disease is shown in Fig. 336-1. Specifics

of diagnosis are discussed in later chapters. The most common causes

of acute liver disease are viral hepatitis (particularly hepatitis A, B, and

C), drug-induced liver injury, cholangitis, and alcoholic liver disease.

Liver biopsy usually is not needed for the diagnosis and management

of acute liver disease, exceptions being situations where the diagnosis

remains unclear despite thorough clinical and laboratory investigation.

Liver biopsy can be helpful in diagnosing drug-induced liver disease

and acute alcoholic hepatitis.

The most common causes of chronic liver disease, in general order

of frequency, are chronic hepatitis C, alcoholic liver disease, nonalcoholic steatohepatitis, chronic hepatitis B, autoimmune hepatitis, sclerosing cholangitis, primary biliary cholangitis, hemochromatosis, and

Wilson disease. Hepatitis E virus is a rare cause of chronic hepatitis,

with cases occurring mostly in persons who are immunosuppressed

or immunodeficient. Strict diagnostic criteria have not been developed for most liver diseases, but liver biopsy plays an important role

in the diagnosis of autoimmune hepatitis, primary biliary cholangitis,

nonalcoholic and alcoholic steatohepatitis, and Wilson disease (with a

quantitative hepatic copper level in the last instance).

Laboratory Testing Diagnosis of liver disease is greatly aided

by the availability of reliable and sensitive tests of liver injury and

function. A typical battery of blood tests used for initial assessment of

liver disease includes measurement of levels of serum alanine (ALT)

and aspartate (AST) aminotransferases, alkaline phosphatase (AlkP),

direct and total serum bilirubin and albumin, and prothrombin time.

The pattern of abnormalities generally points to hepatocellular versus

cholestatic liver disease and helps determine whether the disease is

acute or chronic and whether cirrhosis and hepatic failure are present.

Based on these results, further testing over time may be necessary.

Other laboratory tests may be helpful, such as γ-glutamyl transpeptidase (γGT) to define whether AlkP elevations are due to liver disease;

hepatitis serology to define the type of viral hepatitis; and autoimmune

markers to diagnose primary biliary cholangitis (antimitochondrial

antibody), sclerosing cholangitis (peripheral antineutrophil cytoplasmic antibody), and autoimmune hepatitis (antinuclear, smoothmuscle, and liver-kidney microsomal antibody). A simple delineation

of laboratory abnormalities and common liver diseases is given in

Table 336-3.

The use and interpretation of liver function tests are summarized

in Chap. 337.

Diagnostic Imaging Great advances have been made in hepatobiliary imaging, although no method is adequately accurate in demonstrating underlying cirrhosis in its early stages. Of the many modalities

available for imaging the liver, US, computed tomography (CT), and

magnetic resonance imaging (MRI) are the most commonly employed

and are complementary to one another. In general, US and CT are

highly sensitive for detecting biliary duct dilation and are the firstline options for investigating cases of suspected obstructive jaundice.

All three modalities can detect a fatty liver, which appears bright on

imaging studies. Modifications of CT and MRI can be used to quantify

liver fat, and this information may ultimately be valuable in monitoring

response to therapy in patients with fatty liver disease. Advantages,

disadvantages, and clinical utility of each modality are presented in

Table 336-4. Magnetic resonance cholangiopancreatography (MRCP)

and endoscopic retrograde cholangiopancreatography (ERCP) are the

procedures of choice for visualization of the biliary tree. MRCP offers

several advantages over ERCP: there is no need for contrast media

or ionizing radiation, images can be acquired faster, the procedure is

less operator dependent, and it carries no risk of pancreatitis. MRCP

is superior to US and CT for detecting choledocholithiasis but is less

specific. MRCP is useful in the diagnosis of bile duct obstruction and

congenital biliary abnormalities, but ERCP is considered more valuable

in evaluating ampullary lesions and primary sclerosing cholangitis.

ERCP permits biopsy, direct visualization of the ampulla and common

bile duct, and intraductal ultrasonography and brushings for cytologic

evaluation of malignancy. It also provides several therapeutic options

in patients with obstructive jaundice, such as sphincterotomy, stone

extraction, and placement of nasobiliary catheters and biliary stents.

Doppler US and MRI are used to assess hepatic vasculature

and hemodynamics and to monitor surgically or radiologically

placed vascular shunts, including transjugular intrahepatic portosystemic shunts. Multidetector or spiral CT and MRI with contrast

enhancement are the procedures of choice for the identification and

evaluation of hepatic masses, the staging of liver tumors, and preoperative assessment. With regard to mass lesions, the sensitivity

of hepatic imaging continues to increase; unfortunately, specificity

remains a problem, and often two and sometimes three studies

are needed before a diagnosis can be reached. An emerging imaging modality for the investigation of hepatic lesions is contrastenhanced US. This procedure permits enhancement of liver lesions

in a similar fashion as contrast-enhanced, cross-sectional CT or MRI.

Major advantages are real-time assessment of liver perfusion throughout the vascular phases without risk of nephrotoxicity and radiation

exposure. Other advantages are its widespread availability and lower

cost. Limitations include body habitus of the patient and skill of the

operator. US is the recommended modality for hepatocellular carcinoma (HCC) screening. Contrast-enhanced US, CT, and MRI are

appropriate for further investigation of lesions detected on screening

US. The American College of Radiologists has developed a Liver Imaging Reporting and Data System (LI-RADS) to standardize the reporting and data collection of CT, MRI, and contrast-enhanced US imaging

for HCC. This system allows for more consistent reporting and reduces

imaging interpretation variability and errors.

Recently, several US-based elastographic techniques have been

developed and approved for the measurement of hepatic stiffness,

providing an indirect assessment of fibrosis and cirrhosis. The most

commonly used approaches in clinical practice include transient

elastography, acoustic radiation force impulse imaging, shear-wave

elasticity imaging, and supersonic shear imaging. These techniques

can eliminate the need for liver biopsy if the only indication for the test

is the assessment of disease stage. Magnetic resonance elastography is

TABLE 336-3 Important Diagnostic Tests in Common Liver Diseases

DISEASE DIAGNOSTIC TEST

Hepatitis A Anti-HAV IgM

Hepatitis B

Acute HBsAg and anti-HBc IgM

Chronic HBsAg and HBeAg and/or HBV DNA

Hepatitis C Anti-HCV and HCV RNA

Hepatitis D (delta) HBsAg and anti-HDV

Hepatitis E Anti-HEV IgM and HEV RNA

Autoimmune hepatitis ANA or SMA, elevated IgG levels, and

compatible histology

Primary biliary cholangitis Mitochondrial antibody, elevated IgM levels,

and compatible histology

Primary sclerosing cholangitis P-ANCA, cholangiography

Drug-induced liver disease History of drug ingestion

Alcoholic liver disease History of excessive alcohol intake and

compatible histology

Nonalcoholic steatohepatitis Ultrasound or CT evidence of fatty liver and

compatible histology

α1

 Antitrypsin disease Reduced α1

 antitrypsin levels, phenotype PiZZ

or PiSZ

Wilson disease Decreased serum ceruloplasmin and

increased urinary copper; increased hepatic

copper level

Hemochromatosis Elevated iron saturation and serum ferritin;

genetic testing for HFE gene mutations

Hepatocellular cancer Elevated α-fetoprotein level (to >500 ng/mL);

ultrasound or CT image of mass

Abbreviations: ANA, antinuclear antibody; anti-HBc, antibody to hepatitis B core

(antigen); HAV, HBV, HCV, HDV, HEV, hepatitis A, B, C, D, E virus; HBeAg, hepatitis B

e antigen; HBsAg, hepatitis B surface antigen; P-ANCA, peripheral antineutrophil

cytoplasmic antibody; SMA, smooth-muscle antibody.

2551Approach to the Patient with Liver Disease CHAPTER 336

more sensitive than US elastography but is also more

expensive and requires advanced scheduling and special

equipment. Studies are ongoing to determine whether

hepatic elastography is an appropriate means of monitoring fibrosis and disease progression in untreated

and treated patients. Finally, interventional radiologic

techniques allow for the biopsy of solitary lesions,

the radiofrequency ablation and chemoembolization of

cancerous lesions, the insertion of drains into hepatic

abscesses, the measurement of portal pressure, and the

creation of vascular shunts in patients with portal hypertension. Which modality to use depends on factors such

as availability, cost, and experience of the radiologist

with each technique.

Liver Biopsy Liver biopsy remains the gold standard

in the evaluation of patients with liver disease, particularly chronic liver disease. Liver biopsy is necessary for

diagnosis in selected instances but is more often useful

for assessment of the severity (grade) and stage of liver

damage, prediction of prognosis, and monitoring of the

response to treatment. The size of the liver biopsy sample

is an important determinant of reliability; a length of

1.5–2 cm with 10 portal tracts is necessary for accurate

assessment of fibrosis. Because liver biopsy is an invasive

procedure and not without complications, it should be

used only when it will contribute materially to decisions

about management and therapy. In the future, noninvasive means of assessing disease activity (batteries of blood

tests) and fibrosis (elastography and fibrosis markers) may

replace liver biopsy for the staging and grading of disease.

■ GRADING AND STAGING OF LIVER

DISEASE

Grading refers to an assessment of the severity or activity of liver disease, whether acute or chronic; active or

inactive; and mild, moderate, or severe. Liver biopsy is

the most accurate means of assessing severity, particularly in chronic liver disease. Serum aminotransferase

levels serve as convenient and noninvasive markers for

disease activity but do not always reliably reflect disease

severity. Thus, normal serum aminotransferase levels in

patients with hepatitis B surface antigen in serum may

indicate the inactive carrier state or may reflect mild

chronic hepatitis B or hepatitis B with fluctuating disease activity. Serum testing for hepatitis B e antigen and

hepatitis B virus DNA can help sort out these different

patterns, but these markers can also fluctuate and change

Suspected liver disease

Abnormal liver tests

Acute

<6 months

Chronic

>6 months

Diagnostic

evaluation

1. IgM Anti-HAV

2. HBsAg

3. IgM Anti-HBc

4. Anti-HCV

5. ANA, SMA

6. Monospot,

 heterophile

7. Ceruloplasmin

8. Alcohol history

9. Drug history

Diagnostic

evaluation

1. AMA

2. Drug history

3. Ultrasound/MRI

4. MRCP/ERCP

Liver biopsy in acute liver disease:

Reserved for patients in whom the diagnosis

remains unclear despite medical evaluation

Liver biopsy in chronic liver disease:

Often valuable for diagnosis as well as

staging and grading liver disease

Diagnostic

evaluation

1. HBsAg

2. Anti-HCV

3. Fe saturation,

 ferritin

4. Ceruloplasmin

5. α1AT

6. ANA, SMA

7. Ultrasound

8. Alcohol history

Diagnostic

evaluation

1. Drug history

2. AMA

3. P-ANCA

4. Ultrasound

5. MRCP/ERCP

Hepatitic: ⇑⇑ALT

Mixed: ↑ALT,

 ↑AlkP

Cholestatic:

 ⇑⇑AlkP,

 ⇑⇑gGT,

 ↑ALT

Hepatitic: ⇑⇑ALT

Mixed: ↑ALT,

 ↑AlkP

Cholestatic:

 ⇑⇑AlkP,

 ⇑⇑gGT,

 ↑ALT

FIGURE 336-1 Algorithm for evaluation of abnormal liver tests. For patients with suspected

liver disease, an appropriate approach to evaluation is initial routine liver testing—for example,

measurement of serum bilirubin, albumin, alanine aminotransferase (ALT), AST, and alkaline

phosphatase (AlkP). These results (sometimes complemented by testing of γ-glutamyl transpeptidase

[gGT]) will establish whether the pattern of abnormalities is hepatic, cholestatic, or mixed. In addition,

the duration of symptoms or abnormalities will indicate whether the disease is acute or chronic. If

the disease is acute and if history, laboratory tests, and imaging studies do not reveal a diagnosis,

liver biopsy is appropriate to help establish the diagnosis. If the disease is chronic, liver biopsy can

be helpful not only for diagnosis but also for grading of the activity and staging the progression of

disease. This approach is generally applicable to patients without immune deficiency. In patients

with HIV infection or recipients of bone marrow or solid organ transplants, the diagnostic evaluation

should also include evaluation for opportunistic infections (e.g., with adenovirus, cytomegalovirus,

Coccidioides, hepatitis E virus) as well as for vascular and immunologic conditions (veno-occlusive

disease, graft-versus-host disease). α1

 AT, α1

 antitrypsin; AMA; antimitochondrial antibody; ANA,

antinuclear antibody; anti-HBc, antibody to hepatitis B core (antigen); ERCP, endoscopic retrograde

cholangiopancreatography; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis

C virus; MRCP, magnetic resonance cholangiopancreatography; P-ANCA, peripheral antineutrophil

cytoplasmic antibody; SMA, smooth-muscle antibody.

TABLE 336-4 Diagnostic Tests to Assess Liver Fat

IMAGING MODALITY ADVANTAGES DISADVANTAGES CLINICAL UTILITY

Ultrasound No radiation

Widely available

Operator dependent

Imprecise qualitative assessment of fat severity,

particularly mild steatosis

Initial screening test for suspected liver fat

Transient elastography

with controlled attenuation

parameter

No radiation

Point-of-care assessment of liver fat

Provides semiquantitative assessment

of fat severity

Requires special software

No reliable cutoff for diagnosis of liver fat

Imprecise qualitative assessment of fat severity

Alternate screening test for suspected liver

fat if available

Computed tomography Rapid assessment

Non–operator dependent

Quantitative assessment of fat severity

Requires radiation

Quantification of fat requires specific protocols

Imprecise quantitative assessment of fat

severity, particularly mild steatosis

Not recommended for clinical assessment of

liver fat due to need for radiation exposure

and low sensitivity for mild fat

Magnetic resonance

imaging–proton density fat

fraction

Direct assessment of liver fat

Highly sensitive and specific

Relatively limited accessibility Test of choice for quantitative assessment of

liver fat if available

2552 PART 10 Disorders of the Gastrointestinal System

over time. Similarly, in chronic hepatitis C, serum aminotransferase

levels can be normal despite moderate disease activity. Finally, in both

alcoholic and nonalcoholic steatohepatitis, aminotransferase levels are

quite unreliable in reflecting severity. In these conditions, liver biopsy

is helpful in guiding management and identifying appropriate therapy,

particularly if treatment is difficult, prolonged, and expensive, as is

often the case in chronic viral hepatitis. Of the several well-verified

numerical scales for grading activity in chronic liver disease, the most

commonly used are the METAVIR, histology activity index, and the

Ishak fibrosis scale.

Liver biopsy is also the most accurate means of assessing stage of

disease as early or advanced, precirrhotic, and cirrhotic. Staging of

disease pertains largely to chronic liver diseases in which progression

to cirrhosis and end-stage disease can occur but may require years

or decades. Clinical features, biochemical tests, and hepatic imaging

studies are helpful in assessing stage but generally become abnormal

only in the middle to late stages of cirrhosis. Noninvasive tests that

suggest advanced fibrosis include mild elevations of bilirubin, prolongation of prothrombin time, slight decreases in serum albumin, and

mild thrombocytopenia (which is often the first indication of worsening fibrosis). Combinations of blood test results that include clinical

features, routine laboratory tests, and special laboratory tests such as

serum proteins or small molecules that are affected by or involved with

fibrogenesis have been used to create models for predicting advanced

liver disease, but these models are not reliable enough to use on a regular basis or for repeated measures and only separate advanced from

early disease (Table 336-5). Recently, elastography and noninvasive

breath tests using 13C-labeled compounds have been proposed as a

means of detecting early stages of fibrosis and liver dysfunction, but

their reliability and reproducibility remain to be proven. A major limitation of noninvasive markers is that they can be affected by disease

activity. Even elastography is limited in this regard, in that it measures

liver stiffness, not fibrosis per se, and can be affected by inflammation,

edema, hepatocyte necrosis, and intrasinusoidal cellularity (inflammatory, malignant, or sickled cells). Thus, at present, mild to moderate

stages of hepatic fibrosis are detectable only by liver biopsy. In the

assessment of stage, the degree of fibrosis is usually used as the quantitative measure. The amount of fibrosis is generally staged on a scale of

0 to 4+ (METAVIR scale) or 0 to 6+ (Ishak scale). The importance of

staging relates primarily to prognosis, recommendation of therapy, and

optimal management to prevent complications of chronic liver disease.

Patients with cirrhosis are candidates for screening and surveillance for

esophageal varices and HCC. Patients without advanced fibrosis need

not undergo screening.

TABLE 336-5 Selected Noninvasive Methods of Assessing Hepatic

Fibrosis and Cirrhosis

METHOD PARAMETERS

ADVANCED

FIBROSIS CIRRHOSIS

APRI AST, platelet count >1 >1.5 (1–2)

ELF Age, hyaluronic acid, MMP-3, TIMP-1 >7.7 >9.3

FIB-4 Age, AST, ALT, platelet count >1.45 >3.25

Fibro testa Haptoglobin, α2

-macroglobulin,

apolipoprotein A1, γGT, total bilirubin

>0.45 >0.63

TE Measures speed of a shear wave

generated by vibration through liver

tissue

>7.3 kPa >15 kPa

(9–26.5

kPa)

ARFI Measures speed of shear wave

generated by acoustic radiation force

through liver tissue

>1.3 m/s >1.87 m/s

a

Patented models.

Note: The cut points presented in the table were mostly derived from patients with

chronic hepatitis C. The cut points for the noninvasive models and tests presented

in the table vary among different liver diseases and among patients with the same

disease among different populations.

Abbreviations: ALT, alanine aminotransferase; APRI, AST-to-platelet ratio; ARFI,

acoustic radiation force imaging; AST, aspartate aminotransferase; ELF, enhanced

liver fibrosis panel; γGT, γ-glutamyl transpeptidase; MMP-3, metalloproteinase-3;

TIMP-1, tissue inhibitor of metalloproteinase-1; TE, transient elastography.

Once cirrhosis develops, other scoring systems are employed to

assess compensated versus decompensated disease and prognosis. The

first staging system used for this purpose was the modified Child-Pugh

classification, with a scoring system of 5–15: scores of 5 and 6 represent

Child-Pugh class A (consistent with “compensated cirrhosis”),

scores of 7–9 represent class B, and scores of 10–15 represent class

C (Table 336-6). This scoring system was initially devised to stratify

patients with cirrhosis into risk groups before portal decompressive

surgery. The Child-Pugh score is a reasonably reliable predictor of

survival in many liver diseases and predicts the likelihood of major

complications of cirrhosis, such as bleeding from varices and spontaneous bacterial peritonitis. This classification scheme was used to

assess prognosis in cirrhosis and to provide standard criteria for listing

a patient as a candidate for liver transplantation (Child-Pugh class B).

More recently, the Child-Pugh system has been replaced by the Model

for End-Stage Liver Disease (MELD) system for the latter purpose. The

MELD score is a prospectively derived system designed to predict the

prognosis of patients with liver disease and portal hypertension. This

score is calculated using three readily available objective variables:

the prothrombin time expressed as the international normalized ratio

(INR), the serum bilirubin level, and the serum creatinine concentration. The ability of the MELD score to predict outcome after liver

transplantation is regularly monitored and was modified to increase its

accuracy and improve allocation of donated livers. These modifications

include serum sodium concentration as a factor in the model and a

reweighting of the MELD components. A separate scoring system, the

Pediatric End-Stage Liver Disease (PELD) score, is used for children

(<12 years old). Transient elastography has also been used to stage

cirrhosis and has been shown to be useful in predicting complications

such as variceal hemorrhage, ascites development, and liver-related

death.

The MELD system provides a more objective means of assessing disease severity and has less center-to-center variation than the

Child-Pugh score as well as a wider range of values. The MELD and

PELD systems are currently used to establish priority listing for liver

transplantation in the United States. Convenient MELD and PELD calculators are available via the Internet (https://optn.transplant.hrsa.gov/

resources/allocation-calculators/about-meld-and-peld/).

■ NONSPECIFIC ISSUES IN THE MANAGEMENT OF

PATIENTS WITH LIVER DISEASE

Specifics on the management of different forms of acute or chronic

liver disease are supplied in subsequent chapters, but certain issues

are applicable to any patient with liver disease. These issues include

advice regarding alcohol use, medication use, vaccination, and surveillance for certain liver diseases and complications of liver disease.

Alcohol should be used sparingly, if at all, by patients with liver

TABLE 336-6 Child-Pugh Classification of Cirrhosis

FACTOR 

POINTS TOWARD TOTAL SCORE

UNITS 1 2 3

Serum bilirubin μmol/L <34 34–51 >51

mg/dL <2.0 2.0–3.0 >3.0

Serum albumin g/L >35 30–35 <30

g/dL >3.5 3.0–3.5 <3.0

Prothrombin time seconds

prolonged

<4 4–6 >6

INRa <1.7 1.7–2.3 >2.3

Ascites None Easily

controlled

Poorly

controlled

Hepatic

encephalopathy

None Minimal Advanced

a

International normalized ratio.

Note: The Child-Pugh score is calculated by adding the scores for the five factors

and can range from 5 to 15. The resulting Child-Pugh class can be A (a score of

5–6), B (7–9), or C (≥10). Decompensation indicates cirrhosis, with a Child-Pugh

score of ≥7 (class B). This level has been the accepted criterion for listing a patient

for liver transplantation.

2553Evaluation of Liver Function CHAPTER 337

disease. Abstinence from alcohol should be encouraged for all patients

with alcohol-related liver disease, patients with cirrhosis, and patients

receiving interferon-based therapy for hepatitis B and during antiviral therapy of hepatitis C. With regard to vaccinations, all patients

with liver disease should receive hepatitis A vaccine, and those with

risk factors should receive hepatitis B vaccine as well. Influenza and

pneumococcal vaccination should also be encouraged, with adherence to the recommendations of the Centers for Disease Control and

Prevention (CDC). Patients with liver disease should exercise caution

in using any medications other than those that are most necessary.

Drug-induced hepatotoxicity can mimic many forms of liver disease

and can cause exacerbations of chronic hepatitis and cirrhosis; drugs

should be suspected in any situation in which the cause of exacerbation

is unknown. The CDC now recommends universal one-time testing for

hepatitis C virus among persons aged 18–79 years and screening of all

pregnant women during each pregnancy except in settings where the

prevalence of hepatitis C virus infection (hepatitis C virus RNA positivity) is <0.1%. Finally, consideration should be given to surveillance

for complications of chronic liver disease such as variceal hemorrhage

and HCC. Cirrhosis warrants upper endoscopy to assess the presence

of varices, and the patient should receive chronic therapy with beta

blockers or should be offered endoscopic obliteration if large varices

are found. Moreover, cirrhosis warrants screening and long-term surveillance for development of HCC. While the optimal regimen for such

surveillance has not been established, an appropriate approach is US of

the liver at 6- to 12-month intervals.

■ FURTHER READING

Friedman SL et al: Mechanisms of NAFLD development and therapeutic strategies. Nat Med 24:908, 2018.

Seto WK et al: Chronic hepatitis B virus infection. Lancet 392:2313,

2018.

Spearman CW et al: Hepatitis C. Lancet 394:1451, 2019.

Tapper EB, Lok AS: Use of liver imaging and biopsy in clinical practice.

N Engl J Med 377:756, 2017.

337 Evaluation of Liver

Function

Emily D. Bethea, Daniel S. Pratt

There are a number of tests that can be used to evaluate liver function.

These tests include biochemical tests, radiologic tests, and pathologic tests.

Serum biochemical tests, also commonly referred to as “liver function tests,” can be used to (1) detect the presence of liver disease, (2)

distinguish among different types of liver disorders, (3) gauge the

extent of known liver damage, and (4) follow the response to treatment.

However, serum biochemical tests have shortcomings. They lack sensitivity and specificity; they can be normal in patients with serious liver

disease and abnormal in patients with diseases that do not affect the

liver. Liver tests rarely suggest a specific diagnosis; rather, they suggest

a general category of liver disease, such as hepatocellular or cholestatic,

which then further directs the evaluation. The liver carries out thousands of biochemical functions, most of which cannot be easily measured by blood tests. Laboratory tests measure only a limited number

of these functions. In fact, many tests, such as the aminotransferases

and alkaline phosphatase, do not measure liver function at all. Rather,

they detect liver cell damage or interference with bile flow. Thus, no

one biochemical test enables the clinician to accurately assess the liver’s

total functional capacity.

To increase the sensitivity and the specificity of biochemical tests

in the detection of liver disease, it is best to use them as a battery.

Tests usually employed in clinical practice include the bilirubin,

aminotransferases, alkaline phosphatase, albumin, and prothrombin

time tests. When more than one of these tests provide abnormal findings or the findings are persistently abnormal on serial determinations,

the probability of liver disease is high. When all test results are normal,

the probability of missing occult liver disease is low.

Serum Bilirubin (See also Chap. 49) Bilirubin, a breakdown

product of the porphyrin ring of heme-containing proteins, is found in

the blood in two fractions—conjugated and unconjugated. The unconjugated fraction, also termed the indirect fraction, is insoluble in water

and is bound to albumin in the blood. The conjugated (direct) bilirubin

fraction is water-soluble and can therefore be excreted by the kidney.

Normal values of total serum bilirubin are reported between 1 and

1.5 mg/dL with 95% of a normal population falling between 0.2 and

0.9 mg/dL. If the direct-acting fraction is <15% of the total, the bilirubin can be considered to all be indirect. The most frequently reported

upper limit of normal for conjugated bilirubin is 0.3 mg/dL.

Elevation of the unconjugated fraction of bilirubin is rarely due to

liver disease. An isolated elevation of unconjugated bilirubin is seen

primarily in hemolytic disorders and in a number of genetic conditions

such as Crigler-Najjar and Gilbert’s syndromes (Chap. 49). Isolated

unconjugated hyperbilirubinemia (bilirubin elevated but <15% direct)

should prompt a workup for hemolysis (Fig. 337-1). In the absence of

hemolysis, an isolated, unconjugated hyperbilirubinemia in an otherwise healthy patient can be attributed to Gilbert’s syndrome, and no

further evaluation is required.

In contrast, conjugated hyperbilirubinemia almost always implies

liver or biliary tract disease. The rate-limiting step in bilirubin metabolism is not conjugation of bilirubin, but rather the transport of conjugated bilirubin into the bile canaliculi. Thus, elevation of the conjugated

fraction may be seen in any type of liver disease including fulminant

liver failure. In most liver diseases, both conjugated and unconjugated

fractions of the bilirubin tend to be elevated. Except in the presence of a

purely unconjugated hyperbilirubinemia, fractionation of the bilirubin

is rarely helpful in determining the cause of jaundice.

Although the degree of elevation of the serum bilirubin has not been

critically assessed as a prognostic marker, it is important in a number of

conditions. In viral hepatitis, the higher the serum bilirubin, the greater

is the hepatocellular damage. Total serum bilirubin correlates with

poor outcomes in alcoholic hepatitis. It is also a critical component

of the Model for End-Stage Liver Disease (MELD) score, a tool used

to estimate survival of patients with end-stage liver disease, prioritize

patients awaiting liver transplantation, and assess operative risk of

patients with cirrhosis. An elevated total serum bilirubin in patients

with drug-induced liver disease indicates more severe injury.

Unconjugated bilirubin always binds to albumin in the serum and is

not filtered by the kidney. Therefore, any bilirubin found in the urine

is conjugated bilirubin; the presence of bilirubinuria implies the presence of liver disease or obstructive jaundice. A urine dipstick test can

theoretically give the same information as fractionation of the serum

bilirubin. This test is almost 100% accurate. Phenothiazines may give

a false-positive reading with the Ictotest tablet. In patients recovering

from jaundice, the urine bilirubin clears prior to the serum bilirubin.

Serum Enzymes The liver contains thousands of enzymes, some of

which are also present in the serum in very low concentrations. These

enzymes have no known function in the serum and behave like other

serum proteins. They are distributed in the plasma and in interstitial

fluid and have characteristic half-lives, which are usually measured

in days. Very little is known about the catabolism of serum enzymes,

although they are probably cleared by cells in the reticuloendothelial system. The elevation of a given enzyme activity in the serum is

thought to primarily reflect its increased rate of entrance into serum

from damaged liver cells.

Serum enzyme tests can be grouped into two categories: (1) enzymes

whose elevation in serum reflects damage to hepatocytes and (2)

enzymes whose elevation in serum reflects cholestasis.

ENZYMES THAT REFLECT DAMAGE TO HEPATOCYTES The aminotransferases (transaminases) are sensitive indicators of liver cell injury and

2554 PART 10 Disorders of the Gastrointestinal System

are most helpful in recognizing acute hepatocellular diseases such as

hepatitis. They include aspartate aminotransferase (AST) and alanine

aminotransferase (ALT). AST is found in the liver, cardiac muscle,

skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and erythrocytes in decreasing order of concentration. ALT is found primarily

in the liver and is therefore a more specific indicator of liver injury. The

aminotransferases are normally present in the serum in low concentrations. These enzymes are released into the blood in greater amounts

when there is damage to the liver cell membrane, resulting in increased

permeability. Liver cell necrosis is not required for the release of the

aminotransferases, and there is a poor correlation between the degree

of liver cell damage and the level of the aminotransferases. Thus, the

absolute elevation of the aminotransferases is of no prognostic significance in acute hepatocellular disorders.

The normal range for aminotransferases varies widely among laboratories, but generally ranges from 10 to 40 IU/L. The interlaboratory

variation in normal range is due to technical reasons; no reference standards exist to establish upper limits of normal for ALT and AST. Some

have recommended revisions of normal limits of the aminotransferases

to adjust for sex and body mass index, but others have noted the potential costs and unclear benefits of implementing this change.

Any type of liver cell injury can cause modest elevations in the

serum aminotransferases. Levels of up to 300 IU/L are nonspecific and

may be found in any type of liver disorder. Minimal ALT elevations in

asymptomatic blood donors rarely indicate severe liver disease; studies

Review drug list

Hepatitis C antibody

Hepatitis B surface Ag

Iron, TIBC, ferritin

ANA, SPEP

Ceruloplasmin

 (if patient <40)

Ultrasound to look

 for fatty liver

<15% Direct

Gilbert’s

 syndrome

Isolated elevation

of the bilirubin

Hepatocellular

pattern

(see Table 337-1)

W/U negative

W/U negative

W/U negative

Dilated ducts

W/U

positive

Isolated elevation

of the alkaline

phosphatase

Cholestatic pattern

(see Table 337-1)

Consider liver biopsy

ERCP/Liver Bx

CT/MRCP/ERCP

Liver Bx

Ducts not

dilated

Dilated ducts

AMA AMA positive

 negative

Alkaline phos.

 of liver origin

Alkaline phos.

 of bone origin

Bone Eval

Ducts not dilated

 and/or AMA positive

MRCP

Evaluation for

 hemolysis

Dubin-Johnson or

 Rotor syndrome

Hemolysis

Fractionate

 bilirubin

>15% Direct Check AMA

Review drugs

Ultrasound

Liver Tests

Fractionate the alkaline

 phosphatase or check

 GGT or 5' nucleotidase

 to assess origin of

 alkaline phosphatase

Ultrasound

Review drug list

Check AMA

Liver biopsy

R/O Celiac disease

Consider other

 nonhepatic cause

FIGURE 337-1 Algorithm for the evaluation of chronically abnormal liver tests. Ag, antigen; AMA, antimitochondrial antibody; ANA, antinuclear antibody; Bx, biopsy; CT,

computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; GGT, γ-glutamyl transpeptidase; MRCP, magnetic resonance cholangiopancreatography;

R/O, rule out; SPEP, serum protein electrophoresis; TIBC, total iron-binding capacity; W/U, workup.

have shown that fatty liver disease is the most likely explanation. Striking elevations—that is, aminotransferases >1000 IU/L—occur almost

exclusively in disorders associated with extensive hepatocellular injury

such as (1) viral hepatitis, (2) ischemic liver injury (prolonged hypotension or acute heart failure), or (3) toxin- or drug-induced liver injury.

The pattern of the aminotransferase elevation can be helpful diagnostically. In most acute hepatocellular disorders, the ALT is higher

than or equal to the AST. Whereas the AST:ALT ratio is typically <1

in patients with chronic viral hepatitis and nonalcoholic fatty liver

disease, a number of groups have noted that as cirrhosis develops, this

ratio rises to >1. An AST:ALT ratio >2:1 is suggestive, whereas a ratio

>3:1 is highly suggestive, of alcoholic liver disease. The AST in alcoholic liver disease is rarely >300 IU/L, and the ALT is often normal. A

low level of ALT in the serum is due to an alcohol-induced deficiency

of pyridoxal phosphate.

The aminotransferases are usually not greatly elevated in obstructive

jaundice. One notable exception occurs during the acute phase of biliary obstruction caused by the passage of a gallstone into the common

bile duct. In this setting, the aminotransferases can briefly be in the

1000–2000 IU/L range. However, aminotransferase levels decrease

quickly, and the biochemical tests rapidly evolve into those typical of

cholestasis.

ENZYMES THAT REFLECT CHOLESTASIS The activities of three

enzymes—alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl

transpeptidase (GGT)—are usually elevated in cholestasis. Alkaline