Schiff's Diseases of the Liver

By Eugene R. Schiff, Willis C. Maddrey and Michael F. Sorrell

For over 50 years covering 10 previous editions, Schiff's Diseases of the Liver has provided hepatologists with an outstanding evidence-based clinical reference work covering all aspects of liver disease, and is without doubt one of the world’s leading hepatology textbooks.  Now fully revised and updated, it will serve as your first-stop reference for today’s demanding clinical situations.

With a strong clinical focus, Schiff’s Diseases of the Liver covers anatomy, pathology, testing, imaging, and effects of liver disease on other organs, before moving on to sections that address specific diseases and clinical syndromes.  Its enormous appeal has been due to the clarity of text, combined with the sheer thoroughness of its breadth of content. Key features include:

• An attractive full color design throughout
• Informative section overviews for each section
• Concise key concepts box in every chapter
• Treatment guidelines and management algorithms for every disease
• A full liver transplant section

This 11th edition sees all existing chapters fully revised and refreshed with the very latest in clinical information from the world’s leading hepatologists. Also new to this edition is a companion website containing a variety of important extra materials, including:

• Approximately 100 multiple choice questions of the standard used in ABIM board exams in gastroenterology, to allow the user to self-assess their clinical knowledge 
• All 450+ figures from the book in a high-quality, fully transportable and downloadable electronic format
• High-quality video clips of a variety of surgical procedures, all fully linked to the text
• 35 case studies featuring real-life clinical scenarios. 

Schiff’s Diseases of the Liver remains the key textbook for all gastroenterologists and hepatologists, in training or fully qualified, managing patients with liver disease.

• Language: English
• Publisher: Wiley
• Release date: Oct 19, 2011
• ISBN: 9781119950486

Book preview

PART I

Overview: Clinical Fundamentals of Hepatology

CHAPTER 1

History Taking and Physical Examination for the Patient with Liver Disease

Norton J. Greenberger

Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA

Key concepts

In the care of patients with jaundice, a careful history, physical examination, and review of standard laboratory tests should allow a physician to make an accurate diagnosis in 85% of the cases.

The triad of findings of splenomegaly, ascites, and an increased number of venous collateral vessels on the anterior abdominal wall indicates a diagnosis of portal hypertension.

The presence of two physical findings (ascites and evidence of portasystemic encephalopathy (asterixis)) and two laboratory findings (hypoalbuminemia (<2.8 g/dL) and a prolonged prothrombin time (international normalized ratio >1.6)) indicates a diagnosis of cirrhosis of the liver.

Three physical findings (parotid enlargement, gynecomastia, and Dupuytren contracture) indicate that a patient is almost certainly consuming excessive amounts of alcohol.

In adult patients with a new onset of jaundice, ten disorders account for 98% of the ultimately established diagnoses. They include decompensated chronic liver disease, alcoholic hepatitis, gallstones, malignancy, sepsis/abnormal hemodynamics, drug-induced liver disease, hemolysis (sickle cell anemia), postoperative jaundice, viral hepatitis, and primary biliary cirrhosis and primary sclerosing cholangitis. By the time patients with metastatic liver disease have jaundice, the diagnosis should be obvious because the liver has been extensively replaced by tumor.

Jaundice is a common presentation among patients with liver and biliary tract disease. The terms jaundice and icterus are used to designate skin and eyes appearing yellow resulting from the retention and deposition of biliary pigments (biliary monoglucuronides and diglucuronides). Although bilirubin stains all tissue, jaundice is most evident in the sclerae, face, and trunk. Jaundice is most commonly caused by parenchymal liver diseases such as viral hepatitis or cirrhosis, obstruction of the extrahepatic biliary tree as in choledocholithiasis and carcinoma of the pancreas, and less commonly, disorders associated with brisk hemolysis such as sickle cell anemia. The late Franz Ingelfinger stated in 1958 that the cause of jaundice can be identified in approximately 85% of patients after a careful study of the history and the performance of a physical examination and review of standard laboratory data. The same applies today. Box 1.1 lists specific questions to ask in relation to the different causes of liver and biliary tract disease.

History taking for patients with jaundice or abnormal liver test results

Anorexia is a cardinal symptom of viral hepatitis and of neoplasms involving the liver, colon, biliary tree, or pancreas. Weight loss of more than 10 pounds (4.5 kg) should always raise the question of a neoplastic disorder.

Chills and fever along with headache and myalgia should raise the question of viral hepatitis. Chills and fever along with right upper quadrant abdominal pain suggest a diagnosis of biliary tract disease, especially choledocholithiasis and ascending cholangitis.

Arthritis can be the harbinger of viral hepatitis, autoimmune chronic hepatitis, inflammatory bowel disease with underlying liver disease, primary sclerosing cholangitis, or granulomatous disorders such as sarcoidosis.

Box 1.1 Specific questions to ask patients with jaundice or liver disease.

Questions related to viral hepatitis

Blood transfusions (especially if before 1990)

Intravenous drug use

Sexual practices:

Anal-receptive intercourse

Sex with a prostitute

History of sexually transmitted disease

Multiple sexual partners (>5/year)

Intercourse with individuals with hepatitis B or C

Contact with individuals with jaundice

Changes in taste and smell

Needlestick exposure

Work in renal dialysis units

Surgeons in trauma units or operating rooms exposed to users of intravenous drugs

Shared razors or toothbrushes

Body piercing (ears, nose)

Tattoos

Intranasal cocaine use

Special risk factors for hepatitis A (if not previously immunized)

Travel to endemic areas

Ingestion of raw shellfish (harvested from contaminated waters)

Exposure to patients in places where clusters of hepatitis may occur (e.g., institutions, prisons, preschool nurseries)

Medication-related questions

Review all prescription medications

Ask specifically about all over-the-counter drugs

Ask specifically about vitamins (especially vitamin A)

Ask specifically about any foods, herbal preparations, and home remedies purchased in a health food store

Alcohol use questions

Obtain detailed quantitative history of both recent and previous alcohol use from the patient and family members

Question whether patient has experienced withdrawal symptoms or driving-under-the-influence convictions

CAGE (cut down, annoyed, guilty, eye opener) criteria (see text)

Check for evidence of alcohol-associated illnesses (pancreatitis, peripheral neuropathy)

Miscellaneous questions

Pruritus (suggests cholestasis, either intrahepatic or extrahepatic)

Evolution of jaundice (dark urine, light stools)

Recent changes in menstrual cycle (amenorrhea suggests chronic liver disease, often cirrhosis)

History of anemia, sickle cell disease, known hemoglobinopathy, or artificial heart valves

Symptoms suggestive of biliary colic or chronic cholecystitis

Family history of liver or gallbladder disease

History of inflammatory bowel disease (should raise the question of primary sclerosing cholangitis and receipt, if any, of blood transfusions)

Occupational history and, specifically, exposure to hepatotoxins

Fleeting skin lesions are often present in patients with viral hepatitis type B. Excoriations, indicating pruritus, should raise the question of either intrahepatic or extrahepatic cholestasis, particularly primary biliary cirrhosis or primary sclerosing cholangitis. With regard to abdominal pain, the standard questions to ask concern the location, character, radiation, factors precipitating or relieving pain, and whether there are other systemic symptoms that accompany the pain. Patients should be asked to compare current abdominal discomfort with other causes of abdominal pain that they have experienced in the past (e.g., gastroesophageal reflux symptoms, non-ulcer-type dyspepsia).

Questions to be asked in relation to viral hepatitis include specific questions about blood transfusions, especially whether they were received before 1990. The date is important because before that time no serologic tests were available for the detection of infection with hepatitis C virus. Intravenous drug use is currently the most common cause of hepatitis C. It is important to ask specifically about sexual practices, especially high-risk sexual behavior. In this regard, anal-receptive intercourse is known to be a significant risk factor for hepatitis B. Sexual practices associated with an increased risk of hepatitis C include a history of sexual relations with a prostitute, history of a sexually transmitted disease, and multiple sexual partners per year. In addition, intercourse with patients known to be positive for hepatitis B and C (e.g., spouses) is known to be a risk factor for contracting these forms of hepatitis. Contact with jaundiced individuals may be a risk factor for hepatitis A and B. Changes in taste and smell occur fairly frequently in patients with viral hepatitis. They contribute, in a large part, to the anorexia experienced by such patients. This is in part due to a decreased sense of smell (hyposmia), perception of unpleasant smells from foods that are not ordinarily perceived as unpleasant (dysosmia), a decreased sense of taste (hypogeusia), and perception of unpleasant tastes (dysgeusia). Hypogeusia is often reflected in the fact that patients may spontaneously state that they have lost their taste for cigarettes.

Health care professionals are at risk of contracting hepatitis C. This can occur through needlestick exposure, by working in renal dialysis units, and by working in trauma units, emergency departments, or operating rooms through surgical procedures on patients harboring the hepatitis C virus in whom that diagnosis is not immediately apparent. All users of intravenous drugs should be suspected of harboring the hepatitis C virus. Special risk factors for hepatitis C include tattoos, body piercing (e.g., of the ears and nose), a history of snorting cocaine, and the use of shared razors or toothbrushes.

The incidence of hepatitis A and hepatitis B has decreased markedly due to immunization, however, there are special risk factors for hepatitis A that include travel to endemic areas such as Mexico and Latin America and the African subcontinent, ingestion of raw shellfish that may have been harvested from contaminated waters, and exposure to patients in places where clusters of hepatitis may occur. The latter has been well documented in mental institutions, prisons, preschool nurseries, and close living quarters. Hepatitis A can be transmitted parenterally because there is brief viremia.

Medication use, including all prescription drugs and all over-the-counter drugs, should be carefully reviewed. The constellation of clinical features that include fever, arthritis or arthralgia, rash, and eosinophilia in a patient with jaundice or abnormal results of liver tests should always raise the question of medication-induced liver disease. This can be recalled by the mnemonic FARE, which stands for fever, arthritis, rash, and eosinophilia. The patient should be asked specifically about intake of vitamins, especially vitamin A, and about any foods, herbal preparations, or home remedies purchased in health food stores. Several herbal preparations have been found to be hepatotoxic.

Detailed quantitative information should be obtained from both the patient and family members about recent and previous alcohol use. For reference purposes, 30 mL (1 ounce) of bourbon whiskey contains 10–11 g of alcohol, as does one 360 mL (12-ounce) container of beer or 120 mL (4 ounces) of red table wine. Each one of these can be considered as 1 unit. Ingestion of more than 3 units/day every day or more than 21 units/week is excessive, especially for women. The threshold for alcohol-induced hepatic injury appears to be 30 g/day for women and 60 g/day for men if ingested over 5–10 years. These numbers may have to be modified if additional risk factors for liver disease are present (e.g., hepatitis C). One also needs to determine whether the patient has experienced withdrawal symptoms. The CAGE criteria are reliable indicators of excessive alcohol use. The CAGE criteria relate to the following four questions:

1. Has the patient tried to cut back on alcohol use?

2. Does the patient become angry when asked about his or her alcohol intake?

3. Does the patient feel guilty about his or her alcohol use?

4. Does the patient need an eye opener in the morning?

In this regard, many patients with chronic alcoholism experience morning nausea and dry heaves. The examiner should check for evidence of alcohol-associated illnesses (e.g., pancreatitis and peripheral neuropathy).

Box 1.2 Differential diagnosis of jaundice.

Most common causes

Decompensation of chronic liver disease

Alcoholic hepatitis

Gallbladder disease (cholecystitis, choledocholithiasis)

Sepsis/abnormal hemodynamics

Malignancy (pancreatic cancer, liver metastases)

Common causes

Viral hepatitis

Drug- or toxin-induced liver disease (especially acetaminophen)

Hemolysis (especially sickle cell anemia)

Postoperative (multiple factors)

Primary biliary cirrhosis

Primary sclerosing cholangitis

Less common causes

Hodgkin disease and non-Hodgkin lymphoma

Total parenteral nutrition

Gilbert syndrome; while unconjugated hyperbilirubinemia ≥1.2 mg/dL occurs in 2–5% of the population, serum bilirubin levels infrequently exceed 3.0 mg/dL and detectable jaundice is unusual

Causes and presumed sites of intrahepatic cholestasis

Liver cell (hepatocellular):

Viral hepatitis

Alcoholic liver disease

Chronic active liver disease

α1-Antitrypsin deficiency

Hepatocanalicular:

Drugs (androgens, phenothiazines)

Sepsis

Postoperative state

Total parenteral nutrition

Hodgkin and non-Hodgkin lymphoma

Amyloidosis

Sickle cell anemia

Toxic shock syndrome

Ductular:

Sarcoidosis

Primary biliary cirrhosis

Bile ducts:

Intrahepatic biliary atresia

Caroli disease

Cholangiocarcinoma

Primary sclerosing cholangitis

Recurrent cholestasis:

Benign recurrent intrahepatic cholestasis

Recurrent jaundice of pregnancy

Dubin–Johnson syndrome

A history of pruritus suggests cholestasis, either intrahepatic or extrahepatic. Box 1.2 shows the differential diagnosis of jaundice [1]. The patient should be specifically asked about the evolution of jaundice (i.e., the onset of dark urine and light stools), which may provide clues to the duration of illness. Recent changes in the menstrual cycle, particularly amenorrhea, if present, suggest chronic liver disease and often cirrhosis. A history of anemia, sickle cell disease, and hemoglobinopathy should also be ascertained for African-American patients. Right upper quadrant abdominal pain should prompt detailed questions about whether such pain is consistent with biliary colic or chronic cholecystitis. A history of inflammatory bowel disease should raise the question of primary sclerosing cholangitis or, if the patient has received blood transfusions in the past, hepatitis C. An occupational history should be obtained and questions about specific exposure to a known or suspected hepatotoxin should be asked of industrial workers with jaundice or liver disease.

Physical examination of the patient with jaundice or abnormal results of liver tests

The key elements in the physical examination of a patient with jaundice or abnormal results of liver tests are summarized in Box 1.3. Several important clues are evident on general inspection of the patient. It should be determined whether scleral icterus is present, and this should be done in natural daylight. Scleral icterus can usually be detected if the serum bilirubin level is elevated to values greater than 3.0 mg/dL. The presence of pallor suggests anemia. Wasting suggests advanced chronic liver disease or a neoplastic disorder. Needle tracks or evidence of skin popping suggest intravenous drug abuse. The presence of skin excoriation confirms that the patient has been experiencing pruritus, which can be particularly severe among patients with primary biliary cirrhosis and primary sclerosing cholangitis. The one area where such patients cannot scratch is the interscapular area, and this is usually free of evidence of excoriation. The presence of ecchymosis or petechiae raises the question of clotting problems, especially thrombocytopenia. Muscle tenderness and weakness are not uncommon among patients with chronic alcoholism and alcoholic myopathy. These findings are often overlooked. When associated with severe acute pancreatitis, discoloration of the abdomen is termed the Grey Turner sign. This finding implies increased likelihood of death. Other less common causes of ecchymosis include rhabdomyolysis, muscle infarction, mesentery thrombosis, strangulated bowel with extensive intestinal infarction, and massive intraperitoneal bleeding.

Box 1.3 Physical examination of the patient with jaundice.

General inspection

Scleral icterus

Pallor

Wasting

Needle tracks

Evidence of skin excoriations

Ecchymosis or petechiae

Muscle tenderness and weakness

Lymphadenopathy

Evidence of pneumonia

Evidence of congestive heart failure

Peripheral stigmata of liver disease

Spider angiomata

Palmar erythema

Gynecomastiaa

Dupuytren contracturea

Parotid enlargementa

Testicular atrophy

Paucity of axillary and pubic hair

Eye signs mimicking hyperthyroidism

Abdominal examination

Hepatomegaly

Splenomegaly

Ascites

Prominent abdominal collateral veins

Bruits and rubs

Abdominal masses

Palpable gallbladder

Signs of decompensated hepatocellular disease

Jaundice

Ascites

Oliguric hepatic failure

Hepatic encephalopathy:

Fetor hepaticus

Asterixis

Behavioral alterations (confusion, disorientation, failure to complete simple mental tasks)

aThis triad suggests chronic alcoholism

The presence of lymphadenopathy, if generalized, suggests a lymphoproliferative disorder such as Hodgkin disease or non-Hodgkin lymphoma. Supraclavicular lymphadenopathy should raise the question of underlying malignant disease of the stomach or bronchopulmonary tract. Patients with pneumonia have jaundice in approximately 3% of cases; this is more likely to be the case among patients with pneumococcal pneumonia. Accordingly, a careful examination of the lungs is in order in the evaluation of patients with jaundice. Patients with congestive heart failure quite frequently have chronic passive congestion of the liver, which can result not only in jaundice but also in signs of portasystemic encephalopathy.

There are several peripheral stigmata of chronic parenchymal liver disease. Spider angiomata are usually found in the distribution of the superior vena cava and most commonly on the upper anterior chest, neck, face, and upper thorax. The presence of more than a dozen spider angiomata should raise the question of portal hypertension. The triad of gynecomastia, Dupuytren contracture, and parotid enlargement should always raise the question of chronic alcoholism. Paucity of axillary and pubic hair and eye signs mimicking those of hyperthyroidism are often found among patients with advanced liver disease. Testicular atrophy, defined by a testicular diameter of less than 3 cm, is also common.

The abdominal examination is important in determining the liver size as well as the presence of an enlarged spleen. Percussion of the abdomen is important for several reasons. First, the size of solid organs such as the liver and spleen can be evaluated with percussion. One can often determine whether an increased amount of intraperitoneal fluid (ascites) is present. The upper and lower borders of liver dullness can be assessed by means of percussion along the right midclavicular line from the midchest to the midabdomen (Fig. 1.1). Liver size can be further assessed by having the patient inspire and observing the descent of the liver (Fig. 1.2). The lower border of liver dullness alerts the examiner to the site where the liver edge should be palpable. The liver span as judged by liver dullness measures 10–12 cm in men and 8–11 cm in women. A sudden decrease in liver dullness can occur in several conditions, such as viral hepatitis with the development of submassive or massive liver cell necrosis, localized dilatation of the transverse colon (as in toxic megacolon), fulminant colitis, and ileus associated with peritonitis or a perforated viscus (e.g., duodenal ulcer or diverticulitis). The spleen is normally not palpable. Percussion over the spleen reveals an area of dullness extending from the 10th rib in the posterior midaxillary aspect to the anterior aspect of the chest (Figs 1.2 and 1.3). When the patient inspires, the area of splenic dullness moves inferiorly and to the right.

Figure 1.1 Determination of liver size by means of percussion over the lower right anterior chest and the right upper quadrant of the abdomen.

nc01f001.eps

Figure 1.2 Abdomen and chest showing the location of the liver and the spleen as outlined by means of percussion. The liver descends 1–3 cm with inspiration, which is reflected by a change in liver dullness.

nc01f002.eps

Figure 1.3 Technique for percussion of the spleen. If splenomegaly is present, the percussion note is dull, and with inspiration the spleen moves downward and medially and the percussion note changes accordingly.

nc01f003.eps

The detection of splenic dullness is important for the following three reasons:

1. It may indicate splenic enlargement before the spleen can be palpated.

2. It alerts the examiner to the site where the spleen may be palpated.

3. Increasing dullness of the left flank may be a valuable clue to the diagnosis of traumatic rupture of the spleen or subcapsular hematoma.

All quadrants of the abdomen must be palpated in an orderly manner. When palpating the abdomen, the hand should be warm and the palm and extended fingers of the right hand placed flat in a plane parallel to the surface of the abdomen (Fig. 1.4). The pads of the fingers are used together to perform light general palpation. Light palpation is used on the abdomen first, and as tense muscles relax, deeper palpation should be tried. Quick jabbing movements should be avoided. Any area of tenderness or any increased muscular resistance should be recognized and examined in detail.

Figure 1.4 Technique for palpation of the liver.

nc01f004.eps

Percussion should alert the examiner to the approximate size and lower edge of the liver. Beginning at the right iliac fossa, the right hand is moved gradually upward until the edge of the liver is appreciated (Fig. 1.4). The patient can be asked to slowly take a deep breath. The descent of the diaphragm carries the liver down, which facilitates palpation of the liver edge. The edge of the liver can be felt in most healthy individuals if the patient's abdominal wall muscles are relaxed and the patient takes a slow, deep breath. In some healthy individuals, a very low lying thin segment of the liver can be palpated in the right lower quadrant. This is termed the Riedel lobe of the liver. An alternative approach to feeling the edge is to gently curl the fingers of the right hand below the costal margin and ask the patient to inspire slowly (Fig. 1.5). This is termed the Middleton method. In this manner, the liver descent is appreciated by eight fingertips. This method is important in determining minimal enlargement of the liver or a liver palpable only in the epigastrium, as can occur in advanced cirrhosis.

Figure 1.5 Alternative technique for palpation of the liver. The best results are obtained with gentle pressure of the curled fingers on the anterior abdominal wall.

nc01f005.eps

The examiner should determine whether the liver is soft, firm, hard, or irregular; whether the edge is rounded or sharp; whether discrete masses are present; and whether the left lobe is palpable across the midline. The presence of a palpable left lobe always denotes an abnormality, usually chronic liver disease. The size of the liver should be assessed as judged by the location of the edge below the right midclavicular line and the xiphoid. A normal liver edge is sharp, smooth, and not hard, and the left lobe is not palpable. A rounded edge suggests liver disease; a palpable left lobe suggests either chronic infiltrative or neoplastic liver disease. Modest enlargement of the liver occurs in several disorders, most notably viral hepatitis, chronic liver disease (all causes), chronic hepatitis, cirrhosis, choledocholithiasis, and extrahepatic biliary tract obstruction. Marked enlargement of the liver (edge >10 cm below the costal margin) occurs in relatively few disorders, which include: (i) primary and metastatic tumors of the liver, including lymphoma; (ii) alcoholic liver disease (fatty liver, alcoholic hepatitis, cirrhosis); (iii) severe congestive heart failure; (iv) infiltrative diseases of the liver, such as amyloidosis and myelofibrosis; and (v) chronic myelogenous leukemia. Finally, a pulsatile liver should raise the question of tricuspid regurgitation, which can occur with advanced mitral stenosis, endocarditis of the tricuspid valve, and severe pulmonary hypertension.

Percussion of the left upper quadrant may have alerted the examiner to the presence of an enlarged spleen. Palpation of the spleen should begin in the left iliac fossa and move up to the left costal margin (Fig. 1.6). If the spleen is not felt while the patient is supine, the patient should roll onto his or her right side so the examiner can again examine the left upper quadrant (Fig. 1.7). This method takes advantage of the fact that when the spleen enlarges, it becomes more easily palpable inferiorly and medially. This enlargement is better appreciated when the patient is in the right lateral decubitus position. An alternative is for the examiner to stand at the patient's right side with the patient's left hand placed under the 11th rib to elevate the thorax. The examiner then curls the fingers of either one or both hands below the costal margin and asks the patient to inspire. The splenic margin may then be felt by the fingertips.

Figure 1.6 Technique for palpation of the spleen.

nc01f006.eps

Figure 1.7 Palpation with the patient in the right lateral decubitus position. This should be performed on all patients with suspected splenomegaly if the spleen is not felt with the patient in the supine position.

nc01f007.eps

A common problem in evaluating left upper quadrant masses is differentiating the spleen and the left kidney. Palpation of a notch on the medial surface suggests that the organ being palpated is the spleen. Differentiation of the left lobe of the liver from the spleen can be difficult if massive hepatomegaly is present. One can usually discern a space or open area between the two organs. Common causes of splenomegaly include the following:

1. Portal hypertension caused by cirrhosis of the liver.

2. Infections (viral, bacterial, fungal).

3. Leukemia, lymphoma, and Hodgkin disease.

4. Connective tissue diseases (systemic lupus erythematosus and rheumatoid arthritis).

5. Infiltrative disorders (amyloidosis and sarcoidosis).

6. Hemolytic disorders.

7. Myelofibrosis.

Gallbladder

The gallbladder, when enlarged, can often be palpated in the right upper quadrant at the angle formed by the lateral border of the rectus abdominis muscle and the right costal margin. The gallbladder is palpable in approximately 25% of cases of carcinoma of the head of the pancreas (Courvoisier's law) because of painless distention of the gallbladder. The gallbladder is also palpable in approximately 30% of patients with acute cholecystitis, often because stones are impacted in the neck of the gallbladder. Often in acute cholecystitis, rather marked right upper quadrant tenderness is present, and palpation can be difficult because of intense involuntary spasms of the abdominal muscles. Percussion over the right lower anterior chest and right upper quadrant often elicits pain.

Another sign pointing to acute cholecystitis is right upper quadrant abdominal pain aggravated by inspiration (Murphy's sign). The patient is asked to inspire after the examining fingers are placed high in the right upper quadrant; inspiration causes the gallbladder to descend and come in contact with the extended fingers, causing pain and inspiratory arrest.

Bruits

Bruits are systolic sounds usually produced by the turbulence of blood flowing through diseased or compressed blood vessels. The many causes of abdominal bruits are listed in Table 1.1. The most common causes of such bruits include calcification of the aorta, celiac axis compression, and alcoholic hepatitis. An epigastric bruit can be appreciated in 20% of healthy thin young adults, especially if auscultation is performed after a meal. Such bruits are usually caused by the compression of the celiac axis artery by muscle fibers of the crus of the diaphragm. Abdominal bruits are often important clues leading to the diagnosis of hepatocellular carcinoma, renal artery stenosis, fibromuscular hyperplasia of the renal arteries, intestinal angina, aortic aneurysm, and pancreatic cancer.

Table 1.1 Causes of abdominal bruit [3].

Peritoneal friction rub

A friction rub heard over the liver suggests the diagnosis of liver metastasis or primary hepatocellular carcinoma. Other causes of hepatic friction rub include infarction of the liver (as in sickle cell anemia and polyarteritis nodosa) and liver abscess. A transient friction rub caused by a hematoma around the puncture site is common after liver biopsy but is usually not audible 4–6 hours after biopsy.

Ascites

Assessment of shifting dullness is often used to determine whether ascites is present. When free fluid is present in the abdomen, such fluid gravitates to the flanks, and the intestines float upward when the patient lies on his or her back. Percussion with the patient in this position discloses tympany over the anterior abdomen and dullness over the flanks. If the patient is turned to one side, the dullness shifts, and the percussion on the side that is uppermost becomes tympanic, because that area becomes occupied by gas-filled intestine.

Another physical finding pointing to the diagnosis of ascites is the fluid wave. A fluid wave is demonstrated by tapping the left flank sharply with the right hand while the left hand is placed against the opposite flank (Fig. 1.8). Either the patient or a second examiner must place the ulnar surface of his or her hand along the midline of the abdomen. A positive test result is one in which an impulse on the opposite flank is percussed after the right flank is tapped. Neither the test for shifting dullness nor the test for a fluid wave uniformly reveal modest amounts of ascitic fluid (<1,000 mL). Indeed, both tests have a sensitivity of only approximately 60% compared with ultrasound examination [2]. Furthermore, the test results can be spuriously positive in examinations of obese patients.

Figure 1.8 Technique for eliciting a fluid wave. The examiner's left hand is placed on the right lateral abdomen, and the right hand taps the left flank or loin while a second examiner or the patient's hand compresses the abdomen in the midline.

nc01f008.eps

A third sign, bulging flanks, although often present in ascites, is frequently present in obese patients as well. A fourth test of ascites is elicitation of the puddle sign. In this test, the patient lies prone for a few minutes and then moves to hands and knees. The diaphragm of the stethoscope is placed over the most dependent part of the abdomen, where puddling would be expected to occur. The examiner then repeatedly flicks the near flank of the abdomen while moving the stethoscope toward the opposite flank. A positive test result consists of a definite change in the intensity and character of the percussion note as the stethoscope is moved.

The presence or absence of ascites can be confirmed most reliably with imaging procedures such as ultrasonography and computed tomography (CT). The urinary bladder is often percussed in the hypogastrium, especially if urinary retention is present.

Abdominal masses

All nine areas of the abdomen should be palpated carefully for the presence of abdominal masses. In addition, the examiner should palpate the periumbilical area for the presence of lymph nodes. Such lymph nodes, termed Sister Mary Joseph nodes, reflect intraperitoneal tumor and are the harbinger of peritoneal carcinomatosis.

Signs and symptoms of decompensated liver disease

Signs of decompensated liver disease in patients with cirrhosis include jaundice, ascites, portal hypertension with bleeding esophageal or gastric varices, oliguric hepatic failure, and hepatic encephalopathy. These are discussed in detail in Chapters 11, 13, and 18. A bedside diagnosis of cirrhosis of the liver can be made on the basis of two physical findings and two laboratory findings. The physical findings are ascites and asterixis, and the laboratory findings are a serum albumin level of less than 2.8 g/dL and a prolongation of the prothrombin time of more than 16 seconds.

The topic of hepatic encephalopathy is discussed in detail in Chapter 18. However, this diagnosis can be made readily at physical examination when the following findings are present, especially in a jaundiced patient:

1. Hypothermia, with a temperature of less than 36°C.

2. Fetor hepaticus, which is a pungent odor in the breath caused by the excretion of sulfur-containing amino acid by-products such as dimethyl sulfide, methanethiol, and ethanethiol.

3. Asterixis, which can be elicited by two techniques (Fig. 1.9), and abnormal cognitive functioning as evidenced by an abnormal result of a Reitan trial test or A-deletion test. The latter is performed by asking the patient to delete all the As in one or two paragraphs of newsprint; the examiner tabulates how many As were not deleted.

Figure 1.9 Techniques for eliciting asterixis. (A) The examiner applies his index finger over the dorsum of the patient's wrist while asking the patient to dorsiflex the wrist. Asterixis is the downward drift and abnormal recovery motion of the hand with the fingers either together or outstretched. (B) Alternative method for eliciting asterixis in patients who may not have the requisite extensor tonus. The examiner asks the patient to clench his fingers around the examiner's fingers. Asterixis is elicited with subtle movements of the examiner's wrist. In this manner, one can both feel and see the asterixis movement.

nc01f009.eps

Asterixis, although characteristic of hepatic encephalopathy, is not pathognomonic of this disorder. Asterixis is also found in patients with renal failure, pulmonary insufficiency, and congestive heart failure. Patients with hepatic encephalopathy may have difficulty with seemingly simple tasks such as drawing a square, spiral, or five-cornered star or signing their name.

The diagnosis of chronic portosystemic encephalopathy is usually established on the basis of the following criteria:

1. Documented chronic parenchymal liver disease.

2. Evidence of portosystemic shunting, occurring either naturally (varices) or following the insertion of a transjugular intrahepatic portosystemic shunt (TIPS).

3. Behavioral alterations that can range from subtle abnormalities in cognitive functioning to frank unresponsive coma.

4. Improvement in mental status after measures directed at altering gastrointestinal ammonia metabolism, such as with dietary protein restriction or lactulose therapy.

5. An abnormal result of an electroencephalogram showing a decrease in mean cycle frequency. This is not routinely done.

Role of noninvasive imaging

Noninvasive imaging of the liver and biliary tree in the evaluation of the patient with jaundice and/or liver disease

As noted earlier, in patients with jaundice, a careful history, physical examination, and review of standard laboratory tests should allow a physician to make an accurate clinical diagnosis in 85% of cases. All too often, however, an imaging procedure is done before these basic steps have been completed and such omissions may actually delay establishing the correct diagnosis. The following are offered as guidelines to be considered for ordering imaging procedures:

1. Liver imaging procedures are not indicated in a patient with acute viral hepatitis.

2. Liver imaging procedures are not necessary in a patient with a firm clinical diagnosis of nonalcoholic fatty liver disease.

3. In a patient with jaundice and obstructive-type liver test abnormalities, that is, a disproportionately elevated serum alkaline phosphatase level and serum aminotransferases of less than 300 units, ultrasonography is the usual initial imaging procedure. Ultrasonography is reliable for differentiating medical jaundice, that is, intrahepatic cholestasis, from extrahepatic obstructive jaundice. In a patient with a serum bilirubin greater than 10 mg/dL that has been present for more than 2 weeks, ultrasound has a sensitivity of 95% and a specificity of 95% in differentiating intrahepatic versus extrahepatic causes of jaundice. Box 1.2 lists several causes of intrahepatic cholestasis. In some cases, the level and cause of bile duct obstruction can be identified.

4. If an ultrasound examination in a patient with jaundice reveals evidence of dilated intrahepatic ducts, additional imaging procedures such as CT scanning, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS) with biopsies are often necessary to establish the cause of obstruction. If no dilated ducts are found and the cause of jaundice is deemed to be medical, a liver biopsy is frequently in order.

5. In patients with suspected cholelithiasis, ultrasonography is the primary diagnostic imaging procedure. In patients with suspected choledocholithiasis MRCP is often the next step. However, if there is a question of ascending cholangitis, ERCP is the preferred diagnostic procedure as papillotomy may be indicated.

6. In a patient with new onset of ascites, Doppler ultrasonography is indicated to determine the patency of the portal and hepatic venous systems.

7. In patients with obstructive jaundice due to suspected pancreatic carcinoma, EUS is superior to CT scanning with regard to detecting a pancreatic mass but comparable with regard to tumor staging and predicting either resectability or nonresectability.

8. In patients with unexplained hepatomegaly, either ultrasound or CT scanning are appropriate initial imaging procedures.

Case vignettes: practical considerations

The following are vignettes in which the salient features of a patient's illness alert the clinician to the most likely diagnosis.

1. A 35-year-old woman is referred with the diagnosis of acute viral hepatitis. Liver tests reveal a total serum bilirubin level of 3.0 mg/dL; serum aspartate aminotransferase (AST), 900 U/L; serum alanine aminotransferase (ALT), 880 U/L; serum alkaline phosphatase, 180 U/L; serum albumin, 3.6 g/dL; serum globulins, 5.8 g/dL; and prothrombin time, 15 seconds (international normalized ratio (INR), 1.9).

Key: The presence of marked hypergammaglobulinemia along with prolongation of the prothrombin time suggests that this patient has chronic rather than acute hepatitis. The most likely diagnosis for this 35-year-old woman would be autoimmune chronic hepatitis.

2. A 30-year-old man is referred for evaluation of elevated serum aminotransaminase levels. The patient weighed 230 pounds (103.5 kg) as a high school football player, 250 pounds (112.5 kg) after graduating from college, and 300 pounds (135 kg) 5 years later. Results of all liver tests are normal except for a serum AST level of 65 U/L and a serum ALT level of 80 U/L.

Key: If a patient has no symptoms except that the transaminase values are elevated approximately twice the normal value, six considerations should come to mind. They include: (i) excessive alcohol use; (ii) obesity with a body mass index (BMI) greater than 30; (iii) hepatitis C; (iv) excessive doses of acetaminophen (>4.0 g/day); (v) use of statin-type cholesterol-lowering agents; and (vi) celiac sprue. In this patient, the most likely explanation is obesity, and he may well have nonalcoholic steatohepatitis.

3. A 30-year-old man has severe flu symptoms for 5 days. Cough, myalgia, headache, and anorexia have resulted in markedly diminished intake of food and liquid. He has been ingesting generic acetaminophen 4.0 g/day and acetaminophen plus diphenhydramine (Tylenol PM™) to facilitate sleep. He was found to have a serum AST level of 5,000 U/L and an ALT level of 5,500 U/L.

Key: Ingestion of seemingly therapeutic doses of acetaminophen by a patient who has in essence fasted for 4 or 5 days can result in drug-induced hepatotoxicity. Results of early studies indicated that concurrent ingestion of alcohol and acetaminophen was the most common cause of this presentation. However, the scenario in this case is the more common presentation now. In patients who come to medical attention with serum aminotransaminase values of approximately 5,000 U/L, the differential diagnosis is limited to viral hepatitis, effects of drugs and toxins, and ischemia with shock liver. In the United States, approximately one half of cases of fulminant hepatic failure are related to acetaminophen ingestion.

4. A 63-year-old woman with non-insulin-requiring diabetes mellitus and hypercholesterolemia has been found to have abnormal results of liver tests. Results of liver biopsy establish the diagnosis of cirrhosis, but there is no obvious cause, and the patient is considered to have cryptogenic cirrhosis.

Key: A detailed history reveals that the patient was obese through much of her adult life, weighing in excess of 300 pounds (135 kg; BMI >35). Although she weighed only 200 pounds (90 kg) when she sought medical attention, many years of obesity coupled with diabetes and hypercholesterolemia most likely caused nonalcoholic steatohepatitis, which progressed to cirrhosis. The most common cause of cryptogenic cirrhosis is antecedent nonalcoholic steatohepatitis.

5. A 28-year-old man who has had ulcerative colitis for 10 years is found through routine screening to have a serum alkaline phosphatase level of 500 U/L. Results of all other liver tests are normal.

Key: Persistent elevation of serum alkaline phosphatase level to values greater than twice the normal value in patients with inflammatory bowel disease, especially those with ulcerative colitis, should raise the question of occult primary sclerosing cholangitis. This patient needs an MRCP as the initial screening procedure.

6. A 40-year-old woman is admitted to hospital for therapy for alcohol withdrawal and impending delirium tremens. Laboratory studies reveal serum bilirubin, 2.0 mg/dL; AST, 225 U/L; serum ALT, 45 U/L; prothrombin time, 14 seconds (INR, 1.3); serum iron level, 170 μg/dL; total iron-binding capacity, 200 μg/dL; iron saturation, 85%; and serum ferritin, 700 μg/dL.

Key: The increased percentage of iron saturation and elevated serum ferritin level in this case are not indicative of a diagnosis of hemochromatosis. Serum iron levels and serum ferritin levels are frequently elevated in patients with acute liver disease and marked liver cell necrosis.

7. A 17-year-old boy is referred for evaluation of hepatosplenomegaly and thrombocytopenia. On examination, he is found to have a peculiar wing-beating tremor. When the patient abducts his arms and flexes his forearms, a sustained tremor develops. The patient does not have Kayser–Fleischer rings. The serum ceruloplasmin level is 30 mg/dL.

Key: The presence of a wing-beating tremor in a young man with apparent chronic liver disease is almost pathognomonic of Wilson disease. Examination of a 24-hour urine collection for copper revealed excretion of 1,100 μg of copper. Of the three standard screening tests for Wilson disease – that is, Kayser–Fleischer rings, low serum ceruloplasmin level, and increased urinary excretion of copper – results of all three are abnormal in only one third of patients. In the remaining two thirds of patients, only one test may have a positive result. The clue in this case was the unusual tremor.

8. A 25-year-old Guatemalan man who does not speak English is visiting relatives in the United States. After a large meal, he develops retching and hematemesis. Esophagogastroduodenoscopy reveals esophageal varices. The patient is admitted to hospital and found to have hepatosplenomegaly, thrombocytopenia, a normal serum albumin level, and minimal hyperbilirubinemia (serum bilirubin, 2.0 mg/dL). Through interpreters, it is learned that the patient had his first episode of hematemesis at 10 years of age. He had several subsequent episodes managed by means of banding of varices.

Key: The onset of variceal bleeding at 10 years of age with stigmata of chronic liver disease but with well-preserved liver function indicates that the most likely diagnosis is congenital hepatic fibrosis.

9. A 55-year-old man is referred for evaluation of asymptomatic hepatosplenomegaly. The patient's liver span is over 20 cm with a smooth, rounded edge felt 14 cm below the costal margin with a prominent left lobe. The spleen is palpable 4 cm below the left costal margin. Serum bilirubin, alkaline phosphatase, AST, and ALT levels are normal. The serum albumin level is 3.5 g/dL and serum globulin levels are 3.0 g/dL. The prothrombin time and partial thromboplastin time are normal. The results of a complete blood cell count and routine chemical analyses are normal. Urinalysis is unremarkable except for 2+ proteinuria. Blood glucose levels are normal, and the patient is not overweight.

Key: The finding of marked hepatomegaly with normal liver test results in the evaluation of a patient without symptoms should raise the question of infiltrative liver disease, such as amyloidosis. In addition to amyloidosis, relatively few disorders give rise to marked hepatomegaly. These include primary and metastatic tumors of the liver, alcoholic liver disease, severe congestive heart failure, and advanced chronic myelogenous leukemia.

10. A 49-year-old man has documented end-stage chronic liver disease due to hepatitis C and alcohol ingestion. He has had previous hospital admissions for bleeding esophageal varices and ascites. Because of lack of compliance with a salt- and fluid-restricted diet, the patient has recurrent ascites despite treatment with diuretics. He is known to have diverticular disease, having had one previous episode of diverticulitis. He is admitted to the hospital with a 2-day history of severe abdominal pain, chills, fever, and anorexia. Diagnostic paracentesis reveals the following: white blood cell count, 10,000/μL with 90% polymorphonuclear leukocytes; ascitic fluid protein, 4.0 g/dL; ascitic fluid glucose, 35 mg/dL with a simultaneous serum glucose level of 120 mg/dL and peritoneal fluid of pH 7.1.

Key: This patient does not have spontaneous bacterial peritonitis. Rather, he has primary bacterial peritonitis. The triad of findings of a white blood cell count of 10,000/μL with a left shift, increased serum protein level, and low glucose level points to primary bacterial contamination of the peritoneal cavity, rather than spontaneous bacterial peritonitis, most likely from a perforated viscus. If a flat abdominal radiograph does not reveal evidence of free air, a CT scan should be obtained. If perforation is confirmed, the patient, despite the advanced liver disease, needs surgical exploration.

11. A 47-year-old man is referred for evaluation of ascites believed to be caused by chronic liver disease. There is no history of excessive alcohol use, risk factors for hepatitis B and C, or other gastrointestinal symptoms. There is a remote history of tuberculosis 20 years earlier managed appropriately. Previous physical examinations are said to be unremarkable except for ascites. Repeated physical examination reveals normal vital signs except for pulsus paradoxus of 20 mmHg. Inspiratory distention of the cervical neck veins is noticed. A third heart sound is heard to the left of the sternal border. The lungs are clear to auscultation. Abdominal examination reveals obvious ascites with a fluid wave. There is no peripheral edema. Ultrasound examination confirms the presence of ascites, reveals a liver that spans 15 cm, and a normal-sized spleen. The portal and hepatic veins are patent.

Key: The presence of pulsus paradoxus and a Kussmaul sign (inspiratory distention of the cervical neck veins) point to a diagnosis of constrictive pericarditis manifesting as ascites and masquerading as chronic liver disease. Results of an echocardiogram confirmed the diagnosis.

12. A 47-year-old woman is referred for evaluation of hepatosplenomegaly. The patient has no risk factors for chronic liver disease. These include absence of alcohol intake, no risk factors for hepatitis B and C, and no excessive use of vitamins or herbal teas. Urinalysis, however, reveals the presence of hematuria; a CT scan shows a lesion in the right kidney consistent with renal cell carcinoma. What is the cause of the patient's hepatosplenomegaly?

Key: Although one would be tempted to consider metastatic liver disease to be the most likely explanation for the hepatosplenomegaly, a rare syndrome termed Stauffer syndrome is a form of nephrogenic hepatosplenomegaly. Hypernephroma, in some ill-defined way, may elaborate hepatotropic growth factors that cause enlargement of the liver and spleen. Such patients do not usually have evidence of metastatic liver disease, and with nephrectomy the liver may actually regress in size.

13. A 57-year-old woman is referred for evaluation of ascites. She initially visited her gynecologist, who suspected that she might have ovarian carcinoma. However, a pelvic examination and pelvic and abdominal CT scans did not reveal any evidence of tumor. There is no history to explain the development of ascites except that the patient has been drinking enormous quantities of herbal tea, ingesting 18–24 cups/day for the last 2 years.

Key: An ultrasound examination with determination of portal and hepatic venous flow velocity revealed findings consistent with hepatic venous occlusion. Tumors (hepatocellular carcinoma, pancreatic carcinoma, hypernephroma, and gastric carcinoma) are infrequent causes of Budd–Chiari syndrome. The most common cause is an obvious or incipient myeloproliferative syndrome. Herbal teas may contain alkaloids that can cause both intrahepatic and extrahepatic venoocclusive disease.

14. A 62-year-old woman has been to the hospital because of pruritus and is found to have jaundice. Except for scleral icterus, the findings of the physical examination are unremarkable. The liver span measures 12 cm at percussion. Liver tests reveal the serum bilirubin level to be 8.0 mg/dL; AST, 400 U/L; ALT, 420 U/L; serum alkaline phosphatase, 500 U/L; normal serum prothrombin time; and normal serum albumin and globulin levels. Results of serum albumin, globulin, and antinuclear antibody tests are all either negative or within normal limits. An ultrasound examination shows a normal liver, gallbladder, and pancreas.

Key: A detailed history interview reveals that this woman took amoxicillin–clavulanic acid at a dosage of 2.0 g/day for 2 weeks, but this medication was discontinued 3 weeks earlier. Amoxicillin–clavulanic acid has been frequently reported to cause a cholestatic hepatitis. Jaundice and abnormal results of liver tests can develop 1–4 weeks after discontinuation of treatment. Histologic examination of the liver usually shows evidence of centrilobular (zone 3) or panlobular cholestasis, which, on rare occasions, is associated with a granulomatous hepatitis. The prognosis is excellent.

15. A 43-year-old man with a history of excessive alcohol ingestion (6 to 12 bottles of beer per day for many years) is admitted to the hospital with right upper quadrant pain, chills, fever, dark urine, and pruritus. Physical examination reveals right upper quadrant tenderness, the liver measuring 14 cm with a round, smooth, tender edge palpable 3 cm below the right costal margin. Liver tests reveal serum bilirubin, 8.0 mg/dL; AST, 220 U/L; ALT, 400 U/L; serum albumin, 3.8 g/dL; serum globulins, 3.2 g/dL; serum alkaline phosphatase, 400 U/L; mean corpuscular volume, 94 μm³; white blood cell count, 14,000/μL with a left shift; and prothrombin time, 13 seconds (INR, 1.2).

Key: In patients with alcoholic hepatitis, the AST : ALT ratio is almost invariably 2 : 1 or greater. In this case, although the patient has consumed excessive amounts of alcohol, the disproportionately higher ALT : AST ratio suggests a cause of jaundice other than alcoholic hepatitis. An ultrasound examination showed cholelithiasis and a dilated common bile duct. This patient, although with a history of alcoholism, had biliary tract disease. A clue to the correct diagnosis was the unanticipated reversal of the AST : ALT ratio.

Further reading

Cattau EL Jr, Benjamin SB, Knuff TE, et al. The accuracy of the physical examination in the diagnosis of suspected ascites. JAMA 1982;247:1146.Report of a study that shows that the bedside diagnosis of ascites is inaccurate in approximately one third of cases and that ultrasound examination is helpful in detecting moderate amounts of ascitic fluid.

Greenberger NJ, Hinthorn DH. History Taking and Physical Examination: essentials and clinical correlates. St Louis: Mosby-Year Book, 1992:220–61.A detailed presentation of history taking and physical examination of the abdomen and description of acute and chronic abdominal pain syndromes. Much of the information is directly applicable to patients with diseases of the liver, biliary tree, or pancreas.

Vuppalanchi R, Liangpunsakul S, Chalsani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol 2007;102:558–62.A detailed analysis of the causes of jaundice in 732 cases with a serum bilirubin ≥3.0 mg/dL.

References

1. Vuppalanchi R, Liangpunsakul S, Chalsani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol 2007; 102: 558–62.

2. Cattau EL Jr, Benjamin SB, Knuff TE, et al. The accuracy of the physical examination in the diagnosis of suspected ascites. JAMA 1982; 247: 1146.

3. Greenberger NJ, Hinthorn DH. History Taking and Physical Examination: essentials and clinical correlates. St Louis: Mosby-Year Book, 1992: 220–61.

Multiple choice questions

1.1 Each unit of packed red blood cells transfused to a patient contains bilirubin. Which of the following best approximates the amount infused in one unit?

a. 25 mg.

b. 50 mg.

c. 100 mg.

d. 150 mg.

e. 200 mg.

1.2 A 20-year-old woman is transferred to your hospital because of the onset of jaundice and acute liver failure over a period of 7 days. There is no history of antecedent medication use except for acetaminophen 1.8 g/day for 2 days, no exposure to jaundiced patients, and no recreational drug use. Physical examination revealed marked jaundice, hepatomegaly, and asterixis. Laboratory studies revealed: hemoglobin 8 g/dL, hematocrit 24%, serum bilirubin 15.1 mg/dL, AST 120 U/L, ALT 150 U/L, serum albumin 1.9 g/dL, and hemoglobinuria. What is the most likely etiology of her liver failure?

a. Autoimmune hepatitis.

b. Wilson disease.

c. Leptospirosis.

d. Acetaminophen hepatoxicity.

e. Herpes simples virus.

Answers to the multiple choice questions can be found in the Appendix at the end of the book.

These multiple choice questions are also available for you to complete online.

Visit http://www.schiffsdiseasesoftheliver.com/

CHAPTER 2

Laboratory Tests

H. Franklin Herlong & Mack C. Mitchell Jr

Department of Gastroenterology, Johns Hopkins Bayview Medical School, Baltimore, MD, USA

Key concepts

Biochemical tests can be used to detect acute injury to the liver and chronic diseases of the liver before development of symptoms.

Elevations in serum levels of aminotransferases (aspartate aminotransferase and alanine aminotransferase) reflect hepatocellular injury and/or permeability of the liver cell membrane, but do not correlate with the extent of fibrosis or measures of metabolic functions of the liver.

An elevation of serum alkaline phosphatase occurs in response to intrahepatic cholestasis, extrahepatic obstruction of bile ducts, or infiltration of the liver with granulomatous inflammation, amyloidosis, or venous congestion.

The rate-limiting step in metabolism and disposition of bilirubin is the transport of conjugated bilirubin from the hepatocyte into the bile. An elevation in the conjugated (direct-reacting) fraction of bilirubin is evidence of intrahepatic cholestasis or extrahepatic obstruction of the bile ducts.

Serum levels of albumin may be low in patients with acute or chronic liver disease, but very often drop in response to the acute phase response, making it difficult to evaluate hepatic metabolic function in clinical situations such as infection.

Although single laboratory tests are generally not useful in evaluating the severity of acute or chronic liver diseases, the use of mathematical equations combining tests may be effective as surrogate markers for the extent of fibrosis, steatosis, and inflammation as well as to predict the short-term prognosis in patients with liver disease.

The use of laboratory tests is an important component of the assessment of patients with liver disease. With increasing frequency, elevations in the hepatic enzymes detected on routine screening tests provide the first evidence of liver disease in otherwise asymptomatic patients. In those patients with previously recognized hepatic dysfunction, laboratory tests can help establish the etiology of liver disease and provide valuable prognostic information. Rarely does a single test provide sufficient information to establish a diagnosis or assess severity of liver disease. A combination of tests such as serum bilirubin, albumin, aminotransferases, and alkaline phosphatase is sometimes referred to liver function tests or a liver panel. These tests, in combination with the prothrombin time can provide an initial characterization of the etiology and severity of liver disease. However, one should recognize that the aminotransferases and alkaline phosphatase are tests that reflect hepatic injury not function. Traditionally liver diseases have been characterized as primarily hepatocellular or cholestatic based on the predominance of elevated aminotransferases or alkaline phosphatase. While an individual laboratory test may not provide a specific diagnosis, the pattern of abnormalities can suggest a general category of hepatic dysfunction. Although this distinction helps direct the initial evaluation there is often considerable overlap so that aggregating the diseases is less useful, as in the case of hepatotoxic drug reactions. With regard to drug-induced liver injury (DILI), those instances where the alanine aminotransferase (ALT) is greater than two times the upper limits of normal (ULN) and the ALT : alkaline phosphatase ratio is greater than 5 are considered primarily hepatocellular injuries. Those where the alkaline phosphatase is greater than two times the ULN and the ALT : alkaline phosphatase ratio is less than 2 are considered primarily cholestatic injuries. If the ALT and alkaline phosphatase are more than two times the ULN and the ratio is >2 or <5, the disorder is considered mixed hepatocellular/cholestatic. On occasion, minor elevations in the hepatic enzymes result from metabolic adaptation to drug metabolism and do not represent hepatic injury.

Laboratory tests can sometimes be helpful in assessing the severity of a liver disease, as is the case for using the prothrombin time to identify acute liver failure in a patient with acute liver disease or injury. However, for chronic conditions such as alcoholic liver disease, commonly measured tests of liver function such as the serum albumin can be affected significantly by factors other than extent of liver disease such as malnutrition, malabsorption, or chronic inflammation. The commonly used laboratory tests also lack specificity, which may limit their effectiveness in establishing a diagnosis. For example, an elevation in the alkaline phosphatase can reflect disorders of bone or liver, while elevated aminotransferases can be seen in cardiac disease or disorders of skeletal muscle as well as liver diseases. Unfortunately the commonly measured liver enzymes do not correlate with the extent of fibrosis or measures of metabolic functions of the liver. Consequently, patients with cirrhosis may have no abnormalities in laboratory tests.

Finally laboratory tests provide an important tool to assess the effectiveness of therapy in diseases like viral or autoimmune hepatitis or when injury has resolved after discontinuing a hepatotoxic drug. Serial determinations of liver enzymes are useful in identifying particular causes of liver injury. For example, ischemic necrosis will cause a marked elevation in the aminotransferases that returns to normal within a matter of days, whereas acute viral hepatitis will cause sustained elevations for several weeks. In the evaluation of patients for liver disorders, it is helpful to group these tests into general categories. We have found the following classification most useful:

Tests to detect injury to hepatocytes: these include all the enzyme tests, of which the aminotransferases and alkaline phosphatase are the most useful.

Tests of the biosynthetic capacity of the liver: included in this group are coagulation factors (prothrombin time/international normalized ratio (INR)) serum albumin, ceruloplasmin, ferritin, α1-antitrypsin, and lipoproteins. These substances are synthesized in the liver and transported into the circulation.

Tests of the capacity of the liver to transport organic anions and metabolize drugs: within this category, the serum bilirubin is the most useful. Other tests that assess clearance of organic compounds from the circulation by the liver include indocyanine green (ICG), bile acids, caffeine, lidocaine, and breath tests. These tests are rarely used in clinical medicine, but may have a limited role in some research studies.

Tests to detect fibrosis in the liver: these include proprietary tests such as Fibrosure®, FibroTest®, and the Enhanced Liver Fibrosis® (ELF) test. These tests rely on the use of several biochemical markers that are mathematically combined to estimate the degree of fibrosis assessed by histopathology of the liver (see Chapter 12).

Tests that reflect chronic inflammation or altered immunoregulation: these include specific autoantibodies and immunoglobulins, proteins that are made by B lymphocytes, not hepatocytes. Some of these tests may be helpful in diagnosing autoimmune liver diseases such as autoimmune hepatitis and primary biliary cirrhosis.

Tests for detection of injury to hepatocytes (serum enzyme tests)

The liver contains thousands of enzymes, some of which are also present in serum in very low concentrations. Most of these enzymes have no known function in the serum. They are distributed in the plasma and interstitial fluid and have characteristic half-lives of disappearance, usually measured in days. Little is known about their catabolism or clearance. The elevation of activity for a given enzyme in serum is thought to primarily reflect its increased rate of entry into serum from injured liver cells. Serum enzyme tests can be grouped into two categories: (i) enzymes whose elevation in serum reflects generalized damage to hepatocytes; and (ii) enzymes whose elevation in serum primarily reflects cholestasis.

Enzymes that indicate the presence of hepatocellular necrosis

Aminotransferases

The serum aminotransferases (formerly called transaminases) are sensitive indicators of liver cell injury and are most helpful in recognizing acute hepatocellular diseases like hepatitis. The activities of ALT, formerly serum glutamic-pyruvic transaminase, and aspartate aminotransferase (AST), formerly serum glutamic-oxaloacetic transaminase, in serum are the most frequently measured indicators of liver disease. These enzymes catalyze the transfer of the α-amino groups of alanine and aspartic acid, respectively, to the α-keto group of ketoglutaric acid. This reaction results in the formation of pyruvic acid and oxaloacetic acid (Fig. 2.1). Of the numerous methods developed for measuring ALT and AST activity in serum, the most specific method couples the formation of pyruvate and oxaloacetate – the products of the aminotransferase reactions – to their enzymatic reduction to lactate and malate. The reduced form of nicotinamide adenine dinucleotide (NADH), the cofactor in this reduction, is oxidized to nicotinamide adenine dinucleotide (NAD). Because NADH (but not NAD) absorbs light at 340 nm, the event can be followed spectrophotometrically by means of the loss of absorptivity at 340 nm.

Figure 2.1 Enzymatic assay of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). LDH, lactate dehydrogenase; MDH, malic dehydrogenase; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase.

nc02f001.eps

Both aminotransferases are normally present in serum in low concentration. The precise source of these enzymes in serum has never been firmly identified, although presumably they originate in tissues rich in ALT and AST. AST is present in liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lung, leukocytes, and erythrocytes, in decreasing order of concentration. ALT is present in highest concentration in the liver. ALT and AST both require pyridoxal 5′-phosphate as a cofactor, and both may be present in serum in apoenzyme as well as holoenzyme form [1]. In tissues, ALT is present in the cytosol; whereas AST occurs in two locations, the cytosol and mitochondria. The cytosolic and mitochondrial forms of AST are true isoenzymes and are immunologically distinct. Approximately 80% of AST activity in human liver is contributed by the mitochondrial isoenzyme, whereas most of the circulating AST activity in healthy individuals is derived from the cytosolic isoenzyme. Neither ALT nor AST has isoenzymes that are tissue-specific. Hence, isoenzyme analysis of serum ALT or AST seldom is useful. Patients with acute myocardial infarction and chronic alcoholic liver disease may be exceptions. Large increases in mitochondrial AST occur in serum after extensive tissue necrosis. Because of this, assay of mitochondrial AST has been advocated as an accurate test for the detection of myocardial infarction, but