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The Anton R. Fried, MD, Chair
Department of Medicine
Newton-Wellesley Hospital
Assistant Chief of Medicine
Massachusetts General Hospital
Professor of Medicine
Harvard Medical School
Professor of Medicine
Tufts University School of Medicine
Newton, Massachusetts
PAUL MARTIN, MD, FRCP, FRCPI
Professor of Medicine
Chief, Division of Gastroenterology and Hepatology
University of Miami Miller School of Medicine
Miami, Florida
Sanath Allampati, MD
Assistant Professor
Department of Internal Medicine
West Virginia University
Morgantown, West Virginia
Helen M. Ayles, MBBS, MRCP, DTM&H, PhD
Professor of Infectious Diseases and International Health
Clinical Research Department
London School of Hygiene and Tropical Medicine
London, England
Director of Research
ZAMBART Project
University of Zambia School of Medicine Lusaka, Zambia
Bruce R. Bacon, MD
James F. King MD Endowed Chair in Gastroenterology
Professor of Internal Medicine
Division of Gastroenterology and Hepatology
Saint Louis University School of Medicine
St. Louis, Missouri
Sarah Lou Bailey, BSc, MBChB, MRCP
Clinical Research Fellow
Faculty of Infectious and Tropical Diseases
London School of Hygiene and Tropical Medicine
London, England
William F. Balistreri, MD
Director
Pediatric Liver Care Center
Department of Gastroenterology, Hepatology, and Nutrition
Children’s Hospital Medical Center
Cincinnati, Ohio
Ji Young Bang, MBBS, MPH
Interventional Endoscopist Center for Interventional Endoscopy
Florida Hospital Orlando, Florida
Petros C. Benias, MD Director of Endoscopic Surgery
Northwell Health System
Hofstra University Manhassett, New York
Marina Berenguer, MD, PhD
Professor
Hepatology and Liver Transplantation Unit
La Fe University and Polytechnic Hospital Valencia, Spain
Emily D. Bethea, MD Fellow in Gastroenterology
Gastrointestinal Division
Massachusetts General Hospital Chief Medical Resident Department of Medicine
Brigham and Women’s Hospital Boston, Massachusetts
Kalyan Ram Bhamidimarri, MD, MPH
Assistant Professor of Clinical Medicine Departments of Medicine and Hepatology University of Miami Miami, Florida
Christopher L. Bowlus, MD
Professor and Chief Division of Gastroenterology and Hepatology University of California, Davis Sacramento, California
James H. Lewis, MD
Professor of Medicine and Director of Hepatology
Division of Gastroenterology
Georgetown University Medical Center
Washington, District of Columbia
Keith D. Lillemoe, MD, FACS
Chief of Surgery
Department of Surgery
Massachusetts General Hospital
W. Gerald Austen Professor of Surgery
Harvard Medical School
Boston, Massachusetts
Vincent Lo Re III, MD, MSCE
Associate Professor of Medicine and Epidemiology
Department of Medicine
Division of Infectious Diseases
Department of Biostatistics and Epidemiology
Perelman School of Medicine
University of Pennsylvania Philadelphia, Pennsylvania
Hanisha Manickavasagan, MD
Department of Internal Medicine
Drexel University College of Medicine
Philadelphia, Pennsylvania
Paul Martin, MD, FRCP, FRCPI
Professor of Medicine
Chief, Division of Gastroenterology and Hepatology
University of Miami Miller School of Medicine
Miami, Florida
Marlyn J. Mayo, MD
Associate Professor
Department of Internal Medicine
University of Texas Southwestern Medical Center
Dallas, Texas
Mack C. Mitchell, MD Professor
Department of Internal Medicine
University of Texas Southwestern Medical Center
Dallas, Texas
Kevin D. Mullen, MD, FRCPI, FAASLD
Professor of Medicine
Director of Digestive Diseases
West Virginia University
Morgantown, West Virignia
Santiago J. Muñoz, MD
Director of Hepatology
Medical Director, Liver Transplantation
Hahnemann University Hospital Professor of Medicine
Drexel University College of Medicine
Philadelphia, Pennsylvania
Brent A. Neuschwander-Tetri, MD
Professor of Internal Medicine
Division of Gastroenterology and Hepatology
Saint Louis University School of Medicine
St. Louis, Missouri
Kelvin T. Nguyen, MD
Gastroenterology Fellow
Vatche and Tamar Manoukian Division of Digestive Diseases
David Geffen School of Medicine at University of California, Los Angeles Los Angeles, California
Kavish R. Patidar, DO
Division of Gastroenterology, Hepatology, and Nutrition
Virginia Commonwealth University
Richmond, Virginia
Patricia Pringle, MD Fellow
Divison of Gastroenterology
Department of Medicine
Massachusetts General Hospital Boston, Massachusetts
This fourth edition of Handbook of Liver Disease is the first for which Emmet B. Keeffe did not serve as a coeditor because of his untimely death as the third edition was published in 2012. A tribute to Emmet follows this Preface and the Acknowledgments. Succeeding Emmet as coeditor is Paul Martin, an accomplished editor and hepatologist in his own right.
The field of hepatology has continued to progress at a remarkable pace as the contents of the book illustrate. This is best exemplified by the paradigm-changing advances in the treatment of hepatitis C, which has been transformed from interferon-based therapy to the use of combinations of highly effective, direct-acting antiviral agents. Hepatitis C is now relatively easy to treat— and to cure—and the major challenge to eradication of the virus is the expense of the available drugs. The development of viral resistant mutations during treatment appears to be a less imposing obstacle. Reflecting the extraordinary pace of scientific developments in the field of viral hepatitis, the book now offers four, rather than two, chapters on the topic, with expanded attention to each virus.
Progress in other areas of hepatology has been no less impressive. Primary biliary cholangitis (formerly primary biliary cirrhosis) has a new name, more accurately reflecting the spectrum of disease, as well as a new treatment—obeticholic acid—for nonresponders or incomplete responders to ursodeoxycholic acid. Nonalcoholic fatty liver disease has emerged as the preeminent challenge, both epidemiologically and therapeutically, as hepatitis C is anticipated to come under control. There is much new information as well on autoimmune liver diseases, drug- and alcoholinduced liver disease, cirrhosis and portal hypertension, metabolic disorders of the liver, biliary disorders, and hepatobiliary neoplasms, among other topics, that is reflected in the fourth edition. Liver transplantation continues to have a central role in the practice of hepatology as advances proceed steadily toward new approaches to hepatic replacement and regeneration.
We are delighted to welcome a number of highly regarded new senior authors and their junior associates to the Handbook. The infusion of “new blood” ensures the vitality and currency of the book. Among the new authors are Erin Spengler and Robert J. Fontana (Acute Liver Failure), Kelvin T. Nguyen and Steven-Huy B. Han (Hepatitis A and Hepatitis E), Tram T. Tran (Hepatitis B and Hepatitis D), Elliot B. Tapper and Michael P. Curry (Hepatitis Caused by Other Viruses), James H. Lewis (Drug-Induced and Toxic Liver Disease), Kavish R. Patidar and Arun J. Sanyal (Ascites and Spontaneous Bacterial Peritonitis), Andres Cardenas and Pere Ginès (Hepatorenal Syndrome), Michael L. Schilsky (Wilson Disease and Related Disorders), Andres F. Carrion and Kalyan Ram Bhamidimarri (Liver Transplantation), and Ji Young Bang and Stuart Sherman (Cholelithiasis and Cholecystitis). We are equally grateful to our outstanding returning authors and coauthors.
As in the past, the goal of the Handbook is to provide a concise, accurate, up-to-date, and readily accessible (in print or online) reference for students of the liver and particularly for busy practitioners who need reliable information in “real time.” We continue to use an outline format with many lists, tables, and color figures to convey information efficiently and effectively without compromising the depth and richness of the field. Our continued mission is to provide a resource that will be valuable to practicing gastroenterologists and hepatologists, as well as to internists, family practitioners, other specialists, and students and trainees in gastroenterology and hepatology or internal medicine.
Lawrence S. Friedman
Paul Martin
I am pleased and honored to have been asked to prepare a Foreword for the fourth edition of Handbook of Liver Disease. This handbook has become an incredibly valuable resource for all levels of medical providers who deal with patients who have liver disease. It is easy to use and not overly detailed; nonetheless, all the essentials are present. Reading through the forewords from previous editions of the book shows an interesting array of dramatic adjectives describing the progress that has been made in the field of hepatology. For example, the changes have been described as “astronomical” and “stunning.” That seems still to be the case in light of continued new developments. For the young hepatologists in the field, it might be hard for them to consider a time when we as hepatologists could only identify problems but not do anything about them. Furthermore, I can remember when it was jokingly said that all we had in our armamentarium was furosemide and lactulose. Now, in 2017, the diagnostic and therapeutic advances have been phenomenal. One need only compare the exhibit area at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) over the years. In 1977, there were only 11 exhibitors, whereas in 2017 in Washington, DC, there were 85 exhibitors. Indeed, hepatology has become a very successful growth area.
Perhaps the greatest developments in hepatology over the past 30 years have come in the field of viral hepatitis. In certain parts of the world, hepatitis B vaccination has significantly reduced the frequency of vertical transmission of the hepatitis B virus and in turn has reduced the risk of hepatocellular carcinoma (HCC) in young adults. In much of the United States, hepatitis D (delta) is rarely seen now, and identification of a case of hepatitis E is rare. However, the most dramatic example of progress in hepatology has been in the field of hepatitis C. The progress from the discovery of the hepatitis C virus (HCV) in the late 1980s to the ability to cure more than 90% to 95% of patients—and in some studies up to 100%—is truly remarkable. The new treatment regimens do not include interferon, are well tolerated, are safe, are highly effective, and usually require only 12 weeks of oral treatment. Unfortunately, the biggest current problem related to viral hepatitis, and particularly hepatitis C, is the increase in transmission of HCV associated with the opioid abuse problem in the United States. Also, the frequency of vertical transmission from mother to child is increasing slightly, and, unfortunately, the call for screening in baby boomers has not been vigorously received. Development of a hepatitis C vaccine has been slow, and some observers have opined that with treatment success approaching 100% with direct-acting antiviral agents, the need for a vaccine is not as great as once thought. At any rate, the availability of hepatitis C treatment regimens, with at least seven regimens by the end of 2017, has been a great achievement.
The explosion of successful therapies for hepatitis C has not been equaled for hepatitis B, but many of the scientists, clinicians, and investigators who had been working in hepatitis C are now working on treatments that will lead to cure of hepatitis B. Perhaps by the time the next edition of the Handbook has been prepared, we will have curative, direct-acting antiviral agents being tested for use in patients with hepatitis B.
The other major growth area in hepatology is nonalcoholic steatohepatitis (NASH). Although there may be three to five million Americans with hepatitis C and approximately two million with hepatitis B, it has been estimated that there may be as many as 25 million Americans with nonalcoholic fatty liver disease (NAFLD). Clinical trials are rapidly being initiated, and numerous new agents are being tested, some alone and some in combination. Most patients with NAFLD or NASH have insulin resistance, and it seems likely that two or more mechanisms for defining treatment may be necessary for success. It is also likely that the need for treatment may be longterm and perhaps lifelong. Therefore expense will be a major consideration for access to these treatments, and health care providers will have to be careful about this issue.
A significant number of patients who have elevated liver biochemical test levels are receiving medications known to cause liver dysfunction. The Drug-Induced Liver Injury Network (DILIN) has increased our attention to these disorders and has helped remind us of the need to focus on this area. Accordingly, all patients with abnormal liver enzyme levels must have their medication lists reviewed.
The autoimmune-mediated liver diseases include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and the overlap syndromes. The new findings in these disease states include recognition that overlap syndrome can develop in patients who initially present with AIH and progress to include PBC, or present with PBC and progress to include AIH. Occasionally, treatment needs to be adjusted. Also, the first new treatment in decades approved for patients with PBC is obeticholic acid, which is helpful in about one half of the patients who have had an inadequate or incomplete response to standard treatment with ursodeoxycholic acid. No new treatments have come about in AIH or in PSC, although trials of obeticholic acid in PSC are in progress.
In the area of inherited liver diseases, the changes and advances have not been as great in the past few years as they were in the 1990s, when new genes were being discovered. Most patients who have hereditary hemochromatosis with significant iron overload have two copies of a single mutation (C282Y). This is in stark contrast to the more than 600 disease-causing mutations found in the Wilson disease gene. This indicates that almost all patients with Wilson disease are compound heterozygotes.
Complications of chronic liver disease such as variceal bleeding, hepatic encephalopathy, fluid retention (ascites and edema), and hepatorenal syndrome are usually managed effectively and, when these problems occur, are often the precursors to liver transplantation. A dreaded complication of cirrhosis is the development of HCC, but current guidelines and recommendations for monitoring and standardized evaluation have led to outcomes that are acceptable. Most mid-tolarge academic health centers now have teams of medical oncologists, hepatologists, transplant surgeons, pathologists, and interventional radiologists who meet regularly to discuss the management of patients with HCC. This multidisciplinary approach is necessary for successful outcomes in these complicated patients.
Therefore the developments in diagnosis and treatment for a variety of liver diseases have undergone tremendous advances since the publication of the previous edition of Handbook of Liver Disease. The changes that have developed in our field have led to improved care and better outcomes for our patients. We look with excitement to the future to see even greater changes that will further enhance the care that we provide.
Finally, I cannot resist adding a comment about Dr. Emmet B. Keeffe, to whom this edition of Handbook of Liver Disease is dedicated. I vividly remember several years ago visiting Emmet at Stanford. At the time, he was recovering from valvular heart surgery. It was mid-morning on a sunny day, and we sat outside enjoying a cup of coffee at a small shop. As if it were yesterday, I remember Emmet saying to me, “You know, Bruce, I found out with the recovery from this surgery that there is a life outside the hospital. Having some recovery time like this reminds me that we need to take time to take care of ourselves.” This was vintage Emmet Keeffe and a valuable lesson for all of us as we go about our busy lives.
Congratulations to Drs. Friedman and Martin on an excellent fourth edition of the Handbook of Liver Disease.
Bruce R. Bacon
Paul Martin, MD, FRCP, FRCPI n Lawrence S. Friedman, MD
1 Reflecting the liver’s diverse functions, the colloquial term liver function tests (LFTs) includes true tests of hepatic synthetic function (e.g., serum albumin), tests of excretory function (e.g., serum bilirubin), and tests that reflect hepatic necroinflammatory activity (e.g., serum aminotransferases) or cholestasis (e.g., alkaline phosphatase [ALP]).
2 Abnormal liver biochemical test results are often the first clues to liver disease. The widespread inclusion of these tests in routine blood chemistry panels uncovers many patients with unrecognized hepatic dysfunction.
3 Normal or minimally abnormal liver biochemical test levels do not preclude significant liver disease, even cirrhosis.
4 Laboratory testing can assess the severity of liver disease and its prognosis; sequential testing may allow assessment of the effectiveness of therapy.
5 Although liver biopsy had been the gold standard for assessing the severity of liver disease, as well as for confirming the diagnosis for some causes, fibrosis is increasingly assessed by noninvasive means, most notably by ultrasound elastography, especially in chronic viral hepatitis.
6 Various imaging studies are useful in detecting focal hepatic defects, the presence of portal hypertension, and abnormalities of the biliary tract.
SERUM BILIRUBIN
1. Jaundice
■ Often the first evidence of liver disease
■ Clinically apparent when serum bilirubin exceeds 3 mg/dL; patient may notice dark urine or pale stool before conjunctival icterus
2. Metabolism
■ Bilirubin is a breakdown product of hemoglobin and, to a lesser extent, heme-containing enzymes; 95% of bilirubin is derived from senescent red blood cells.
■ After red blood cell breakdown in the reticuloendothelial system, heme is degraded by the enzyme heme oxygenase in the endoplasmic reticulum.
■ Bilirubin is released into blood and tightly bound to albumin; free or unconjugated bilirubin is lipid soluble, is not filtered by the glomerulus, and does not appear in urine. CHAPTER
■ Unconjugated bilirubin is taken up by the liver by a carrier-mediated process, attaches to intracellular storage proteins (ligands), and is conjugated by the enzyme uridine diphosphate (UDP)–glucuronyl transferase to form a diglucuronide and, to a lesser extent, a monoglucuronide.
■ Conjugated bilirubin is water soluble and thus appears in urine.
■ When serum levels of bilirubin glucuronides are elevated, some binding to albumin occurs (delta bilirubin), leading to absence of bilirubinuria despite conjugated hyperbilirubinemia; this phenomenon explains delayed resolution of jaundice during recovery from acute liver disease until albumin-bound bilirubin is catabolized.
■ Conjugated bilirubin is excreted by active transport across the canalicular membrane into bile.
■ Bilirubin in bile enters the small intestine; in the distal ileum and colon, bilirubin is hydrolyzed by beta-glucuronidases to form unconjugated bilirubin, which is then reduced by intestinal bacteria to colorless urobilinogens; a small amount of urobilinogen is reabsorbed by the enterohepatic circulation and mostly excreted in the bile, with a smaller proportion undergoing urinary excretion.
■ Urobilinogens or their colored derivatives urobilins are excreted in feces.
3. Measurement of serum bilirubin
a. van den Bergh reaction
■ Total serum bilirubin represents all bilirubin that reacts with diazotized sulfanilic acid to form chromogenic pyrroles within 30 minutes in the presence of alcohol (an accelerating agent).
■ Direct serum bilirubin is the fraction that reacts with the diazo reagent in an aqueous medium within 1 minute and corresponds to conjugated bilirubin.
■ Indirect serum bilirubin represents unconjugated bilirubin and is determined by subtracting the direct reacting fraction from the total bilirubin level.
b. More specific methods (e.g., high-pressure liquid chromatography) demonstrate that the van den Bergh reaction often overestimates the amount of conjugated bilirubin; however, the van den Bergh method remains the standard test.
4. Classification of hyperbilirubinemia
a. Unconjugated (bilirubin nearly always <7 mg/dL)
■ Overproduction (presentation to liver of bilirubin load that exceeds hepatic capacity for uptake and conjugation): Hemolysis, ineffective erythropoiesis, resorption of hematoma
■ Defective uptake and storage of bilirubin: Gilbert syndrome (idiopathic unconjugated hyperbilirubinemia)
b. Conjugated
■ Hereditary: Dubin-Johnson and Rotor syndromes, bile transport protein defects
■ Cholestasis (Bilirubin is not a sensitive test of hepatic dysfunction.)
– Intrahepatic: Cirrhosis, hepatitis, primary biliary cholangitis, drug induced
– Extrahepatic biliary obstruction: Choledocholithiasis, stricture, neoplasm, biliary atresia, sclerosing cholangitis
c. Very high bilirubin levels
■ >30 mg/dL: Usually signifies hemolysis plus parenchymal liver disease or biliary obstruction; urinary excretion of conjugated bilirubin may help prevent even higher levels of hyperbilirubinemia; renal failure contributes to hyperbilirubinemia.
■ >60 mg/dL: Seen in patients with hemoglobinopathies (e.g., sickle cell disease) in whom obstructive jaundice or acute hepatitis develops.
d. The diagnostic approach to the evaluation of an isolated serum bilirubin level is shown in Fig. 1.1
Elevated ALT
History and physical examination
Obesity, diabetes mellitus, hyperlipidemia
Risk factors for viral hepatitis
Autoimmune features
Miscellaneous considerations
Imaging and liver biopsy based on findings and course
Consider NAFLD
Serologic tests for viral hepatitis: HBsAg, anti-HCV
Serum IgG level, ANA, SMA
Tests for Hemochromatosis: Fe, TIBC, ferritin
Wilson disease: Cu, ceruloplasmin
AAT deficiency: AAT level
Celiac disease: transglutaminase antibody
Fig. 1.2 Algorithm for the approach to a patient with a persistently elevated serum alanine aminotransferase level. AAT, Alpha-1 antitrypsin; ANA, antinuclear antibodies; anti-HCV, antibody to hepatitis C virus; Cu, copper; Fe, iron; HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; NAFLD, nonalcoholic fatty liver disease; SMA, smooth muscle antibodies; TIBC, total iron binding capacity.
■ Mild-to-moderate elevations of aminotransferase levels are typical of chronic viral hepatitis, autoimmune hepatitis, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson disease, and celiac disease.
■ In obstructive jaundice, aminotransferase values are usually lower than 500 U/L; rarely, values may reach 1000 U/L in acute choledocholithiasis or 3000 U/L in acute cholecystitis, followed by a rapid decline to normal.
3. The approach to the patient with a persistently elevated ALT level is shown in Fig. 1.2.
4. Abnormally low aminotransferase levels have been associated with uremia and chronic hemodialysis; chronic viral hepatitis in this population may not result in aminotransferase elevation.
1. Hepatic ALP is one of several ALP isoenzymes found in humans and is bound to the hepatic canalicular membrane; various laboratory methods are available for its measurement, and comparison of results obtained by different techniques may be misleading.
2. This test is sensitive for detection of biliary tract obstruction (a normal value is highly unusual in significant biliary obstruction); interference with bile flow may be intrahepatic or extrahepatic.
■ An increase in serum ALP results from increased hepatic synthesis of the enzyme, rather than leakage from bile duct cells or failure to clear circulating ALP; because it is synthesized in response to biliary obstruction, the ALP level may be normal early in the course of acute cholangitis when the serum aminotransferases are already elevated.
■ Increased bile acid concentrations may promote the synthesis of ALP.
■ Serum ALP has a half-life of 17 days; levels may remain elevated up to 1 week after relief of biliary obstruction and return of the serum bilirubin level to normal.
3. Isolated elevation of alkaline phosphatase
■ This may indicate infiltrative liver disease: Tumor, abscess, granulomas, or amyloidosis.
■ High levels are associated with biliary obstruction, sclerosing cholangitis, primary biliary cholangitis, immunoglobulin (Ig) G4–associated cholangitis, acquired immunodeficiency syndrome, cholestatic drug reactions, and other causes of vanishing bile duct syndrome; in critically ill patients with sepsis, high levels may result from secondary sclerosing cholangitis from ischemia with rapid progression to cirrhosis.
■ Nonhepatic sources of ALP are bone, intestine, kidney, and placenta (different isoenzymes); elevations are seen in Paget disease of the bone, osteoblastic bone metastases, small bowel obstruction, and normal pregnancy.
■ A hepatic origin of an elevated ALP level is suggested by simultaneous elevation of either serum gamma-glutamyltranspeptidase (GGTP) or 5ʹ-nucleotidase (5NT).
■ Hepatic ALP is more heat stable than bone ALP. The degree of overlap makes this test less useful than GGTP or 5NT.
■ The diagnostic approach to an isolated elevated ALP level is shown in Fig. 1.3.
4. Mild elevations of serum ALP are often seen in hepatitis and cirrhosis.
5. Low serum levels of ALP may occur in hypothyroidism, pernicious anemia, zinc deficiency, congenital hypophosphatasia, and fulminant Wilson disease.
1. Although present in many different organs, GGTP is found in particularly high concentrations in the epithelial cells lining biliary ductules.
2. It is a very sensitive indicator of hepatobiliary disease but is not specific. Levels are elevated in other conditions, including renal failure, myocardial infarction, pancreatic disease, and diabetes mellitus.
3. GGTP is inducible, and thus levels may be elevated by ingestion of phenytoin or alcohol in the absence of other clinical evidence of liver disease.
4. Because of its long half-life of 26 days, GGTP is limited as a marker of surreptitious alcohol consumption.
5. Its major clinical use is to exclude a bone source of an elevated serum ALP level.
6. Many patients with isolated serum GGTP elevation have no other evidence of liver disease; an extensive evaluation is usually not warranted. Patients should be retested after avoiding alcohol and other hepatotoxins for several weeks.
1. 5NT is found in the liver in association with canalicular and sinusoidal plasma membranes.
2. Although 5NT is distributed in other organs, serum levels are believed to reflect hepatobiliary release by the detergent action of bile salts on plasma membranes.
3. Serum 5NT levels correlate well with serum ALP levels; an elevated serum 5NT level in association with an elevated ALP level is specific for hepatobiliary dysfunction and is superior to GGTP in this regard.
■ Vitamin K deficiency as the cause of a prolonged prothrombin time can be excluded by administration of vitamin K 10 mg; intravenous administration can cause severe reactions, and the oral route is preferable, if possible. (Subcutaneous administration is not recommended because of erratic absorption.) Correction or improvement of the prothrombin time by at least 30% within 24 hours implies that hepatic synthetic function is intact.
■ The international normalized ratio (INR) is used to standardize prothrombin time determinations performed in different laboratories; however, the results are less consistent in patients with liver disease than in those taking warfarin unless liver-disease controls are used.
■ The prothrombin time and INR correlate with the severity of liver disease but not with the risk of bleeding because of counterbalancing decreases in levels of anticoagulant factors (e.g., proteins C and S, antithrombin) and enhanced fibrinolysis in patients with liver disease.
Various drugs that undergo purely hepatic metabolism with predictable bioavailability have been used to assess hepatic metabolic capacity. Typically, a metabolite is measured in plasma, urine, or breath following intravenous or oral administration of the parent compound. These tests are not widely used in practice.
1. Antipyrine is metabolized by cytochrome P-450 oxygenase with good absorption after oral administration and elimination entirely by the liver.
2. In chronic liver disease, good correlation exists between prolongation of the antipyrine half-life and disease severity as assessed by the Child-Turcotte-Pugh score (see Chapter 11).
3. Clearance of antipyrine is less impaired in acute liver disease and obstructive jaundice than in chronic liver disease.
4. Disadvantages of this test include its long half-life in serum, which requires multiple blood sampling, poor correlation with in vitro assessment of hepatic microsomal capacity, and alteration of antipyrine metabolism by increased age, diet, alcohol, smoking, and environmental exposure.
1. This test is based on detection of [14C]O2 in breath 2 hours after an oral dose of [14C]dimethyl aminoantipyrine (aminopyrine), which undergoes hepatic metabolism.
2. Excretion is diminished in patients with cirrhosis as well as those with acute liver disease.
3. The test has been used to assess prognosis in patients with alcoholic hepatitis and in cirrhotic patients who are undergoing surgery.
4. A limitation of the aminopyrine breath test is its lack of sensitivity in hepatic dysfunction resulting from cholestasis or extrahepatic obstruction.
1. Caffeine clearance after oral ingestion can be assessed by measuring levels in either saliva or serum; the accuracy appears similar to the [14C]aminopyrine breath test, without the need for a radioisotope.
2. Results are clearly abnormal in clinically severe liver disease, but the test is insensitive in mild hepatic dysfunction.
3. Caffeine clearance decreases with age or cimetidine use and increases with cigarette smoking.
1. Galactose clearance from blood as a result of hepatic phosphorylation can be determined after either intravenous or oral administration; serial serum levels of galactose are obtained 20 to 50 minutes after an intravenous bolus, with correction for urinary galactose excretion.
2. At plasma concentrations >50 mg/dL, removal of galactose reflects hepatic functional mass, whereas at concentrations lower than this plasma level, clearance reflects hepatic blood flow.
3. [14C]galactose is distributed in extracellular water and is affected by changes in volume.
4. Galactose clearance is impaired in acute and chronic liver disease as well as in patients with metastatic hepatic neoplasms but is typically unaffected in obstructive jaundice.
5. The oral galactose tolerance test incorporates [14C]galactose with measurement of breath [14C]O2; the results of this breath test correlate with [14C]aminopyrine testing.
6. [14C]galactose testing is no more accurate than standard liver biochemical tests in assessing prognosis in patients with chronic liver disease.
1. Monoethylglycinexylidide (MEGX), a product of hepatic lidocaine metabolism, is easily measured by a fluorescence polarization immune assay 15 minutes after administration of an intravenous dose of lidocaine.
2. The test may offer prognostic information about the likelihood of life-threatening complications in cirrhotic patients.
3. The test has also been used to assess the viability of donor liver allografts.
4. The test is easy to perform and has few adverse reactions, although it may be unsuitable for some cardiac patients. Test results may be affected by simultaneous use of certain drugs metabolized by cytochrome P-450 3A4 and high bilirubin levels; test results are affected by age and body mass index and are higher in men than in women.
1. Bile acids are synthesized from cholesterol in the liver, conjugated to glycine or taurine, and excreted in the bile. Bile acids facilitate fat digestion and absorption within the small intestine. They recycle through the enterohepatic circulation; secondary bile acids form by the action of intestinal bacteria.
2. Detection of elevated serum bile acid levels is a sensitive marker of hepatobiliary dysfunction.
3. Various methods are available to assay individual and total bile acids; assaying an individual bile acid is probably as useful as measuring total bile acid concentration.
4. Numerous different bile acid tests have been described, including fasting and postprandial levels and determination of levels after a bile acid load, either oral or intravenous.
5. Normal bile acid levels in the presence of hyperbilirubinemia suggest hemolysis or Gilbert syndrome.