2583Acute Viral Hepatitis CHAPTER 339
personnel following a needle stick or other nonpercutaneous exposure
to HCV-infected material, sexual partners of persons with hepatitis C,
and children born to HCV-positive mothers (Table 339-4).
For stable, monogamous sexual partners, sexual transmission of
hepatitis C is unlikely, and sexual barrier precautions are not recommended. For persons with multiple sexual partners or with sexually
transmitted diseases, the risk of sexual transmission of hepatitis C is
increased, and barrier precautions (latex condoms) are recommended.
A person with hepatitis C should avoid sharing such items as razors,
toothbrushes, and nail clippers with sexual partners and family
members. No special precautions are recommended for babies born
to mothers with hepatitis C, and breast-feeding does not have to be
restricted.
Hepatitis E For prevention of hepatitis E, IG derived from HEVendemic populations does not appear to be effective. Two safe and
effective three-dose (0, 1, and 6 months), recombinant genotype 1
capsid protein vaccines, which protect against other genotypes as well,
have been shown in randomized, placebo-controlled trials to be highly
protective against symptomatic acute hepatitis E. A Chinese vaccine,
Hecolin, achieved 100% 12-month efficacy and was licensed in China
in 2011; its long-lasting protection (87% efficacy) was documented for
up to 4.5 years. A second vaccine developed by GlaxoSmithKline and
the U.S. Army vaccine achieved a 12-month 96% efficacy. The second
vaccine was never developed commercially. The Chinese vaccine is
available in China but is not FDA approved or available in the
United States.
■ FURTHER READING
Buckley GJ, Strom BL (eds). Eliminating the Public Health Problem
of Hepatitis B and C in the United States: Phase One Report. Washington DC, National Academies Press, 2016.
Centers for Disease Control and Prevention: Recommendations for the identification of chronic hepatitis C virus infection
among persons born during 1945–1965. MMWR Morb Mortal
Wkly Rep 61(RR-4):1, 2012.
Chang M-H et al: Long-term effects of hepatitis B immunization of
infants in preventing liver cancer. Gastroenterology 151:472, 2016.
Debing Y et al: Update on hepatitis E virology: Implications for clinical practice. J Hepatol 65:200, 2016.
Denniston MM et al: Chronic hepatitis C virus infection in the
United States, National Health and Nutrition Examination Survey
2003–2010. Ann Intern Med 160:293, 2014.
Ditah I et al: Current epidemiology of hepatitis E virus infection in
the United States: Low seroprevalence in the National Health and
Nutrition Survey. Hepatology 60:815, 2014.
Doshani M et al: Recommendations of the Advisory Committee
on Immunization Practices for use of hepatitis A vaccine for persons experiencing homelessness. MMWR Morb Mortal Wkly Rep
68:153, 2019.
Douam F et al: The mechanism of HCV entry into host cells. Prog
Mol Biol Transl Sci 129:63, 2015.
Edlin BR et al: Toward a more accurate estimate of the prevalence of
hepatitis C in the United States. Hepatology 62:1353, 2015.
European Association for the Study of the Liver: EASL clinical practice guidelines on hepatitis E virus infection. J Hepatol
68:1256, 2018.
Foster M et al: Hepatitis A outbreaks associated with drug use and
homelessness—California, Kentucky, Michigan, and Utah 2017.
MMWR Morb Mortal Wkly Rep 67:1208, 2018.
Freedman M et al: Advisory Committee on Immunization Practices.
Recommended adult immunization schedule, United States, 2020.
Ann Intern Med 172:337, 2020.
Goldberg D et al: Changes in the prevalence of hepatitis C virus
infection, nonalcoholic steatohepatitis, and alcoholic liver disease
among patients with cirrhosis and liver failure on the waitlist for
liver transplantation. Gastroenterology 152:1090, 2017.
Joy JB et al: The spread of hepatitis C virus genotype 1a in North
America: A retrospective phylogenetic study. Lancet Infect Dis
16:698, 2016.
Koh C et al: Pathogenesis of and new therapies for hepatitis D. Gastroenterology 156:461, 2019.
Le MH et al: Chronic hepatitis B prevalence among foreign-born
and U.S.-born adults in the United States, 1999-2016. Hepatology
71:431, 2020.
Lee MH et al: Chronic hepatitis C virus infection increases mortality
from hepatic and extrahepatic diseases: A community-based longterm prospective study. J Infect Dis 206:469, 2012.
Lemon SM et al: Type A viral hepatitis: A summary and update on
the molecular virology, epidemiology, pathogenesis, and prevention. J Hepatol 68:167, 2018.
Lin H-H et al: Changing hepatitis D virus epidemiology in a hepatitis
B virus endemic area with a national vaccination program. Hepatology 61:1870, 2016.
Nelson NP et al: Update: Recommendations of the Advisory Committee on Immunization Practices for use of hepatitis A vaccine
for postexposure prophylaxis and for preexposure prophylaxis
for international travel. MMWR Morb Mortal Wkly Rep 67:1216,
2018.
Pan CQ et al: Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med 374:2324, 2016.
Polaris Observatory Collaborators: Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: A modelling study. Lancet Gastroenterol Hepatol 3:383, 2018.
Polaris Observatory HCV Collaborators: Global prevalence
and genotype distribution of hepatitis C virus infection in 2015: A
modelling study. Lancet Gastroenterol Hepatol 2:161, 2017.
Rizzetto M et al: Hepatitis delta: The rediscovery. Clin Liver Dis
17:475, 2013.
Roberts H et al: Prevalence of chronic hepatitis B virus (HBV)
infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988–2012. Hepatology 63:388, 2016.
Robinson CL et al: Advisory Committee on Immunization Practices
recommended immunization schedule for children and adolescents
aged 18 years or younger—United States, 2020. MMWR Morb Mortal Wkly Rep 69:130, 2020.
Rosenberg ES et al: Prevalence of hepatitis C virus infection in US
States and District of Columbia, 2013-2016. JAMA Network Open
1:e186371, 2018.
Ryerson AB et al: Vital signs: Newly reported acute and chronic
hepatitis C cases—United States, 2009–2018. MMWR Morb Mortal
Wkly Rep 69:399, 2020.
Schillie S et al: Prevention of hepatitis B virus infection in the
United States: Recommendation of the Advisory Committee on
Immunization Practices. MMWR Morb Mortal Wkly Rep 67:1,
2018.
Schillie S et al: CDC recommendations for hepatitis C screening
among adults—United States, 2020. MMWR Recommend Rep
69(No. RR #2):1, 2020.
Schweitzer A et al: Estimations of worldwide prevalence of chronic
hepatitis B virus infection: A systematic review of data published
between 1965 and 2013. Lancet 386:1546, 2015.
Sureau C et al: The hepatitis delta virus: replication and pathogenesis. J Hepatol 64:S102, 2016.
Trépo C et al: Hepatitis B virus infection. Lancet 384:2053, 2014.
U.S. Preventive Services Task Force: Screening for hepatitis B
virus infection in pregnant women: US Preventive Services Task
Force reaffirmation recommendation statement. JAMA 322:349,
2019.
U.S. Preventive Services Task Force: Screening for hepatitis C
virus infection in adolescents and adults: US Preventive Services
Task Force recommendation statement. JAMA 323:970, 2020.
Waked I et al: Screening and treatment program to eliminate hepatitis C in Egypt. N Engl J Med 382:1166, 2020.
2584 PART 10 Disorders of the Gastrointestinal System
Liver injury is a possible consequence of ingestion of any xenobiotic,
including industrial toxins, pharmacologic agents, and complementary
and alternative medications (CAMs). Among patients with acute liver
failure, drug-induced liver injury (DILI) is the most common cause,
and evidence for hepatotoxicity detected during clinical trials for drug
development is the most common reason for failure of compounds to
reach approval status. DILI requires careful history-taking to identify
unrecognized exposure to chemicals used in work or at home, drugs
taken by prescription or bought over the counter, and herbal or dietary
supplement medicines. Hepatotoxic drugs can injure the hepatocyte
directly, for example, via a free-radical or metabolic intermediate that
causes peroxidation of membrane lipids and that results in liver cell
injury. Alternatively, a drug or its metabolite may activate components of the innate or adaptive immune system, stimulate apoptotic
pathways, or initiate damage to bile excretory pathways (Fig. 340-1).
Interference with bile canalicular pumps can allow endogenous bile
acids, which can injure the liver, to accumulate. Such secondary injury,
in turn, may lead to necrosis of hepatocytes; injure bile ducts, producing cholestasis; or block pathways of lipid movement, inhibit protein
synthesis, or impair mitochondrial oxidation of fatty acids, resulting in
lactic acidosis and intracellular triglyceride accumulation (expressed
histologically as microvesicular steatosis). In other instances, drug
metabolites sensitize hepatocytes to toxic cytokines. The differences
observed between susceptible and nonsusceptible drug recipients may
be attributable to human leukocyte antigen (HLA) haplotypes that
determine binding of drug-related haptens on the cell surface as well
as to polymorphisms in elaboration of competing, protective cytokines,
as has been suggested for acetaminophen hepatotoxicity (see below).
Immune mechanisms may include cytotoxic lymphocytes or antibodymediated cellular cytotoxicity. In addition, a role has been shown for
activation of nuclear transporters, such as the constitutive androstane
receptor (CAR) or, more recently, the pregnane X receptor (PXR), in
the induction of drug hepatotoxicity.
■ DRUG METABOLISM
Most drugs, which are water-insoluble, undergo a series of metabolic
steps, culminating in a water-soluble form appropriate for renal or
biliary excretion. This process begins with oxidation or methylation
mediated initially by the microsomal mixed function oxygenases,
cytochrome P450 (phase I reaction), followed by glucuronidation or
sulfation (phase II reaction) or inactivation by glutathione. Most drug
hepatotoxicity is the result of formation of a phase I toxic metabolite,
but glutathione depletion, precluding inactivation of harmful compounds by glutathione S-transferase, can contribute as well by ensuring
that the toxic compound is not abrogated.
■ LIVER INJURY CAUSED BY DRUGS
In general, two major types of chemical hepatotoxicity have been recognized: (1) direct toxic and (2) idiosyncratic. As shown in Table 340-1,
direct toxic hepatitis occurs with predictable regularity in individuals
exposed to the offending agent and is dose-dependent. The latent
period between exposure and liver injury is usually short (often several
hours), although clinical manifestations may be delayed for 24–48 h.
Agents producing toxic hepatitis are generally systemic poisons or are
converted in the liver to toxic metabolites. The direct hepatotoxins
result in morphologic abnormalities that are reasonably characteristic
and reproducible for each toxin. Examples of rare toxins currently
include carbon tetrachloride and trichloroethylene that characteristically produce a centrilobular zonal necrosis. The hepatotoxic octapeptides of Amanita phalloides usually produce massive hepatic necrosis;
the lethal dose of the toxin is ~10 mg, the amount found in a single
340
deathcap mushroom. Acetaminophen, the prime example of a direct
toxin, is discussed below.
In idiosyncratic drug reactions, the occurrence of liver injury is
infrequent (1 in 103
–105
patients) and unpredictable; the response
is not as clearly dose-dependent as is injury associated with direct
hepatotoxins, and liver injury may occur at any time after exposure to
the drug but typically between 5 and 90 days following its initiation.
Although regarded as not dose-related in the fashion of direct toxins,
most agents causing idiosyncratic toxicity are given at relatively high
daily doses, typically exceeding 100 mg, suggesting a role for dose—
drugs with low potency must be given in higher doses that engender
greater chances for “off-target” effects. Likewise, drugs given in milligram amounts are of high potency and rarely cause liver or other
off-target effects. Adding to the difficulty of predicting or identifying
idiosyncratic drug hepatotoxicity is the occurrence of mild, transient,
nonprogressive serum aminotransferase elevations that resolve with
continued drug use. Such “adaptation,” the mechanism of which
is unknown, is well recognized for drugs such as isoniazid (INH),
valproate, phenytoin, and HMG-CoA reductase inhibitors (statins).
Extrahepatic manifestations of hypersensitivity, such as rash, arthralgias, fever, leukocytosis, and eosinophilia, occur in a small fraction of
patients with idiosyncratic hepatotoxic drug reactions but are characteristic for certain drugs (phenytoin, trimethoprim-sulfamethoxazole)
and not others. Both primary immunologic injury and direct hepatotoxicity related to idiosyncratic differences in generation of toxic
metabolites have been invoked to explain idiosyncratic drug reactions.
The most current data implicate the adaptive immune system responding to the formation of immune stimulatory compounds resulting from
phase I metabolic activation of the offending drug. Differences in host
susceptibility may result from varying kinetics of toxic metabolite generation and genetic polymorphisms in downstream drug-metabolizing
pathways or cytokine activation; in addition, certain HLA haplotypes
have been associated with hepatotoxicity of certain drugs such as
amoxicillin-clavulanate and flucloxacillin. Occasionally, however, the
clinical features of an allergic reaction (prominent tissue eosinophilia,
autoantibodies, etc.) are difficult to ignore and suggest activation of
IgE pathways. A few instances of drug hepatotoxicity are observed to
be associated with autoantibodies, including a class of antibodies to
liver-kidney microsomes, anti-LKM2, directed against a cytochrome
P450 enzyme. Four agents that specifically have a phenotype of autoimmune hepatitis with a high likelihood of positive antinuclear antibodies (ANAs) include nitrofurantoin, minocycline, hydralazine, and
α-methyldopa.
Idiosyncratic reactions lead to a morphologic pattern that is more
variable than those produced by direct toxins; a single agent is often
capable of causing a variety of lesions, although certain patterns tend to
predominate. Depending on the agent involved, idiosyncratic hepatitis
may result in a clinical and morphologic picture indistinguishable from
that of viral hepatitis (e.g., INH or ciprofloxacin). So-called hepatocellular injury is the most common form, featuring spotty necrosis in the
liver lobule with a predominantly lymphocytic infiltrate resembling
that observed in acute hepatitis A, B, or C. Drug-induced cholestasis
ranges from mild to increasingly severe: (1) bland cholestasis with limited hepatocellular injury (e.g., estrogens, 17,α-substituted androgens);
(2) inflammatory cholestasis (e.g., amoxicillin-clavulanic acid [the
most frequently implicated antibiotic among cases of DILI], oxacillin,
erythromycin estolate); (3) sclerosing cholangitis (e.g., after intrahepatic infusion of the chemotherapeutic agent floxuridine for hepatic
metastases from a primary colonic carcinoma); and (4) disappearance
of bile ducts, “ductopenic” cholestasis or vanishing bile duct syndrome,
similar to that observed in chronic rejection (Chap. 345) following
liver transplantation (e.g., carbamazepine, levofloxacin). Cholestasis
may result from binding of drugs to canalicular membrane transporters, accumulation of toxic bile acids resulting from canalicular pump
failure, or genetic defects in canalicular transporter proteins. Clinically,
the distinction between a hepatocellular and a cholestatic reaction is
indicated by the R value, the ratio of alanine aminotransferase (ALT) to
alkaline phosphatase values, both expressed as multiples of the upper
limit of normal. An R value of >5.0 is associated with hepatocellular
Toxic and Drug-Induced
Hepatitis
William M. Lee, Jules L. Dienstag
2585Toxic and Drug-Induced Hepatitis CHAPTER 340
injury, R <2.0 with cholestatic injury, and R between 2.0 and 5.0 with
mixed hepatocellular-cholestatic injury.
Morphologic alterations may also include hepatic granulomas
(e.g., sulfonamides) or macrovesicular or microvesicular steatosis or
steatohepatitis. Severe hepatotoxicity associated with steatohepatitis,
most likely a result of mitochondrial toxicity, was recognized with certain antiretroviral therapies, although most of these drugs have been
withdrawn (Chap. 202). Another potential target for idiosyncratic drug
A
Membrane
Hepatocyte
B
Canaliculus
Transport
pumps (MRP3)
P-450 Heme
Drug
C
D
E
F
Endoplasmic
reticulum
Enzyme-drug
adduct
Cytokines
Vesicle
Triglycerides Free fatty
acid
Inhibition of
β-oxidation, respiration,
or both
Lactate
Mitochondrion
Other
caspases
Cell death
Other
caspases
Caspase
Caspase Caspase
DD DD
DD DD
TNF-α receptor,
Fas
Cytolytic
T cell
Six Mechanisms of Liver Injury
A. Rupture of cell membrane.
B. Injury of bile canaliculus (disruption of transport pumps).
C. P-450-drug covalent binding (drug adducts).
D. Drug adducts targeted by CTLs/cytokines.
E. Activation of apoptotic pathway by TNFα/Fas.
F. Inhibition of mitochondrial function.
FIGURE 340-1 Potential mechanisms of drug-induced liver injury. The normal hepatocyte may be affected adversely by drugs through (A) disruption of intracellular calcium
homeostasis that leads to the disassembly of actin fibrils at the surface of the hepatocyte, resulting in blebbing of the cell membrane, rupture, and cell lysis; (B) disruption
of actin filaments next to the canaliculus (the specialized portion of the cell responsible for bile excretion), leading to loss of villous processes and interruption of transport
pumps such as multidrug resistance–associated protein 3 (MRP3), which, in turn, prevents the excretion of bilirubin and other organic compounds; (C) covalent binding of
the heme-containing cytochrome P450 enzyme to the drug, thus creating nonfunctioning adducts; (D) migration of these enzyme-drug adducts to the cell surface in vesicles
to serve as target immunogens for cytolytic attack by T cells, stimulating an immune response involving cytolytic T cells and cytokines; (E) activation of apoptotic pathways
by tumor necrosis factor α (TNF-α) receptor or Fas (DD denotes death domain), triggering the cascade of intercellular caspases, resulting in programmed cell death; or (F)
inhibition of mitochondrial function by a dual effect on both β-oxidation and the respiratory-chain enzymes, leading to failure of free fatty acid metabolism, a lack of aerobic
respiration, and accumulation of lactate and reactive oxygen species (which may disrupt mitochondrial DNA). Toxic metabolites excreted in bile may damage bile-duct
epithelium (not shown). CTLs, cytolytic T lymphocytes. (From WM Lee: Drug-induced hepatotoxicity. N Engl J Med 349:474, 2003. Copyright © 2003, Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.)
2586 PART 10 Disorders of the Gastrointestinal System
hepatotoxicity is sinusoidal lining cells; when these are injured, such as
by high-dose chemotherapeutic agents (e.g., cyclophosphamide, melphalan, busulfan) administered prior to bone marrow transplantation,
veno-occlusive disease can result. Nodular regenerative hyperplasia,
a subtle form of portal hypertension, may also result from vascular
injury to portal or hepatic venous endothelium following systemic
chemotherapy, such as with oxaliplatin, as part of adjuvant treatment
for colon cancer.
Not all adverse hepatic drug reactions can be classified as either
toxic or idiosyncratic. For example, oral contraceptives, which combine
estrogenic and progestational compounds, may result in impairment
of liver tests and, occasionally, jaundice; however, they do not
produce necrosis or fatty change, manifestations of hypersensitivity
are generally absent, and susceptibility to the development of oral
contraceptive–induced cholestasis appears to be genetically determined. Such estrogen-induced cholestasis is more common in women
with cholestasis of pregnancy, a disorder linked to genetic defects in
multidrug resistance–associated canalicular transporter proteins.
Any idiosyncratic reaction that occurs in <1:10,000 recipients will
go unrecognized in most clinical trials, which involve at most several
thousand subjects. The U.S. Food and Drug Administration (FDA) and
pharmaceutical companies have learned to look for even subtle indications of serious toxicity and monitor regularly the number of trial subjects in whom any aminotransferase elevations develop, as a possible
surrogate for more serious toxicity. Even more valid as a predictor of
severe hepatotoxicity is the occurrence of jaundice in patients enrolled
in a clinical drug trial, so-called “Hy’s Law,” named after Dr. Hyman
Zimmerman, one of the pioneers of the field of drug hepatotoxicity. He
recognized that, if jaundice occurred during a phase 3 trial, more serious liver injury was likely, with a 10:1 ratio between cases of jaundice
and liver failure (i.e., 10 patients with jaundice would result in 1 patient
with acute liver failure). Thus, the finding of such Hy’s Law (jaundiced)
cases during drug development often portends failure of approval, particularly if any of the subjects sustains a bad outcome. Troglitazone, a
peroxisome proliferator–activated receptor γ agonist, was the first in its
class of thiazolidinedione insulin-sensitizing agents. Although in retrospect, Hy’s Law cases of jaundice had occurred during phase 3 trials, no
instances of liver failure were recognized until well after the drug was
introduced, emphasizing the importance of postmarketing surveillance
in identifying toxic drugs and in leading to their withdrawal from use.
Fortunately, such hepatotoxicity is not characteristic of the secondgeneration thiazolidinediones rosiglitazone and pioglitazone; in clinical
trials, the frequency of aminotransferase elevations in patients treated
with these medications did not differ from that in placebo recipients,
and isolated reports of liver injury among recipients are extremely rare.
Since troglitazone was withdrawn from the market in 2001, no fully
approved drugs have had to be withdrawn from the market by the FDA.
Several agents have received black box warnings indicating that caution
is needed; overall, the industry and FDA in concert have been able to
avert severe toxicity in approved agents over the past 20 years.
Proving that an episode of liver injury is caused by a drug (causality) is difficult in many cases. DILI is nearly always a presumptive
diagnosis, and many other disorders produce a similar clinicopathologic picture. Thus, causality may be difficult to establish and requires
several separate supportive assessment variables to lead to a high level
of certainty, including temporal association (time of onset, time to
resolution), clinical-biochemical features, type of injury (hepatocellular vs cholestatic), extrahepatic features, likelihood that a given agent
is to blame based on its past record, and exclusion of other potential
causes. Scoring systems such as the Roussel-Uclaf Causality Assessment Method (RUCAM) yield residual uncertainty and have not been
adopted widely. Currently, the U.S. Drug-Induced Liver Injury Network
(DILIN) relies on a structured expert opinion process requiring
detailed data on each case and a comprehensive review by three experts
who arrive at a consensus on a five-degree scale of likelihood (definite,
highly likely, probable, possible, unlikely); however, this approach is
not practical for routine clinical application.
Generally, drug hepatotoxicity is not more frequent in persons with
underlying chronic liver disease, although the severity of the outcome
may be amplified. Reported exceptions include hepatotoxicity of aspirin, methotrexate, INH (only in certain experiences), antiretroviral
therapy for HIV infection, and certain drugs such as conditioning regimens for bone marrow transplantation in the presence of hepatitis C.
TREATMENT
Toxic and Drug-Induced Hepatic Disease
Treatment is largely supportive, except in acetaminophen hepatotoxicity (for which N-acetylcysteine is effective, see below). Acute
liver failure develops in 10% of patients with DILI; spontaneous
recovery, once that threshold is reached, occurs in <30%, and
liver transplantation is performed in >40% of those who reach the
level of severity of acute liver failure (coagulopathy and hepatic
encephalopathy) (Chap. 345). Withdrawal of the suspected agent
is indicated at the first sign of an adverse reaction or when
aminotransferase levels reach five times the upper limit of normal.
A number of studies have suggested that lethal outcomes follow
continued use of an agent in the face of symptoms and signs of liver
injury. In the case of the direct toxins, liver involvement should not
divert attention from renal or other organ involvement, which may
also threaten survival. Agents used occasionally but of questionable
value include glucocorticoids for DILI with allergic features, silibinin for mushroom poisoning, and ursodeoxycholic acid for cholestatic drug hepatotoxicity; these medications have been shown to be
effective and cannot be recommended. A double-blind, randomized
controlled trial of the use of N-acetylcysteine for nonacetaminophen acute liver failure, including cases of DILI, demonstrated
benefit, particularly for patients with early-stage hepatic encephalopathy; however, the drug has not been approved by FDA for this
indication.
In Table 340-2, several classes of chemical agents are listed together
with examples of the pattern of liver injury they produce. Certain drugs
appear to be responsible for the development of chronic as well as acute
hepatic injury. For example, nitrofurantoin, minocycline, hydralazine,
and methyldopa have been associated with moderate to severe chronic
hepatitis with autoimmune features. Methotrexate, tamoxifen, and
TABLE 340-1 Some Features of Toxic and Drug-Induced Hepatic Injury
FEATURES
DIRECT TOXIC EFFECTa IDIOSYNCRATICa OTHERa
CARBON
TETRACHLORIDE ACETAMINOPHEN
AMOXICILLINCLAVULANATE ISONIAZID CIPROFLOXACIN
ESTROGENS/
ANDROGENIC STEROIDS
Predictable and doserelated toxicity
+ + 0 0 0 +
Latent period Short Short Delayed onset Variable May be short Variable
Arthralgia, fever, rash,
eosinophilia
0 0 0 0 0 0
Liver morphology Necrosis, fatty
infiltration
Centrilobular
necrosis
Mixed hepatocellular/
cholestatic
Hepatocellular injury
resembling viral
hepatitis
Hepatocellular injury
resembling viral
hepatitis
Cholestasis without portal
inflammation
a
The drugs listed are typical examples.
2587Toxic and Drug-Induced Hepatitis CHAPTER 340
TABLE 340-2 Principal Alterations of Hepatic Morphology Produced by Some Commonly Used Drugs and Chemicalsa
PRINCIPAL MORPHOLOGIC
CHANGE CLASS OF AGENT EXAMPLE
Cholestasis Anabolic steroid
Antibiotic
Anticonvulsant
Antidepressant
Anti-inflammatory
Antiplatelet
Antihypertensive
Antithyroid
Calcium channel blocker
Immunosuppressive
Lipid-lowering
Oncotherapeutic
Oral contraceptive
Oral hypoglycemic
Tranquilizer
Methyl testosterone, many other body-building supplements
Erythromycin estolate, nitrofurantoin, rifampin, amoxicillin-clavulanic acid, oxacillin
Carbamazepine
Duloxetine, mirtazapine, tricyclic antidepressants
Sulindac
Clopidogrel
Irbesartan, fosinopril
Methimazole
Nifedipine, verapamil
Cyclosporine
Ezetimibe
Anabolic steroids, busulfan, tamoxifen, irinotecan, cytarabine, temozolomide
Norethynodrel with mestranol
Chlorpropamide
Chlorpromazineb
Fatty liver Antiarrhythmic
Antibiotic
Anticonvulsant
Antiviral
Oncotherapeutic
Amiodarone
Tetracycline (high-dose, IV)
Valproic acid
Dideoxynucleosides (e.g., zidovudine), protease inhibitors (e.g., indinavir, ritonavir)
Asparaginase, methotrexate, tamoxifen
Hepatitis Anesthetic
Antiandrogen
Antibiotic
Anticonvulsant
Antidepressant
Antifungal
Antihypertensive
Anti-inflammatory
Antipsychotic
Antiviral
Calcium channel blocker
Cholinesterase inhibitor
Diuretic
Laxative
Norepinephrine reuptake inhibitor
Oral hypoglycemic
Halothane, fluothane
Flutamide
Isoniazid,c
rifampicin, nitrofurantoin, telithromycin, minocycline,d
pyrazinamide,
trovafloxacine
Phenytoin, carbamazepine, valproic acid, phenobarbital
Iproniazid, amitriptyline, trazodone, venlafaxine, fluoxetine, paroxetine, duloxetine,
sertraline, nefazodonee
Ketoconazole, fluconazole, itraconazole
Methyldopa,c
captopril, enalapril, lisinopril, losartan
Ibuprofen, indomethacin, diclofenac, sulindac, bromfenac
Risperidone
Zidovudine, didanosine, stavudine, nevirapine, ritonavir, indinavir, tipranavir, zalcitabine
Nifedipine, verapamil, diltiazem
Tacrine
Chlorothiazide
Oxyphenisatinc,e
Atomoxetine
Troglitazone,e
acarbose
Mixed hepatitis/cholestatic Antibiotic
Antibacterial
Antifungal
Antihistamine
Immunosuppressive
Lipid-lowering
Amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole
Clindamycin
Terbinafine
Cyproheptadine
Azathioprine
Nicotinic acid, lovastatin, ezetimibe
Toxic (necrosis) Analgesic
Hydrocarbon
Metal
Mushroom
Solvent
Acetaminophen
Carbon tetrachloride
Yellow phosphorus
Amanita phalloides
Dimethylformamide
Granulomas Antiarrhythmic
Antibiotic
Anticonvulsant
Anti-inflammatory
Xanthine oxidase inhibitor
Quinidine, diltiazem
Sulfonamides
Carbamazepine
Phenylbutazone
Allopurinol
Vascular injury Chemotherapeutic Oxaliplatin, melphalan
a
Several agents cause more than one type of liver lesion and appear under more than one category. b
Rarely associated with primary biliary cirrhosis–like lesion. c
Occasionally associated with chronic hepatitis or bridging hepatic necrosis or cirrhosis. d
Associated with an autoimmune hepatitis–like syndrome. e
Withdrawn from use
because of severe hepatotoxicity.
2588 PART 10 Disorders of the Gastrointestinal System
amiodarone have been implicated in the development of cirrhosis. Portal
hypertension in the absence of cirrhosis, termed nodular regenerative
hyperplasia, may result from alterations in hepatic architecture produced by excessive intake of vitamin A or following chemotherapy
with oxaliplatin. Oral contraceptives have been implicated in the
development of focal nodular hyperplasia or hepatic adenoma (both
benign lesions) and, rarely, hepatocellular carcinoma and hepatic vein
occlusion (Budd-Chiari syndrome). Another unusual lesion, peliosis
hepatis (blood cysts of the liver), has been observed in some patients
treated with anabolic or contraceptive steroids. The existence of these
hepatic disorders expands the spectrum of liver injury induced by
chemical agents and emphasizes the need for a thorough drug history
in all patients with liver dysfunction. The comprehensive, authoritative
LiverTox website, which contains up-to-date information on DILI,
is available as a valuable reference through the National Institutes of
Health and the National Library of Medicine (livertox.nih.gov).
The following are patterns of adverse hepatic reactions for some
prototypic agents.
■ ACETAMINOPHEN HEPATOTOXICITY
(DIRECT TOXIN)
Acetaminophen represents the most prevalent cause of acute liver failure in the Western world; up to 72% of patients with acetaminophen
hepatotoxicity in Scandinavia—somewhat lower frequencies in the
United Kingdom and the United States—progress to encephalopathy
and coagulopathy. Acetaminophen causes dose-related centrilobular
hepatic necrosis after single-time-point ingestions, as intentional
self-harm, or over extended periods, as unintentional overdoses,
when multiple drug preparations or inappropriate drug amounts are
used daily for several days, for example, for relief of pain or fever.
In these instances, 8 g/d, twice the daily recommended maximum
dose, over several days can readily lead to liver failure. Use of opioidacetaminophen combinations appears to be particularly harmful,
because habituation to the opioid may occur with a gradual increase
in opioid-acetaminophen combination dosing over days or weeks. A
single dose of 10–15 g, occasionally less, may produce clinical evidence
of liver injury. Fatal fulminant disease is usually (although not invariably) associated with ingestion of ≥25 g. Blood levels of acetaminophen
correlate with severity of hepatic injury (levels >300 μg/mL 4 h after
ingestion are predictive of the development of severe damage; levels
<150 μg/mL suggest that hepatic injury is highly unlikely). Nausea,
vomiting, diarrhea, abdominal pain, and shock are early manifestations occurring 4–12 h after ingestion. Then 24–48 h later, when
these features are abating, hepatic injury becomes apparent. Maximal
abnormalities and hepatic failure are evident 3–5 days after ingestion,
and aminotransferase levels exceeding 10,000 IU/L are not uncommon
(i.e., levels far exceeding those in patients with viral hepatitis). Renal
failure and myocardial injury may be present. Whether or not a clear
history of overdose can be elicited, clinical suspicion of acetaminophen
hepatotoxicity should be raised by the presence of the extremely high
aminotransferase levels in association with low bilirubin levels that
are characteristic of this hyperacute injury. This biochemical signature
should trigger further questioning of the subject if possible; however,
outright denial (or denial of high doses) or altered mentation may
confound diagnostic efforts. In this setting, a presumptive diagnosis is
reasonable, and the proven antidote, N-acetylcysteine, is both safe and
will be effective if given early (within 12 h) but is also used even when
injury has evolved.
Acetaminophen is metabolized predominantly by a phase II reaction to innocuous sulfate and glucuronide metabolites; however, a
small proportion is metabolized by a phase I reaction to a hepatotoxic
metabolite formed from the parent compound by cytochrome P450
CYP2E1. This metabolite, N-acetyl-p-benzoquinone-imine (NAPQI),
is detoxified by binding to “hepatoprotective” glutathione to become
harmless, water-soluble mercapturic acid, which undergoes renal
excretion. When excessive amounts of NAPQI are formed, or when
glutathione levels are low, glutathione levels are depleted and overwhelmed, permitting covalent binding to nucleophilic hepatocyte
macromolecules forming acetaminophen-protein “adducts.” These
adducts, which can be measured in serum by high-performance liquid
chromatography, hold promise as diagnostic markers of acetaminophen hepatotoxicity, and a point-of-care assay for acetaminophen-Cys
adducts is under development. The binding of acetaminophen to
hepatocyte macromolecules is believed to lead to hepatocyte necrosis;
the precise sequence and mechanism are unknown. Hepatic injury
may be potentiated by prior administration of alcohol, phenobarbital,
INH, or other drugs; by conditions that stimulate the mixed-function
oxidase system; or by conditions such as starvation (including inability to maintain oral intake during severe febrile illnesses) that reduce
hepatic glutathione levels. Alcohol induces cytochrome P450 CYP2E1;
consequently, increased levels of the toxic metabolite NAPQI may
be produced in chronic alcoholics after acetaminophen ingestion,
but the role of alcohol in potentiating acute acetaminophen injury is
still debated. Alcohol also suppresses hepatic glutathione production.
Therefore, in chronic alcoholics, the toxic dose of acetaminophen may
be as low as 2 g, and alcoholic patients should be warned specifically
about the dangers of even standard doses of this commonly used drug.
In a 2006 study, aminotransferase elevations were identified in 31–44%
of normal subjects treated for 14 days with the maximal recommended
dose of acetaminophen, 4 g daily (administered alone or as part of
an acetaminophen-opioid combination); because these changes were
transient and never associated with bilirubin elevation, the clinical
relevance of these findings remains to be determined. Although underlying hepatitis C virus (HCV) infection was found to be associated
with an increased risk of acute liver injury in patients hospitalized for
acetaminophen overdose, generally, in patients with nonalcoholic liver
disease, acetaminophen taken in recommended doses is well tolerated. Acetaminophen use in cirrhotic patients has not been associated
with hepatic decompensation. On the other hand, because of the link
between acetaminophen use and liver injury and because of the limited
safety margin between safe and toxic doses, the FDA has recommended
that the daily dose of acetaminophen be reduced from 4 g to 3 g (even
lower for persons with chronic alcohol use), that all acetaminophencontaining products be labeled prominently as containing acetaminophen, and that the potential for liver injury be prominent in the
packaging of acetaminophen and acetaminophen-containing products.
Within opioid combination products, the limit for the acetaminophen
component has been lowered to 325 mg per tablet.
TREATMENT
Acetaminophen Overdosage
Treatment includes gastric lavage, supportive measures, and oral
administration of activated charcoal or cholestyramine to prevent
absorption of residual drug. Neither charcoal nor cholestyramine
appears to be effective if given >30 min after acetaminophen ingestion; if they are used, the stomach lavage should be done before
other agents are administered orally. The chances of possible, probable, and high-risk hepatotoxicity can be derived from a nomogram
plot (Fig. 340-2), readily available in emergency departments,
as a function of measuring acetaminophen plasma levels 4–8 h
after ingestion. In patients with high acetaminophen blood levels
(>200 μg/mL measured at 4 h or >100 μg/mL at 8 h after ingestion), the administration of N-acetylcysteine reduces markedly the
severity of hepatic necrosis. This agent provides sulfhydryl donor
groups to replete glutathione, which is required to render harmless
toxic metabolites that would otherwise bind covalently via sulfhydryl linkages to cell proteins, resulting in the formation of drug
metabolite-protein adducts. Therapy should be begun within 8 h of
ingestion but may be at least partially effective when given as late
as 24–36 h after overdose. Routine use of N-acetylcysteine has substantially reduced the occurrence of fatal acetaminophen hepatotoxicity. N-acetylcysteine may be given orally but is more commonly
used as an IV solution, with a loading dose of 140 mg/kg over 1 h,
followed by 70 mg/kg every 4 h for 15–20 doses. Whenever a patient
with potential acetaminophen hepatotoxicity is encountered, a
local poison control center should be contacted. Treatment can be
2589Toxic and Drug-Induced Hepatitis CHAPTER 340
stopped when plasma acetaminophen levels indicate that the risk
of liver damage is low. If signs of hepatic failure (e.g., progressive
jaundice, coagulopathy, confusion) occur despite N-acetylcysteine
therapy for acetaminophen hepatotoxicity, liver transplantation
may be the only option. Early arterial blood lactate levels among
such patients with acute liver failure may distinguish patients highly
likely to require liver transplantation (lactate levels >3.5 mmol/L)
from those likely to survive without liver replacement. Acute renal
injury occurs in nearly 75% of patients with severe acetaminophen
injury but is virtually always self-limited.
Survivors of acute acetaminophen overdose rarely, if ever, have
ongoing liver injury or sequela but may be subject to repeat overdosing.
■ ISONIAZID HEPATOTOXICITY (TOXIC AND IDIOSYNCRATIC REACTION)
INH remains central to most antituberculous prophylactic and therapeutic regimens, despite its long-standing recognition as a hepatotoxin.
In 10% of patients treated with INH, elevated serum aminotransferase
levels develop during the first few weeks of therapy; however, these
elevations in most cases are self-limited, are mild (values for ALT
<200 IU/L), and resolve despite continued drug use. This adaptive
response allows continuation of the agent if symptoms and progressive
enzyme elevations do not follow the initial elevations. Acute hepatocellular DILI secondary to INH is evident with a variable latency period
up to 6 months and is more frequent in alcoholics and patients taking
certain other medications, such as barbiturates, rifampin, and pyrazinamide. If the clinical threshold of encephalopathy is reached, severe
hepatic injury is likely to be fatal or to require liver transplantation.
Liver biopsy reveals morphologic changes similar to those of viral hepatitis or bridging hepatic necrosis. Substantial liver injury appears to be
age-related, increasing substantially after age 35; the highest frequency
is in patients over age 50, and the lowest is in patients under the age
of 20. Even for patients >50 years of age monitored carefully during
therapy, hepatotoxicity occurs in only ~2%, well below the risk estimate derived from earlier experiences. Fever, rash, eosinophilia, and
other manifestations of drug allergy are distinctly unusual. Antibodies
to INH have been detected in INH recipients, but a link to causality
of liver injury remains unclear. A clinical picture resembling chronic
hepatitis has been observed in a few patients. Many public health
programs that require INH prophylaxis for a positive tuberculin skin
test or blood test (Quantiferon or T-Spot) include monthly monitoring
of aminotransferase levels, although this practice has been called into
question. Even more effective in limiting serious outcomes may be
encouraging patients to be alert for symptoms such as nausea, fatigue,
or jaundice, because most fatalities occur in the setting of continued
INH use despite clinically apparent illness. The incidence of severe
INH toxicity may be declining as a result of less frequent use and/or
better management.
■ SODIUM VALPROATE HEPATOTOXICITY (TOXIC AND IDIOSYNCRATIC REACTION)
Sodium valproate, an anticonvulsant useful in the treatment of petit
mal and other seizure disorders, has been associated with the development of severe hepatic toxicity and, rarely, fatalities, predominantly
in children but also in adults. Among children listed as candidates for
liver transplantation, valproate is the most common antiepileptic drug
implicated. Asymptomatic elevations of serum aminotransferase levels
have been recognized in as many as 45% of treated patients. These
“adaptive” changes, however, appear to have no clinical importance,
because major hepatotoxicity is not seen in the majority of patients
despite continuation of drug therapy. In the rare patients in whom
jaundice, encephalopathy, and evidence of hepatic failure are found,
examination of liver tissue reveals microvesicular fat and bridging
hepatic necrosis, predominantly in the centrilobular zone. Bile duct
injury may also be apparent. Most likely, sodium valproate is not
directly hepatotoxic, but its metabolite, 4-pentenoic acid, may be
responsible for hepatic injury. Valproate hepatotoxicity is more common in persons with mitochondrial enzyme deficiencies and may be
ameliorated by IV administration of carnitine, which valproate therapy
can deplete. Valproate toxicity has been linked to HLA haplotypes
(DR4 and B*
1502) and to mutations in mitochondrial DNA polymerase
gamma 1.
■ NITROFURANTOIN HEPATOTOXICITY
(IDIOSYNCRATIC REACTION)
This commonly used antibiotic for urinary tract infections may cause
an acute hepatitis leading to fatal outcome or, more frequently, chronic
hepatitis of varying severity but indistinguishable from autoimmune
hepatitis. These two scenarios may reflect the frequent use and reuse of
the drug for treatment of recurrent cystitis in women. Although most
toxic agents manifest injury within 6 months of first ingestion, nitrofurantoin may have a longer latency period, in part perhaps because of
its intermittent, recurrent use. Autoantibodies to nuclear components,
smooth muscle, and mitochondria are seen and may subside after resolution of injury; however, glucocorticoid or other immunosuppressive
medication may be necessary to resolve the autoimmune injury, and
cirrhosis may be seen in cases that are not recognized quickly. Interstitial pulmonary fibrosis presenting as chronic cough and dyspnea may
be present and resolve slowly with medication withdrawal. Histologic
findings are identical to those of autoimmune hepatitis. A similar disease pattern can be observed with minocycline, which is used repeatedly for the treatment of acne in teenagers, as well as with hydralazine
and α-methyldopa.
■ AMOXICILLIN-CLAVULANATE HEPATOTOXICITY
(IDIOSYNCRATIC MIXED REACTION)
Currently, the most common agent implicated as causing DILI in the
United States and in Europe is amoxicillin-clavulanate (most frequent
brand name: Augmentin). This medication causes a very specific
syndrome of mixed or primarily cholestatic injury. Because hepatotoxicity may follow amoxicillin-clavulanate therapy after a relatively long
latency period, the liver injury may begin to manifest after the drug
has been withdrawn. The high prevalence of hepatotoxicity reflects
in part the very frequent use of this drug for respiratory tract infections, including community-acquired pneumonia. The mechanism of
4000
3000
2000
1300
1000
500
100
50
30
µmol/L µg/mL
5
10
50
100
150
200
300
400
500
4 8 12 16 20 24 28
Hours after acetaminophen ingestion
Lower limit for high-risk group
Lower limit for probable-risk group
Study nomogram line
Plasma acetaminophen concentration
FIGURE 340-2 Nomogram to define risk of acetaminophen hepatotoxicity according
to initial plasma acetaminophen concentration. (Reproduced with permission from
Pediatrics, 55:871. Copyright © 1975 by the AAP.)
2590 PART 10 Disorders of the Gastrointestinal System
hepatotoxicity is unclear, but the liver injury is thought to be caused
by amoxicillin toxicity that is potentiated in some way by clavulanate,
which itself appears not to be toxic. Symptoms include nausea, anorexia,
fatigue, and jaundice—which may be prolonged—with pruritus. Rash
is quite uncommon. On occasion, amoxicillin-clavulanate, like other
cholestatic hepatotoxic drugs, causes permanent injury to small bile
ducts, leading to the so-called “vanishing bile duct syndrome.” In vanishing bile duct syndrome, initially, liver injury is minimal except for
severe cholestasis; however, over time, histologic evidence of bile duct
abnormalities is replaced by a paucity and eventual absence of discernible ducts on subsequent biopsies.
■ AMIODARONE HEPATOTOXICITY (TOXIC AND IDIOSYNCRATIC REACTION)
Therapy with this potent antiarrhythmic drug is accompanied in
15–50% of patients by modest elevations of serum aminotransferase
levels that may remain stable or diminish despite continuation of the
drug. Such abnormalities may appear days to many months after beginning therapy. A proportion of those with elevated aminotransferase
levels have detectable hepatomegaly, and clinically important liver disease develops in <5% of patients. Features that represent a direct effect
of the drug on the liver and that are common to the majority of longterm recipients are ultrastructural phospholipidosis, unaccompanied
by clinical liver disease, and interference with hepatic mixed-function
oxidase metabolism of other drugs. The cationic amphiphilic drug and
its major metabolite desethylamiodarone accumulate in hepatocyte
lysosomes and mitochondria and in bile duct epithelium. The relatively
common elevations in aminotransferase levels are also considered a
predictable, dose-dependent, direct hepatotoxic effect. On the other
hand, in the rare patient with clinically apparent, symptomatic liver
disease, liver injury resembling that seen in alcoholic liver disease is
observed. The so-called pseudoalcoholic liver injury can range from
steatosis, to alcoholic hepatitis–like neutrophilic infiltration and Mallory’s hyaline, to cirrhosis. Electron-microscopic demonstration of
phospholipid-laden lysosomal lamellar bodies can help to distinguish
amiodarone hepatotoxicity from typical alcoholic hepatitis. This category of liver injury appears to be a metabolic idiosyncrasy that allows
hepatotoxic metabolites to be generated. Rarely, an acute idiosyncratic
hepatocellular injury resembling viral hepatitis or cholestatic hepatitis
occurs. Hepatic granulomas have occasionally been observed. Because
amiodarone has a long half-life, liver injury may persist for months
after the drug is stopped.
■ ANABOLIC STEROIDS (CHOLESTATIC REACTION)
The most common form of liver injury caused by CAMs is the profound cholestasis associated with anabolic steroids used by body
builders. Unregulated agents sold in gyms and health food stores as
diet supplements, which are taken by athletes to improve their performance, may contain anabolic steroids. In a young male, jaundice that
is accompanied by a cholestatic, rather than a hepatitic, laboratory
profile almost invariably will turn out to be caused by the use of one
of a variety of androgen congeners. Such agents have the potential to
injure bile transport pumps and to cause intense cholestasis; the time
to onset is variable, and resolution, which is the rule, may require many
weeks to months. Initially, anorexia, nausea, and malaise may occur,
followed by pruritus in some but not all patients. Serum aminotransferase levels are usually <100 IU/L, and serum alkaline phosphatase
levels are generally moderately elevated with bilirubin levels frequently
exceeding 342 μmol/L (20 mg/dL). Examination of liver tissue reveals
cholestasis without substantial inflammation or necrosis. Anabolic steroids have also been used by prescription to treat bone marrow failure.
In this setting, hepatic centrizonal sinusoidal dilatation and peliosis
hepatis have been reported in rare patients, as have hepatic adenomas
and hepatocellular carcinoma. Recently, a large series of cases with a
uniform phenotype has been described. Unfortunately, no genomic
signature has become evident despite the unique features of the injury.
No permanent sequelae are evident besides prolonged jaundice, lasting
frequently 10 weeks or more.
■ TRIMETHOPRIM-SULFAMETHOXAZOLE
HEPATOTOXICITY (IDIOSYNCRATIC REACTION)
This antibiotic combination is used routinely for urinary tract infections in immunocompetent persons and for prophylaxis against and
therapy of Pneumocystis jirovecii pneumonia in immunosuppressed
persons (transplant recipients, patients with AIDS). With its increasing use, its occasional hepatotoxicity is being recognized with growing frequency. Its likelihood is unpredictable, but when it occurs,
trimethoprim-sulfamethoxazole hepatotoxicity follows a relatively
uniform latency period of several weeks and is often accompanied by
eosinophilia, rash, and other features of a hypersensitivity reaction,
including the drug reaction with eosinophilia and systemic symptoms
(DRESS) syndrome. Biochemically and histologically, acute hepatocellular necrosis predominates, but cholestatic features are quite frequent.
Occasionally, cholestasis without necrosis occurs, and very rarely, a
severe cholangiolytic pattern of liver injury is observed. In most cases,
liver injury is self-limited, but rare fatalities have been recorded. The
hepatotoxicity is attributable to the sulfamethoxazole component of the
drug and is similar in features to that seen with other sulfonamides; tissue eosinophilia and granulomas may be seen. The risk of trimethoprimsulfamethoxazole hepatotoxicity is increased in persons with HIV
infection. In a recent study, unique HLA associations in European
Americans and in African Americans have been identified.
■ HMG-COA REDUCTASE INHIBITORS (STATINS) (IDIOSYNCRATIC MIXED HEPATOCELLULAR AND
CHOLESTATIC REACTION)
Between 1 and 2% of patients taking lovastatin, simvastatin, pravastatin, fluvastatin, or one of the newer statin drugs for the treatment of
hypercholesterolemia experience asymptomatic, reversible elevations
(greater than threefold) of aminotransferase activity. Acute hepatitislike histologic changes, centrilobular necrosis, and centrilobular
cholestasis have been described in a very small number of cases. In a
larger proportion, minor aminotransferase elevations appear during
the first several weeks of therapy. Careful laboratory monitoring can
distinguish between patients with minor, transitory changes, who may
continue therapy, and those with more profound and sustained abnormalities, who should discontinue therapy. Because clinically meaningful aminotransferase elevations are so rare after statin use and do not
differ in meta-analyses from the frequency of such laboratory abnormalities in placebo recipients, a panel of liver experts recommended to
the National Lipid Association’s Safety Task Force that liver test monitoring was not necessary in patients treated with statins and that statin
therapy need not be discontinued in patients found to have asymptomatic isolated aminotransferase elevations during therapy. Statin
hepatotoxicity is not increased in patients with chronic hepatitis C,
hepatic steatosis, or other underlying liver diseases, and statins can be
used safely in these patients.
■ ALTERNATIVE AND COMPLEMENTARY
MEDICINES (IDIOSYNCRATIC HEPATITIS,
STEATOSIS)
Herbal medications that are of scientifically unproven efficacy and
that lack prospective safety oversight by regulatory agencies account
currently for >20% of DILI in the United States. Besides anabolic
steroids, the most common category of dietary or herbal products is
weight loss agents. Included among the herbal remedies associated
with toxic hepatitis are Jin Bu Huan, xiao-chai-hu-tang, germander,
chaparral, senna, mistletoe, skullcap, gentian, comfrey (containing
pyrrolizidine alkaloids), ma huang, bee pollen, valerian root, pennyroyal oil, kava, celandine, Impila (Callilepis laureola), LipoKinetix,
Hydroxycut, OxyElite Pro, Herbalife, herbal nutritional supplements,
and herbal teas containing Camellia sinensis (green tea extract). Well
characterized are the acute hepatitis-like histologic lesions following
Jin Bu Huan use: focal hepatocellular necrosis, mixed mononuclear
portal tract infiltration, coagulative necrosis, apoptotic hepatocyte
degeneration, tissue eosinophilia, and microvesicular steatosis. Megadoses of vitamin A can injure the liver, as can pyrrolizidine alkaloids,
which often contaminate Chinese herbal preparations and can cause a
2591Chronic Hepatitis CHAPTER 341
veno-occlusive injury leading to sinusoidal hepatic vein obstruction.
Because some alternative medicines induce toxicity via active metabolites, alcohol and drugs that stimulate cytochrome P450 enzymes
may enhance the toxicity of some of these products. Conversely, some
alternative medicines also stimulate cytochrome P450 and may result
in or amplify the toxicity of recognized drug hepatotoxins. In many
instances, herbal and dietary supplements actually contain chemicals rather than only leaves, roots, and bark. Antirheumatic “herbs”
have been found to contain a nonsteroidal anti-inflammatory drug
(NSAID) such as diclofenac, for example. Given the widespread use
of such poorly defined herbal preparations, hepatotoxicity is likely to
be encountered with increasing frequency; therefore, a drug history
in patients with acute and chronic liver disease should include use of
“alternative medicines” and other nonprescription preparations sold
in so-called health food stores.
■ CHECKPOINT INHIBITOR AND OTHER
IMMUNOTHERAPIES FOR CANCER
The introduction of a new class of immunotherapeutic agents for
melanoma and other cancers has ushered in a new kind of hepatotoxicity, that associated with activation of the immune response. The
three classes of immune-active molecules are cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4), programmed cell death receptor 1
(PD-1), and programmed cell death receptor ligand 1 (PD-L1). Within
weeks of beginning treatment with any one of several agents, including
ipilimumab (CTLA-4), pembrolizumab (PD-1), or nivolumab (PD-1),
an active hepatitis evolves that is associated with positive ANAs and
appears to respond to glucocorticoid therapy. Histologically, liver
histology does not resemble autoimmune hepatitis but, instead, a
nonspecific hepatic injury, assumed to result from the release of host
modulation of anti-self-immune responses. Immune-mediated injury
to thyroid, muscle, and colon is also commonly seen. Few deaths have
been reported related to these immunotherapies; while these novel
agents may need to be halted temporarily, in many cases, they can be
restarted (and are tolerated better on retreatment) if patients are showing a favorable antitumor response.
■ HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
FOR HIV INFECTION (MITOCHONDRIAL TOXIC,
IDIOSYNCRATIC, STEATOSIS; HEPATOCELLULAR,
CHOLESTATIC, AND MIXED)
The recognition of drug hepatotoxicity in persons with HIV infection
is complicated in this population by the many alternative causes of
liver injury (chronic viral hepatitis, fatty infiltration, infiltrative disorders, mycobacterial infection, etc.), but drug hepatotoxicity associated
with highly active antiretroviral therapy (HAART) was a common
type of liver injury in HIV-infected persons in the early days of HIV
therapy; however, it is less frequent now (Chap. 202). Implicated
most frequently are combinations including the nucleoside analogue
reverse transcriptase inhibitors zidovudine, didanosine, and, to a lesser
extent, stavudine; the protease inhibitors ritonavir and indinavir (and
amprenavir when used together with ritonavir), as well as tipranavir;
and the nonnucleoside reverse transcriptase inhibitors nevirapine
and, to a lesser extent, efavirenz. Distinguishing the impact of HAART
hepatotoxicity in patients with HIV and hepatitis virus co-infection is
made challenging by the following: (1) both chronic hepatitis B and
hepatitis C can affect the natural history of HIV infection and the
response to HAART, and (2) HAART can have an impact on chronic
viral hepatitis. For example, immunologic reconstitution with HAART
can result in immunologically mediated liver-cell injury in patients
with chronic hepatitis B co-infection if treatment with an antiviral
agent for hepatitis B (e.g., nucleoside analogues such as tenofovir)
is withdrawn. Infection with HIV, especially with low CD4+ T-cell
counts, has been reported to increase the rate of hepatic fibrosis associated with chronic hepatitis C, and HAART therapy can increase levels
of serum aminotransferases and HCV RNA in patients with hepatitis C
co-infection. Didanosine or stavudine should not be used with ribavirin in patients with HIV/HCV co-infection because of an increased
risk of severe mitochondrial toxicity and lactic acidosis.
Acknowledgment
Kurt J. Isselbacher, MD, contributed to this chapter in previous editions
of Harrison’s.
■ FURTHER READING
Ahmad J et al: Sclerosing cholangitis-like changes on magnetic resonance cholangiography in patients with drug-induced liver injury.
Clin Gastroenterol Hepatol 17:789, 2019.
Björnsson ES, Hoofnagle JL: Categorization of drugs implicated in
causing liver injury: Critical assessment based upon published case
reports. Hepatology 63:590, 2016.
Chalasani N et al: Features and outcomes of 899 patients with
drug-induced liver injury: The DILIN prospective study. Gastroenterology 148:1340, 2015.
Cirulli ET et al: A missense variant in PTPN22 is a risk factor for
drug-induced liver injury. Gastroenterology 156:1707, 2019.
de Boer YS et al: Features of autoimmune hepatitis in patients with
drug-induced liver injury. Clin Gastroenterol Hepatol 15:103, 2017.
Kaplowitz N, Deleve LD (eds): Drug-Induced Liver Disease, 3rd ed.
London, Elsevier/Academic Press, 2013.
Kleiner DE: Histopathological challenges in suspected drug-induced
liver injury. Liver Int 38:198, 2018.
Lee WM et al: Intravenous N-acetylcysteine improves transplant-free
survival in early stage non-acetaminophen acute liver failure. Gastroenterology 137:856, 2009.
Peeraphatdit TB et al: Hepatotoxicity from immune checkpoint
inhibitors: A systematic review and management recommendation.
Hepatology 72:315, 2020.
Stolz A et al: Severe and protracted cholestasis in 44 young men taking bodybuilding supplements: Assessment of genetic, clinical and
chemical risk factors. Aliment Pharmacol Ther 49:1195, 2019.
341 Chronic Hepatitis
Jules L. Dienstag
Chronic hepatitis represents a series of liver disorders of varying
causes and severity in which hepatic inflammation and necrosis continue for at least 6 months. Milder forms are nonprogressive or only
slowly progressive, while more severe forms may be associated with
scarring and architectural reorganization, which, when advanced, lead
ultimately to cirrhosis. Several categories of chronic hepatitis have been
recognized. These include chronic viral hepatitis, drug-induced chronic
hepatitis (Chap. 340), and autoimmune chronic hepatitis. In many
cases, clinical and laboratory features are insufficient to allow assignment into one of these three categories; these “idiopathic” cases are also
believed to represent autoimmune chronic hepatitis. Finally, clinical
and laboratory features of chronic hepatitis are observed occasionally
in patients with such hereditary/metabolic disorders as Wilson’s disease
(copper overload), α1
antitrypsin deficiency (Chaps. 344 and 415), and
nonalcoholic fatty liver disease (Chap. 343) and even occasionally in
patients with alcoholic liver injury (Chap. 342). Although all types of
chronic hepatitis share certain clinical, laboratory, and histopathologic
features, chronic viral and chronic autoimmune hepatitis are sufficiently
distinct to merit separate discussions. For discussion of acute hepatitis, see Chap. 339.
CLASSIFICATION OF CHRONIC HEPATITIS
Common to all forms of chronic hepatitis are histopathologic distinctions based on localization and extent of liver injury. These
vary from the milder forms, previously labeled chronic persistent
hepatitis and chronic lobular hepatitis, to the more severe form,
formerly called chronic active hepatitis. When first defined, these
No comments:
Post a Comment
اكتب تعليق حول الموضوع