Hepatocellular injury is characterized by significant elevations in the serum aminotransferases, which usually precede elevations in total bilirubin levels and alkaline phosphatase levels.7 Most injuries occur within 1 year of initiating the offending agent. Hepatocellular injury can lead to fulminant hepatitis with a corresponding 20% survival rate with supportive care.8 For those patients who present with the combination of hepatocellular injury and jaundice, there is a 10% mortality rate.9 Acarbose, allopurinol, fluoxetine, and losartan are capable of causing hepatocellular injury.7
Hepatocellular injuries can be further subdivided by specific histologic patterns and clinical presentations. Centrolobular necrosis, steatohepatitis (steatonecrosis), phospholipidosis, and generalized hepatocellular necrosis are each identifiable by particular biopsy results and subtle differences in clinical presentation.
Centrolobular necrosis is often a dose-related, predictable reaction; however, it also can be associated with idiosyncratic reactions. Also called direct or metabolite-related hepatotoxicity, centrolobular necrosis is usually the result of the production of a toxic metabolite (eFig. 17-1). The damage spreads outward from the middle of a lobe of the liver.
A general diagram of biotransformation. aHepatic blood flow, which changes proportionately with changes in cardiac output, delivers the drug to the liver. bProtein binding is most affected by nutritional status and competing drugs. cThe drug is actively transported into the hepatocyte by the organic anion transport pump, a transmembrane protein. dThe metabolite (drug) interacts with one of a number of enzymes, the most common being CYP2C9, 2C19, 2D6, and 3A4. This family of enzymes is regulated by the complementary DNA xenobiotic receptor. The xenobiotic receptor is in turn upregulated by other drugs, changes in cholesterol catabolism, and bile acids. The immediate result of the action of these phase I enzymes is the production of a reactive metabolite. eThe unstable metabolite then reacts with glucuronidase, various transferases, or hydroxylases to form a conjugated metabolite. The efficacy of these enzymes is affected by the patient’s nutritional state and genetic polymorphism, leading to variations in individual risk for toxicity. fThe conjugated metabolite is removed from the hepatocyte by the canalicular membrane export pump, one of a large family of membrane proteins (other members of this family pump conjugated metabolites back into the blood for excretion by the kidney). These proteins are subject to genetic polymorphism as well, again leading to some patients having an increased risk for toxicity. gIf unable to form a conjugate, the unstable metabolite can participate in oxidative reactions that damage lipids, proteins, or even DNA. hThe normal process of cellular aging, death, and reabsorption by surrounding cells. iWidespread, rapid cellular death with the creation of multiple antigens. jActivation Kupffer cells, killing cells, B-cells, and other T-cells with the associated production of inflammatory cytokines the relative numbers of which and the innate activity of each mediated by genetic polymorphism. kDrugs or active metabolites that are transported or diffuse into the mitochondria or the nucleus can damage DNA, leading to mutagenicity and ultimately hepatic cancers.
Patients suffering from centrolobular necrosis tend to present in one of two ways, depending on the extent of necrosis. Mild drug reactions, involving only small amounts of parenchymal liver tissue, may be detected as asymptomatic elevations in the serum aminotransferases. If the reaction is diagnosed at this stage, most of these patients will recover with minimal cirrhosis and thus minimal chronic liver impairment. More severe forms of centrolobular necrosis are accompanied by nausea, vomiting, upper abdominal pain, and jaundice.10,11
These reactions are predictable, often dose-related effects in the liver caused by specific agents. When taken in overdose, acetaminophen becomes bioactivated to a toxic intermediate known as N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is very reactive, with a high affinity for sulfhydryl groups. The protein glutathione provides a ready source of available sulfhydryl groups within the hepatocyte. When the liver’s glutathione stores are depleted and there are no longer sulfhydryl groups available to detoxify this metabolite, it begins to react directly with the hepatocyte (see eFig. 17-1). In addition, the depletion of glutathione changes the mitochondrial oxidized to reduced glutathione ratio resulting in catastrophic shifts in mitochondrial function, accelerating cell necrocytolysis.12 Continuing mitochondrial damage leading to fragmentation of mitochondrial DNA leads directly to necrosis.13 Replenishing the liver’s sulfhydryl capacity through the administration of N-acetylcysteine early after ingestion of the overdose halts this process.12 During the first hours after ingestion, some patients report mild symptoms of nausea and vomiting, but no elevations of the commonly measured liver enzymes are seen. Serum elevations in the liver enzymes begin 40 to 50 hours after ingestion.14 Circulating cell-free microRNA (liver-specific miR-122) begins to rise after only 1 hour in rat models of acetaminophen overdose. This may lead the way to earlier detection of many drug-induced liver disorders in the future.15
Nonalcoholic steatohepatitis (NASH), also known as steatohepatitis and steatonecrosis, results from the accumulation of fatty acids in the hepatocyte. In the preacute stages, this is known as nonalcoholic fatty liver disease (NAFLD). Drugs or their metabolites that cause NAFLD do so by affecting fatty-acid esterification and oxidation rates within the mitochondria of the hepatocyte (see eFig. 17-1). Hepatic vesicles become engorged with fatty acids, eventually disrupting hepatocyte homeostasis. In patients with diabetes, various dyslipidemias and even hypertension, the de novo production of free fatty acids from excess circulating carbohydrates, accelerates this process of accumulation. The liver biopsy is marked by a massive infiltration by polymorphonuclear leukocytes, degeneration of the hepatocytes, and the presence of Mallory bodies.16
Alcohol is the drug that most commonly produces steatonecrotic changes in the liver. When alcohol is converted into acetaldehyde, the synthesis of fatty acids is increased.17,18 The hepatocyte can become completely engorged with microvesicular fat, resulting in alcoholic fatty liver. Metabolically this type of de novo free fatty acid synthesis depletes NADPH in favor of NADP+ and reduces the hepatocytes’ ability to respond to stress, bypassing normal apoptosis and increasing the rate of necrocytolysis. In NAFLD, the same end point is often achieved through oxidation of lipid peroxidases.19 If the offending agent is withdrawn before significant numbers of hepatocytes become necrotic, the process is completely reversible without long-term sequelae. If not, then ever increasing rates of necrocytolysis will induce an innate immune response and result in hepatitis.
Tetracycline produces NAFLD and NASH.20 The lesions are characterized by large vesicles of fat found diffused throughout the liver. The development of this reaction is related to the high concentrations achieved when tetracycline is given IV and in doses greater than 1.5 g/day. The mortality of tetracycline steatohepatitis is high (70% to 80%), and those who do survive often develop cirrhosis. Sodium valproate also can produce steatonecrosis through the process of bioactivation. Cytochrome P450 (CYP450) converts valproate to delta-4-valproic acid, a potent inducer of microvesicular fat accumulation.21
Patients experiencing steatohepatitis may present with abdominal fullness or pain as their only complaint. Patients with more severe steatonecrosis will present with all the symptoms characteristic of alcoholic hepatitis such as nausea, vomiting, steatorrhea, abdominal pain, pruritus, and fatigue.
Phospholipidosis is the accumulation of phospholipids instead of fatty acids. The phospholipids usually engorge the lysosomal bodies of the hepatocyte.22 Amiodarone is associated with this reaction. Patients treated with amiodarone who develop overt hepatic disease tend to have received higher doses of the drug. These patients also have higher amiodarone-to-N-desethyl-amiodarone ratios, indicating a greater accumulation of the parent compound. Amiodarone and its major metabolite N-desethyl-amiodarone remain in the liver of all patients for several months after therapy is stopped. Usually the phospholipidosis develops in patients treated for more than 1 year. The patient can present with either elevated aminotransferases or hepatomegaly; jaundice is rare.16,23
Generalized Hepatocellular Necrosis
Generalized hepatocellular necrosis mimics the changes associated with the more common viral hepatitis. The onset of symptoms is usually delayed as much as a week or more after exposure to toxin. Bioactivation is often important for toxic hepatitis to develop. Many drugs that are associated with toxic hepatitis produce metabolites that are not inherently toxic to the liver. Instead, they bind with proteins to create haptens, which serve as neoantigens and induce the innate immune response (see eFig. 17-1).24
The rate of bioactivation can vary between males and females and between individuals of the same sex.25,26 The superfamily of CYP450 enzymes metabolizes lipophilic substrates that are actively pumped into the hepatocyte by an organic anion (or cation) transporting protein. The CYP450 subspecies 2C, 2D, 3A, and 4A are regulated by the highly inducible xenobiotic receptor on complementary DNA. The receptor is found in the liver, and to a lesser extent in the cells lining the intestinal tract, and is responsible for cholesterol catabolism and bile acid homeostasis. The activity of this receptor is subject to genetic polymorphism. This results in a wide variation in the sensitivity of the population to hepatic damage.27
The long-term administration of isoniazid can lead to hepatic dysfunction in 10% to 20% of those receiving the drug. Yet severe toxic hepatitis develops in only 1% or less of this population.28 The N-acetyltransferase2 (NAT2) genotype appears to play a role in determining a patient’s relative risk. A study of patients who developed elevated liver enzymes (defined as at least 2.5 times upper normal) or jaundice found that 29 out of 41 (70%) of these patients were slow acetylators.29 Isoniazid is metabolized by several pathways, acetylation being the major pathway. It is acetylated to acetylisoniazid, which, in turn, is hydrolyzed to acetylhydrazine.30 The acetylhydrazine, and to a lesser extent the acetylisoniazid, are directly toxic to the cellular proteins in the hepatocyte, but rapid acetylators detoxify acetylhydrazine very rapidly, converting it to diacetylhydrazine (a nontoxic metabolite). Therefore, it is the rate and efficiency of this reaction sequence that ultimately determines if hepatocellular damage will ensue.
Isoniazid simultaneously is an example of the potential predictability of drug-induced liver disease based on single nucleotide polymorphism and a lesson in the limitations of our current understanding. There are definite links to NAT2 genotype and toxicity.31 The risk for this reaction is also influenced heavily by the age of the patient, with older patients having a much higher risk than younger patients. In fact, age may be more important than genotype.28,29,31 In one prospective series focused on drug-induced liver disease, cases involving isoniazid had a median onset at 6 months of therapy with around 30% of isoniazid-induced liver disease clustered between 6 and 8 months.6
Ketoconazole produces generalized hepatocellular necrosis or milder forms of hepatic dysfunction in 1% to 2% of patients treated for fungal infections. The onset is usually early in therapy. In immunocompromised patients in whom ketoconazole is used, special care should be taken to watch for changes in liver function.32
The scarring effect of hepatitis in the liver leads to the development of cirrhosis. Some drugs tend to cause such a mild case of hepatitis that it may not be detected. Mild hepatitis can be easily mistaken for a more routine generalized viral infection. If the offending drug or agent is not discontinued, this damage will continue to progress. The patient eventually presents not with hepatitis, but with cirrhosis.
Methotrexate causes periportal fibrosis in most patients who experience hepatotoxicity. The lesion results from the action of a bioactivated metabolite produced by CYP450.33 This process occurs most commonly in patients treated for psoriasis and arthritis. Periodic liver biopsies have a low yield in patients without other risk factors for liver disease, and should be reserved for select high-risk patients.34 Vitamin A is normally stored in liver cells, and causes significant hypertrophy and fibrosis when taken for long periods in high doses. Hepatomegaly is a common finding, along with ascites and portal hypertension. In patients with vitamin A toxicity, gingivitis and dry skin are also very common. This is accelerated by ethanol, which competes with retinol for aldehyde dehydrogenase.17
A second pattern of hepatic damage is an injury that primarily involves the bile canalicular system and is known as cholestatic injury. Cholestatic disease is more often seen in patients over the age of 60 (compared with under age 60) and is slightly more common in males.35 In cholestatic disease, disturbance of the subcellular actin filaments around the canaliculi prevents the movement of bile through the canalicular system.36 In addition mutations in hepatic transporter genes can result in slower function prior to toxin exposure.37 The inability of the liver to remove bile causes intrahepatic accumulation of toxic bile acids and excretion products.36,37
Drug-induced cholestasis can occur as an acute disorder (e.g., cholestasis with or without hepatitis and cholestasis with bile duct injury) or as a chronic disorder (e.g., vanishing bile duct syndrome, sclerosing cholangitis, and cholelithiasis).38,39 However, the most common form of drug-induced cholestasis is cholestasis with hepatitis. Most patients with this acute disorder present with nausea, malaise, jaundice, and pruritus.7 Elevations in serum alkaline phosphatase levels are more prominent and usually precede the elevations of other liver enzymes in serum.3 A liver biopsy is not usually required, but is sometimes pursued when other causes of cholestatic disease are suspected.38 Although the antipsychotic drug chlorpromazine appears to be the prototype drug for this disorder, other medications are associated with other forms of cholestatic injury, such as erythromycin estolate, amoxicillin–clavulanic acid, and carbamazepine.8
Cholestatic injury, also known as cholestatic jaundice or cholestasis, can be classified by the area of the bile canalicular or ductal system that is impaired. Canalicular cholestasis is often associated with long-term, high-dose estrogen therapy. These patients are often asymptomatic and present with mild-to-moderate elevations of serum bilirubin.40 An IV form of vitamin E, α-tocopherol acetate, causes cholestatic jaundice, primarily involving the canalicular duct in premature infants. The incidence of this reaction in those receiving this formulation was high (>10%) and the mortality even higher (>50%).41
The administration of total parenteral nutrition for periods greater than 1 week induces cholestatic changes and nonspecific enzyme elevations in some patients. Patients with low serum albumin concentrations may be at greater risk than patients with normal serum albumin concentrations.16 This reaction occurs rarely with dicloxacillin, sulfonamides, sulfonylureas, erythromycin estolate and ethylsuccinate, captopril, lisinopril, and other phenothiazines.41,42
Mixed Hepatocellular and Cholestatic Injury
The final pattern of hepatic damage is a combining of the previous two patterns. This presentation can be the result of three different processes. In some patients, an injury may begin as hepatocellular (or cholestatic) and simply spread so rapidly that by the time the patient presents for diagnosis and treatment, all areas of the liver are affected. In other patients, the underlying mechanism of damage is such that cells are injured regardless of their anatomical location or primary metabolic role.
Focal lesions in hepatic venules, sinusoids, and portal veins occur with various drugs. The most commonly associated drugs are the cytotoxic agents used to treat cancer, the pyrrolizidine alkaloids, and the sex hormones. A centralized necrosis often follows and can result in cirrhosis. Azathioprine and herbal teas that contain comfrey (a source of pyrrolizidine alkaloids) are associated with the development of venoocclusive disease. The exact incidence is rare and may be dose related.16 Peliosis hepatitis is a rare type of hepatic vascular lesion that can be seen as both an acute and a chronic disease. The liver develops large, blood-filled lacunae (space or cavity) within the parenchyma. Rupture of the lacunae can lead to severe peritoneal hemorrhage. Peliosis hepatitis is associated with exposure of the liver to androgens, estrogens, tamoxifen, azathioprine, and danazol. Androgens with a methyl alkylation at the 17-carbon position of the testosterone structure are the most frequently reported agents that cause peliosis hepatitis, usually after at least 6 months of therapy.43