Exploring psychotherapeutic issues and agents in clinical practice
With a few exceptions (e.g., lithium, gabapentin, pregabalin), most psychotropic drugs are metabolized in the liver. For this reason, many patients want to know whether medications they take can harm the liver and whether blood testing is necessary. This article reviews the effects of anticonvulsant, antidepressant, and antipsychotic drugs on the liver, providing information that will be useful for nurses in clinical practice.
Drug-Induced Liver Injury
Drug-induced liver injury is the fourth leading cause of liver damage and the second main cause of acute liver failure worldwide; moreover, it is the primary cause of liver failure in the United States (Bernal, Auzinger, Dhawan, & Wendon, 2010). Liver toxicity is the leading reason for withdrawal of marketed drugs and is a common reason for terminating the development and marketing of investigational drugs. Antidepressant, antipsychotic, and anticonvulsant drugs can be associated with hepatotoxicity, but their relative risk of causing significant liver injury or liver failure is considerably less compared with other nonpsychotropic drug classes, such as analgesic drugs, antimicrobial agents, herbal medicines, and other drugs (Bernal et al., 2010; Reuben, Koch, Lee, & Acute Liver Failure Study Group, 2010).
Indeed, paracetamol (acetaminophen [Tylenol®]) is by far the most common cause of drug-induced liver failure, either by intentional or unintentional overdose. In the United States, approximately one half of cases of acetaminophen-associated liver failure are due to intentional overdose. In addition, excessive alcohol use is the fourth leading preventable cause of death, accounting for approximately 10% of deaths among adults, and the two most frequent chronic causes of alcohol-attributable death are alcoholic liver disease and cirrhosis (Stahre, Roeber, Kanny, Brewer, & Zhang, 2014). Combining acetaminophen and alcohol is associated with an increased risk of severe hepatotoxicity; however, alcohol use is not clearly or consistently identified as a risk factor for liver injury associated with other drugs (Björnsson, 2009).
Liver injury can be broadly classified as hepatocellular (i.e., referring to hepatocyte involvement) or cholestatic (i.e., referring to bile flow), but these pathological changes can be mixed. “Liver function tests” is a catch-all phrase for laboratory determinations of various chemical products, enzymes, and proteins relevant to the liver that can be measured in serum. The enzymes alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP), as well as the hemoglobin breakdown product bilirubin, are most commonly used as markers of liver injury. Mild or transient elevation of liver enzymes (i.e., less than three times the upper laboratory limit of normal [ULN] for ALT or less than two times the ULN for ALP) occurs much more commonly with the use of antidepressant, antipsychotic, or anticonvulsant drugs than severe hepatotoxicity (Au & Pockros, 2013; U.S. National Library of Medicine, 2014; Voican, Corruble, Naveau, & Perlemuter, 2014).
Anticonvulsant Drugs and the Liver
Phenytoin (Dilantin®), which is not typically used in psychiatry, is more likely to be associated with liver failure in adults compared with other anticonvulsant drugs, such as valproic acid (Depakote®), carbamazepine (Tegretol®), lamotrigine (Lamictal®), topiramate (Topamax®), and gabapentin (Neurontin®), which are used in psychiatric practice (Mindikoglu, Magder, & Regev, 2009; Reuben et al., 2010). Severe hepatotoxicity (including liver failure) associated with valproic acid and carbamazepine occurs primarily in pediatric populations, often when used together with multiple anticonvulsant drugs (Au & Pockros, 2013; Mindikoglu et al., 2009). Antidepressant and antipsychotic drugs are less likely to cause significant liver injury or failure than anticonvulsant drugs.
With the use of valproic acid, transient elevations in ALT and AST occur in 10% to 15% of patients, as well as increased bilirubin in up to 44% of patients (Au & Pockros, 2013). Elevations of GGT and ALP are less common. Severe hepatotoxicity is rare, idiosyncratic, unpredictable, and generally unrelated to dose. Should patients stop taking valproic acid if their liver function tests are abnormally elevated? The recommendation is that patients can continue to take the drug if their levels are not excessively elevated (i.e., less than three times the ULN for ALT or AST; less than two times the ULN for ALP; less than two times the ULN for bilirubin). Clinical monitoring (i.e., assessing for fatigue, poor appetite, abdominal pain, nausea, vomiting, dark urine, jaundice) and laboratory monitoring should be conducted during follow up. Ammonia is a breakdown product of proteins and is converted to urea in the liver. Valproic acid can inhibit this conversion, resulting in elevated ammonia levels that can sometimes cause confusion or hepatic encephalopathy (i.e., a more severe delirium-like state). Monitoring ammonia levels is not routinely necessary, but it should be done if confusion develops. Ammonia levels will drop and confusion will resolve by stopping valproic acid.
Asymptomatic elevations of liver function tests (most commonly GGT) occur in up to 60% of patients taking carbamazepine (Au & Pockros, 2013). Similar to valproic acid, carbamazepine can be continued with clinical and laboratory monitoring as long as the elevations are not excessive. Severe hepatotoxicity is unpredictable, idiosyncratic, and uncommon. Hypersensitivity (i.e., allergic) reactions to carbamazepine, which are characterized by skin rash, fevers, eosinophilia, and (rarely) the Stevens-Johnson syndrome, can also involve the liver in approximately 10% of patients. Carbamazepine should be discontinued when clinical evidence of hypersensitivity exists.
Elevations of liver function tests are uncommon with the use of lamotrigine, occurring in less than 1% of patients, and severe hepatotoxicity is rare (Au & Pockros, 2013). Similar to carbamazepine, hypersensitivity reactions to lamotrigine can sometimes involve the liver. To avoid hypersensitivity reactions, the recommended use of lamotrigine includes low starting doses and a slow upward dose titration schedule.
Less than 1% of patients develop elevations in liver enzymes during long-term topiramate therapy, and significant hepatotoxicity is rare and usually seen in patients taking multiple anticonvulsant drugs (U.S. National Library of Medicine, 2014). Gabapentin is not metabolized by the liver and is not associated with an increased frequency of liver enzyme elevations or liver toxicity (U.S. National Library of Medicine, 2014). Rare case reports of gabapentin-associated liver injury have been published, but the causal relationship cannot be established because of other concurrent medications and/or medical conditions (U.S. National Library of Medicine, 2014).
Antidepressant Drugs and the Liver
Antidepressant drugs have been associated with mild asymptomatic elevations of liver enzymes in up to 10% of patients (U.S. National Library of Medicine, 2014; Voican et al., 2014). Severe hepatotoxicity and liver failure can occur with any antidepressant drug, but it is rare, idiosyncratic, unpredictable, and generally unrelated to dose. Compared with anticonvulsant and other nonpsychotropic drugs, antidepressant drugs are less likely to cause significant liver injury or failure. Among different antidepressant drugs, whether certain drugs are more likely to be associated with significant liver injury cannot be definitively established because their relative frequency of use, the reasons for their use, and the types of patients for whom they are used often differ. In addition, limitations in the methodology of studies that investigate this issue and the well-known problems in establishing causality based on case reports make it difficult to determine the relative risk of liver injury across different antidepressant drugs.
However, despite the uncertainty, nefazodone (Serzone®) and duloxetine (Cymbalta®) have been singled out for their potential hepatotoxicity. The product label for nefazodone includes a black-box warning stating that cases of life-threatening hepatic failure have been described. The warning also recommends that nefazodone should not be used in patients with pre-existing liver disease or increased liver enzymes; however, the statement acknowledges that no evidence exists that these patient characteristics increase the likelihood of developing nefazodone-associated liver failure. The product label for duloxetine has a general precaution statement indicating that hepatotoxicity, including hepatitis, jaundice, elevated transaminase levels, and fatal liver failure, has been reported. Some of these reports have been in the context of patients who have concurrent chronic liver disease, cirrhosis, or heavy alcohol use. The precaution recommends that duloxetine should ordinarily not be prescribed for patients with substantial alcohol use or evidence of chronic liver disease.
Laboratory monitoring of liver function tests before and during treatment with antidepressant drugs is not generally recommended because doing so has not been shown to increase the likelihood of detecting or preventing significant liver injury or failure. Patients taking antidepressant drugs who have abnormally elevated liver function tests can continue to take them as long as their levels are not excessively elevated (following similar guidelines and monitoring as previously described for valproic acid).
Antipsychotic Drugs and the Liver
With the exception of chlorpromazine (Thorazine®), which has been associated with cholestatic liver injury (Björnsson & Jonasson, 2013), typical (i.e., first generation) and atypical (i.e., second generation) antipsychotic drugs are rarely associated with severe liver injury. During the 1960s and early 1970s, chlorpromazine was one of the most common causes of drug-induced liver disease (U.S. National Library of Medicine, 2014). Cholestatic hepatitis is characterized by prominent elevations of ALP and bilirubin, with symptoms that include nausea, fatigue, pruritus, dark urine, and jaundice. Chlorpromazine is classified as a phenothiazine drug; although other phenothiazine antipsychotic drugs can cause cholestatic hepatitis, this condition occurs much less frequently than with chlorpromazine. Similar to anti-depressant drugs, antipsychotic medications can be associated with mild asymptomatic elevated levels of liver enzymes, which do not predict a progression to severe liver injury.
Anticonvulsant, antidepressant, and antipsychotic drugs can be associated with significant liver injury or failure, but it is relatively rare. More commonly, mild asymptomatic elevations in liver function tests are seen, and these elevations are not predictive of progression to more severe liver injury. Laboratory monitoring of liver function before and during treatment is recommended with the use of valproic acid and carbamazepine, but not for other psychotropic drugs. However, regular laboratory testing is not a reliable method for detecting or preventing severe liver injury. Abnormal liver function can be associated with other comorbid conditions or concurrent medications. In addition, increased liver enzyme tests have been demonstrated in healthy patients taking placebo in clinical trials (Rosenzweig, Miget, & Brohier, 1999) and in healthy placebo-treated patients in clinical trials who are hospitalized (Narjes & Nehmiz, 2000). Therefore, interpretation of liver function tests is not always straightforward. Clinical monitoring for signs and symptoms suggesting hepatotoxicity or hypersensitivity reactions is more important. Nurses should be familiar with these signs and symptoms, and they should educate patients and families about them as well, encouraging them to call between appointments should they notice any changes. Nurses should also routinely counsel patients about their use of acetaminophen and alcohol, as these are much more likely to adversely affect liver function and cause severe liver injury or liver failure.
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