INTRODUCTION — Hepatotoxicity is a potentially serious adverse effect of methotrexate (MTX) therapy, even in the relatively low doses of the drug commonly used to treat rheumatic diseases, including rheumatoid arthritis (RA). However, strategies for prevention and monitoring can minimize the risk and allow MTX to be used with relative safety for the treatment of rheumatic diseases and other nonmalignant conditions.
The risk factors, prevention, and management of hepatotoxicity associated with the use of low-dose MTX are reviewed here. Other adverse effects of low-dose MTX, hepatotoxicity and other adverse effects of high-dose MTX, and the use of MTX for the treatment of RA are described in detail separately. (See "Major side effects of low-dose methotrexate" and "Therapeutic use and toxicity of high-dose methotrexate" and "Methotrexate-induced lung injury" and "Use of methotrexate in the treatment of rheumatoid arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)
EPIDEMIOLOGY — Minor elevations in aminotransferases are common in patients treated with low-dose methotrexate (MTX), but hepatic steatosis, fibrosis, and cirrhosis may infrequently occur. Severe hepatotoxicity is very uncommon in patients managed using appropriate prevention strategies. (See 'Prevention and monitoring' below and 'Management of patients with abnormal liver function tests during monitoring' below.)
In a cohort of 659 United States military veterans age 65 and older who were newly receiving MTX for a rheumatic disease, moderate elevations (at least 1.5 times the upper limit of normal) of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) were observed over a mean follow-up of 7 months in 45 (6 percent) of the patients [1]. Higher rates were seen among patients with obesity, untreated high cholesterol, AST or ALT elevations above the upper limits of normal at baseline (before starting MTX), use of a biologic agent in addition to the MTX, and lack of folic acid supplementation.
RISK FACTORS
Genetic and other pre-existing factors and features of therapy — Multiple factors have been associated, mostly in observational studies, with an increased risk of developing hepatic dysfunction and injury in association with use of methotrexate (MTX). These include both pre-existing factors and treatment strategies during MTX therapy:
●Pre-existing factors:
•Genetic polymorphisms – MTX inhibits the effects of several intracellular enzymes in eukaryotic cells. Several of these enzymes are associated with genetic polymorphisms in the expression of the enzyme (protein) produced [2]. These single nucleotide polymorphisms (SNPs) can affect both the efficacy and toxicity of MTX.
The genetics of MTX efficacy and toxicity are complex and involve the enzymes associated with cellular uptake (reduced folate carrier) [3]; the enzyme that polyglutamates MTX (folylpolyglutamate synthase [FPGS]) [4]; and several other target enzymes, including dihydrofolate reductase (DHFR) [5], 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) [6], methylenetetrahydrofolate reductase (MTHFR) [7], serine hydroxymethyltransferase (SHMT) [8], and others [3]. The mix of the SNPs that have been identified with these proteins will affect the efficacy and toxicity of the drug.
As an important example, if an SNP is associated with greater intracellular levels of polyglutamated MTX or diminished levels of the target enzyme, it can render a patient more susceptible to toxicity [9].
•Pre-existing liver disease – Pre-existing liver disease, including alcoholic liver disease, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD). Hepatic injury, as shown by elevated aminotransferases, is associated with increased risk [1]. (See 'Other liver disease' below.)
•Certain comorbidities – Certain medical comorbidities, including obesity and dyslipidemia [1].
●During MTX therapy:
•Additional hepatotoxin exposure – Exposure during MTX therapy to other hepatotoxins, including alcohol and a variety of medications, including nonsteroidal antiinflammatory drugs (NSAIDs) and other agents. (See 'Alcohol' below and 'Hepatotoxic medications' below.)
•Dosing strategies associated with increased risk – Higher cumulative MTX dose, which has been shown in patients with psoriasis [10], and daily rather than intermittent dosing, which was associated with a twofold increase in the risk of cirrhosis and fibrosis [11,12]. The route of administration will only affect risk if changing the route is associated with greater absorption. This can occur when going from oral to subcutaneous MTX as bioavailability is improved when given subcutaneously.
•Lack of folate supplementation – Lack of prophylactic use of folic acid supplementation during treatment [1].
•Biologic disease-modifying antirheumatic drug (DMARD) therapy – Treatment with biologic agents in addition to MTX [1].
Other liver disease — Patients with pre-existing liver disease are at increased risk with the addition of MTX. As examples, patients with chronic hepatitis B and C infections may experience worsening of liver disease from drug-related injury and may be at risk of worsening of the infectious process. NAFLD and NASH are increasingly common, and although prospective trials of MTX in patients with NAFLD (which is subdivided into nonalcoholic fatty liver [NAFL] and NASH) have not been performed, it is likely that the addition of MTX in this setting could accelerate changes to NASH. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
Beneficial effects of MTX in certain autoimmune liver diseases such as primary biliary cholangitis (see "Overview of the management of primary biliary cholangitis") and granulomatous hepatitis [13,14] should not be misinterpreted as showing that MTX is not itself potentially hepatotoxic. Rather, its salutary effects on autoimmune liver disease may outweigh its potential for hepatotoxicity, particularly in short- and intermediate-term studies.
Alcohol — Alcohol has been identified as a major risk factor for liver disease in patients with psoriasis on MTX [15]. To our knowledge, there is only one study that has examined the relationship of the amount of prior alcohol consumption with both transaminase elevations and liver histology from biopsy tissue [16]. The amount of alcohol intake was related to subtle worsening in hepatic histology in patients with rheumatoid arthritis (RA) on weekly MTX, when annual liver biopsies were read in a blinded fashion from sequential samples. There appeared to be a linear correlation with increasing amounts of alcohol from a few drinks per week to daily consumption.
Hepatotoxic medications — The concomitant use of each of several medications has been associated with an increased risk of hepatotoxicity in patients using MTX. These include:
●Leflunomide [17]
●Retinoids
Data from a large cohort of patients with RA (1953 patients) and psoriatic arthritis (151 patients), enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) database in the United States, showed an increased risk of transaminase elevations with a combination of MTX and leflunomide compared with either drug used alone [17]. The overall incidence of elevations in aminotransferase enzymes in patients with RA receiving MTX, leflunomide, MTX plus leflunomide, and neither was 22, 17, 31, and 14 percent, respectively. Patients with psoriatic arthritis were 2.76-fold (CI 1.84-4.15) more likely to exhibit elevations in these enzymes than patients with RA.
PATHOGENESIS — The mechanism by which methotrexate (MTX) adversely affects the liver is unclear, although hepatotoxicity due to MTX may result from direct damage to hepatocytes; and in patients with concomitant viral hepatitis, MTX may enhance viral damage. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Hepatic folate stores are depleted by MTX in the doses used in rheumatoid arthritis (RA; 15 to 25 mg once weekly), and these stores can be repleted by short-term administration of oral leucovorin (folinic acid) [18]. A direct relationship between folate depletion and hepatic toxicity has not been established; however, supplementation with either folic acid or leucovorin (folinic acid) is associated with a reduced incidence of serum transaminase elevation [19,20].
Genetic polymorphisms in the enzymes involved in MTX uptake and metabolism have important effects that also contribute to toxicity. (See 'Genetic and other pre-existing factors and features of therapy' above.)
SYMPTOMS AND FINDINGS
Symptoms and physical findings — Most patients with hepatotoxicity associated with low-dose methotrexate (MTX) lack any symptoms or physical findings related to this adverse effect, given the relatively mild changes they exhibit. Features such as malaise, pruritus, or jaundice, which may be associated with more severe liver disease, are extremely rare.
Biochemical abnormalities — Use of MTX for both rheumatologic and neoplastic diseases has been associated with abnormalities of liver biochemical tests [2,16,21-23]. The reported incidence of MTX-induced increases in serum alanine aminotransferase (ALT) is approximately 14 percent, while the incidence of increases into the abnormal range of aspartate aminotransferase (AST) is 8 percent [16,21]. Reductions in serum albumin may also be seen, and in patients whose albumin is not decreased due to disease activity, this is also a marker of potential liver injury [21]. The enzymes may rise with each course of MTX and are also higher in patients receiving the drug more frequently than once per week [24]. The abnormal liver enzymes in patients on low-dose MTX for rheumatic disease usually resolve within a month of discontinuation of the drug. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Methotrexate'.)
Histopathology — MTX can induce a variety of histologic changes, including steatosis, stellate (Ito) cell hypertrophy, anisonucleosis (nuclei of varying sizes), and hepatic fibrosis (picture 1) [16,21,22]. Fatty change is common on follow-up, but while early fibrosis can be seen with special staining, it is less common. Biopsies can become normal in those with baseline normal histology if patients are monitored and doses adjusted to avoid allowing transaminase elevations to persist [21].
Imaging — Routine imaging studies have not shown any findings specific for MTX hepatotoxicity. Findings in the liver using ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can reveal changes of steatosis, early and later fibrosis, and cirrhosis, if present, as are found in other diseases that may also have the potential to cause progressive liver injury, such as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Radiographic examinations' and "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis", section on 'Imaging studies'.)
Ultrasound elastography has been investigated for the detection of liver stiffness associated with fibrotic changes in patients with established liver injury. (See 'Investigative use of noninvasive imaging technologies' below and "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography" and "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)
PREVENTION AND MONITORING
Pretreatment evaluation — Before initiating methotrexate (MTX) therapy, we do the following with respect to monitoring for hepatotoxicity:
●History and examination for all patients – Patients should have a careful history and physical examination with particular emphasis on alcohol intake, potential exposure to viral hepatitis (eg, illicit drug use), and any family history of liver disease.
●Laboratory testing for all patients – Baseline laboratory studies should include aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum albumin. Some experts also obtain a serum bilirubin and prothrombin time, but such testing is not suggested in the guidelines developed by the American College of Rheumatology (ACR) [21,25].
We also test for hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C antibody before starting MTX therapy. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation'.)
Some experts limit screening for hepatitis viruses, particularly hepatitis C, to patients at increased risk of hepatitis, such as those who have a history of intravenous drug abuse, have had multiple sex partners in the previous six months, or who are health care workers [25,26].
●Liver biopsy in selected high-risk patients – Although we generally avoid the use of MTX in patients with a history of alcohol abuse, viral hepatitis, or other liver disease, a pretreatment liver biopsy should be performed in patients who will nonetheless be starting MTX treatment who have a history of excessive alcohol consumption, persistently abnormal AST or ALT values, or chronic hepatitis B or C infection.
The use of elastography has been proposed as an alternative or preliminary screening technique for such patients, and if it is abnormal, we would not start MTX (and could avoid the need for liver biopsy). However, elastography has the limitation that this is less sensitive for detection of early fibrosis than evaluation of histopathology with trichrome staining of a tissue specimen obtained by liver biopsy. (See 'Histopathology' above and 'Investigative use of noninvasive imaging technologies' below.)
●Baseline ultrasound evaluation of patients at risk of NAFLD and NASH – Patients with evidence of nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), particularly those with elevated hepatic transaminases or decreased serum albumin, should be monitored closely, typically monthly for at least several months, when initiating therapy. Thus, patients with an elevated body mass index (BMI) of ≥30 (calculator 1) and increases in transaminase enzymes above the upper limit of normal (confirmed on repeat testing or by review of prior laboratory findings showing a pattern of elevated values) should have a hepatic ultrasound to determine if the patient may have NAFLD. However, we would not view a single isolated elevated value without persistence as a contraindication for MTX therapy. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Management of nonalcoholic fatty liver disease in adults".)
Pretreatment evaluation for issues other than hepatotoxicity is described separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Precautions and prevention of adverse effects'.)
Counseling and preventive therapy for all patients
●Folate supplementation – Folate supplementation may help prevent hepatotoxicity and other adverse effects in patients taking MTX but does not substitute for ongoing monitoring and appropriate MTX dose adjustments if transaminase elevation occurs. Folate supplementation is described in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Folic acid supplementation'.)
●Alcoholic beverages – Patients on MTX therapy should be counseled about the potential adverse effect of alcohol on the liver when combined with MTX. This conversation should be documented in the medical record. The amount of alcohol that can be safely consumed while on MTX is likely to be highly idiosyncratic and specific to a patient's genetic profile. There is great variation in the enzymes associated with alcohol metabolism and the intracellular metabolism of MTX [2]. The clinician is therefore unable to prejudge how much alcohol a particular patient can tolerate while on MTX.
An evolving rule of thumb is to recommend no more than two to three drinks (where one drink equals one mixed drink, 5 to 6 ounces of wine, or 12 ounces of beer) per week to start, accompanied by ongoing monitoring of transaminase enzymes and serum albumin with dose adjustments or counseling regarding alcohol avoidance in the event of abnormalities. (See 'Approach to monitoring in rheumatoid arthritis' below.)
Occasional and low-level alcohol consumption may be tolerated for some patients, but the specifics of the intake recommendations should be highly individualized and require real-time monitoring of hepatic aminotransferase enzymes for increases into the abnormal range that could reflect an incipient problem. Alcohol intake might be liberalized if enzymes remain in the normal range while testing occurs at the standard monitoring intervals. However, some experts advocate that all patients on MTX should be cautioned that the safest approach is to avoid alcohol altogether because of the potential risk, variability in individual tolerance, and uncertainty regarding the efficacy of recommendations that permit some alcohol intake.
Approach to monitoring in rheumatoid arthritis — Based upon the above observations, the ACR has published guidelines for monitoring MTX-induced hepatic toxicity in patients with rheumatoid arthritis (RA) [21,25]. It should be noted, however, that these recommendations are based upon expert opinion. In general agreement with these guidelines, we recommend the following:
●Medical history – Patients should also be periodically questioned about their adherence to avoidance of intake of alcoholic beverages, any intercurrent medical issues, and to confirm proper self-administration of their MTX once weekly.
Regarding alcohol use, it is best if the clinician has a repeated dialogue with the patient regarding the extent of alcohol consumption, particularly if new elevations of transaminase enzymes are detected while on chronic MTX therapy. (See 'Counseling and preventive therapy for all patients' above.)
●Routine blood testing – Blood sampling for measurement of aminotransferases and serum albumin should be obtained at four- to eight-week intervals. The 2008 ACR recommendations indicate that, in patients on a stable dose of MTX, monitoring at an interval of every 8 to 12 weeks is appropriate after 3 months of therapy and monitoring every 12 weeks can be performed beyond 6 months of therapy [25].
●Indications for more frequent blood tests:
•Use of other hepatotoxic medications – In general, more frequent monitoring than that mentioned in the guidelines should be considered when other potential hepatotoxins are first combined with MTX therapy. These may include azathioprine, retinoids, sulfasalazine, cyclosporine, and, especially, leflunomide.
•Elevated body mass index with abnormal blood tests – Patients with an elevated BMI (≥30) (calculator 1) and transaminase enzyme increases that may be viewed as trivial at baseline should be monitored particularly carefully (monthly) for the evolution of NASH while on MTX. In patients in whom abnormalities persist for several months, the dose of MTX should be lowered; and if the transaminases continue to be elevated into the abnormal range despite dose reductions, the MTX should be discontinued.
NAFLD and NASH are increasingly common, and although prospective trials of MTX in patients with NAFLD have not been performed, it is likely that the addition of MTX in this setting could accelerate changes to NASH. The features, diagnosis, and management of NAFLD are described in detail separately. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Management of nonalcoholic fatty liver disease in adults".)
●Indications for liver biopsy – Liver biopsy should be performed if 6 of 12 tests are abnormal in any year (or 5 of 9 if testing is performed at 6-week instead of monthly intervals). Abnormal aminotransferases are defined as any elevation into the abnormal range, while low serum albumin is defined as a value ≤3.4 g/dL (≤34 g/L). Routine monitoring biopsies after a fixed interval or specific cumulative dose of MTX are no longer recommended.
Guidelines for the monitoring for hepatotoxicity in patients being treated for RA with MTX were adopted when rheumatologists began using MTX for patients with RA [27], and prospective studies were done in which baseline and multiple liver biopsies were performed [16,22]. The rheumatology studies measured the serum AST and albumin concentrations at regular and frequent intervals during the period leading up to liver biopsy and between sequential biopsies, finding that elevations of AST into the abnormal range were predictive of abnormal or worsening histologic grade on liver biopsy [22,23]. Furthermore, no deterioration was noted on serial liver biopsies when the MTX dose was adjusted for abnormalities in serum AST and albumin [22].
By contrast, early studies from the dermatology literature had described severe liver disease, including cirrhosis, in patients with psoriasis who were treated with MTX and noted an inability of liver function testing to predict actual liver toxicity [10,15,28,29]. Thus, historically, the dermatology community had recommended monitoring for liver disease by liver biopsy performed after a total cumulative dose of 1.5 g of MTX and again after each additional 1 g cumulative dose [10]. The studies on which the past recommendations were based had several limitations, including the performance of blood sampling only on the day of the liver biopsy and the lack of control for exposure to other hepatotoxins (such as alcohol and arsenic). The guidelines from the American Academy of Dermatology no longer recommend liver biopsies in all patients administered MTX [30]. (See "Treatment of psoriasis in adults", section on 'Methotrexate' and "Treatment of psoriasis in adults", section on 'Hepatotoxicity'.)
Nonetheless, the recommendations contained in the suggested guidelines were derived from published cohorts of patients who did not use alcohol [31-33]. These patients, when managed under the recommended guidelines, had a safe long-term outcome with respect to liver toxicity. One study, for example, prospectively evaluated 27 patients with RA who were treated with MTX; no clinically meaningful changes by light or electron microscopy were found in the 170 liver biopsies obtained over a mean of eight years [22].
Approach to monitoring in other rheumatic diseases — Studies of the predictive value of serial blood sampling and hepatic histologic outcome have been performed only in patients with RA. It is presently uncertain, because of the absence of data, if serial monitoring of aminotransferases and serum albumin can be universally applied to other groups receiving MTX, such as patients with systemic lupus erythematosus, granulomatosis with polyangiitis and other vasculitides, juvenile idiopathic arthritis, and psoriatic arthritis. As a group, patients with psoriatic arthritis have higher BMI levels and may have an independent risk of steatohepatitis.
There is some evidence that patients with psoriasis may have an enhanced predisposition to hepatic damage, particularly if they have underlying type 2 diabetes mellitus or are overweight [15,34]. Other observational studies have shown no increase in abnormal liver function tests compared with patients with RA [35]. (See "Treatment of psoriasis in adults" and "Treatment of psoriasis in adults", section on 'Hepatotoxicity'.)
Investigative use of noninvasive imaging technologies — Other approaches are under development for the detection of changes related to hepatic fibrosis, including noninvasive imaging techniques [36]. As an example, ultrasound-based transient elastography has been used in preliminary studies of patients receiving MTX for inflammatory arthritis, psoriasis, and gastroenterologic disorders but has not been adequately evaluated for its utility in monitoring patients with RA receiving MTX in clinical practice [37-41]. This diagnostic modality measures changes that are related to hepatic fibrosis; consequently, it may fail to detect early changes (prior to the development of fibrosis) that would not be sufficiently advanced to be detected by elastography. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)
MANAGEMENT OF PATIENTS WITH ABNORMAL LIVER FUNCTION TESTS DURING MONITORING — A key feature of these suggested guidelines that is sometimes overlooked is the need to adjust the methotrexate (MTX) dose in the event of an abnormality in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or a decrease in serum albumin concentration. Thus, after obtaining an abnormal value, the clinician should review the patient's history (eg, for alcohol consumption and for exposure to concomitant medications, including nonsteroidal antiinflammatory drugs [NSAIDs] and other potential hepatotoxins); and MTX should be continued, reduced, or withheld, depending upon the degree of abnormality initially and with counseling, and the results of dose adjustment observed with close follow-up monitoring (algorithm 1). MTX should be discontinued if no other reasons for transaminase enzymes elevations are found and the enzymes remain elevated above the laboratory-defined upper limit of normal. The same approach is taken for a patient with a baseline normal serum albumin who then develops hypoalbuminemia of <3.4 g/L. In our experience, although this careful monitoring places a great deal of responsibility on the clinician, it will make it unlikely that patients should have to undergo a liver biopsy.
The management of an overdose of MTX in patients being treated with chronic low-dose MTX is discussed in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Management of overdose'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Toxic hepatitis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Methotrexate (MTX) can induce a variety of histologic changes in the liver, including steatosis, stellate (Ito) cell hypertrophy, anisonucleosis (nuclei of varying sizes), hepatic fibrosis, and cirrhosis, and its use has been associated with abnormalities of liver biochemical tests. Abnormal liver enzymes that may occur usually resolve within a month of discontinuation of the drug. (See 'Pathogenesis' above and 'Histopathology' above.)
●The mechanism by which MTX adversely affects the liver is unclear. Hepatic folate stores are depleted by MTX in the doses used in rheumatoid arthritis (RA), and these stores can be repleted by short-term administration of oral leucovorin (folinic acid). Folate supplementation may help prevent hepatotoxicity in patients taking MTX but does not substitute for ongoing monitoring and appropriate MTX dose adjustments if transaminase elevation occurs. (See 'Pathogenesis' above and 'Genetic and other pre-existing factors and features of therapy' above and 'Counseling and preventive therapy for all patients' above.)
●Studies in RA have shown that repeated elevations of aspartate aminotransferase (AST) into the abnormal range were predictive of abnormal or worsening histologic grade on liver biopsy, but that no deterioration was noted on serial liver biopsies when the MTX dose was adjusted for abnormalities in serum AST and albumin. (See 'Risk factors' above and 'Pathogenesis' above and 'Approach to monitoring in rheumatoid arthritis' above.)
●Before initiating MTX therapy, patients should have a careful history and physical examination with particular emphasis on alcohol intake, potential exposure to viral hepatitis (eg, illicit drug use), and any family history of liver disease. Baseline laboratory studies should include AST, alanine aminotransferase (ALT), serum albumin, and serologic testing for hepatitis B and C virus infection. (See 'Pretreatment evaluation' above.)
●A pretreatment liver biopsy should be strongly considered in patients with a history of excessive alcohol consumption, persistently abnormal AST or ALT values, or chronic hepatitis B or C infection. Particular caution regarding the use of MTX is also warranted in the setting of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). (See 'Pretreatment evaluation' above.)
●Individual patients differ in their degree of risk for additional hepatic toxicity when alcohol is combined with MTX. It is best for patients to initially limit consumption to two to three drinks per week and to continue to monitor hepatic transaminase enzymes while reducing the limits if the laboratory results are elevated into the abnormal range. Alcohol intake might be liberalized if enzymes remain in the normal range while testing occurs at the standard monitoring intervals. (See 'Counseling and preventive therapy for all patients' above and 'Approach to monitoring in rheumatoid arthritis' above.)
●In patients being treated for RA, serum aminotransferases and albumin should be obtained at four- to eight-week intervals in the first three to four months of treatment as the dose of MTX is increased. Once on a stable dose, a patient with normal enzymes and serum albumin can usually be monitored at three-month intervals. The MTX dose should be adjusted in the event of an abnormality in AST or ALT, or a decrease in serum albumin concentration, and liver biopsy should be performed if 6 of 12 tests are abnormal in any year (or 5 of 9 if testing is performed at 6-week instead of monthly intervals). (See 'Approach to monitoring in rheumatoid arthritis' above.)
●It is not known whether the guidelines used for RA are applicable to other conditions, but similar guidelines have been adopted for the treatment of psoriasis. (See 'Approach to monitoring in other rheumatic diseases' above.)
