|MANAGING A SIDE EFFECT
|Year : 2021 | Volume
| Issue : 2 | Page : 106-112
Drug-induced liver injury: What a dermatologist should know?
Anwita Sinha1, Shekhar Neema2, Manish Manrai3, Biju Vasudevan2, S Radhakrishnan2
1 Department of Dermatology, MH Kirkee, Pune, Maharashtra, India
2 Department of Dermatology, AFMC, Pune, Maharashtra, India
3 Department of Gastroenterology, AFMC, Pune, Maharashtra, India
|Date of Submission||03-Aug-2020|
|Date of Decision||15-Oct-2020|
|Date of Acceptance||02-Jun-2021|
|Date of Web Publication||14-Dec-2021|
Department of Dermatology, AFMC, Pune - 411 040, Maharashtra.
Source of Support: None, Conflict of Interest: None
Dermatological practice involves the use of systemic drugs; some of them carrying boxed warnings of hepatotoxicity while others causing inadvertent or idiosyncratic liver damage. Drug-induced liver injury (DILI) is a common problem faced by dermatologists and refers to liver damage caused by medications, herbs, or other xenobiotics which can sometimes be fatal. Diagnosis of DILI remains challenging due to nonspecific clinical presentations compounded by a lack of knowledge in this area. With careful patient selection and systematic monitoring, liver injury should be rare in the dermatological setup. This review article is written with the aim of increasing awareness of DILI among dermatologists and thereby preventing liver injuries from common drugs.
Keywords: Drug induced liver injury, DILI, dermatology, liver function tests
|How to cite this article:|
Sinha A, Neema S, Manrai M, Vasudevan B, Radhakrishnan S. Drug-induced liver injury: What a dermatologist should know?. Indian J Drugs Dermatol 2021;7:106-12
|How to cite this URL:|
Sinha A, Neema S, Manrai M, Vasudevan B, Radhakrishnan S. Drug-induced liver injury: What a dermatologist should know?. Indian J Drugs Dermatol [serial online] 2021 [cited 2022 Jan 25];7:106-12. Available from: https://www.ijdd.in/text.asp?2021/7/2/106/332426
| Introduction|| |
Drugs are estimated to be responsible for 10% of cases of hepatitis in adults and account for about 25% of cases of fulminant hepatitis. Drug-induced liver injury (DILI) is a term used to describe the damage caused by drugs to liver cells with presentations ranging from asymptomatic liver enzyme elevations to acute liver failure (ALF). A plethora of common drugs used in dermatology such as methotrexate (MTX), dapsone, azathioprine, tumor necrosis factor alpha inhibitors, and oral antifungals are implicated in causing DILI, making it imperative for dermatologists to be aware of the intricacies of this condition. Diagnosis of DILI is challenging because of its relatively low incidence, variable clinical phenotype, and absence of specific biomarkers. Moreover, the unsupervised rampant use of herbal and dietary supplements (HDSs) for chronic dermatological disorders further adds to this conundrum. This review article focuses on the mechanisms, risk factors, diagnosis, prevention, and management of DILI with special interest to dermatological pharmacotherapy.
| Pathomechanisms of Drug-Induced Liver Injury:|| |
The susceptibility of the liver to adverse drug reactions occurs because of its central role in drug metabolism. The phases of drug metabolism include Phase I (oxidative reactions) mediated by cytochrome P-450 enzymes followed by Phase II (conjugation reactions) mediated by enzymes such as UDP glucuronyl transferase, N-acetyl transferases, and sulfotransferases. The overall goal of these reactions is detoxification, i.e., conversion of reactive metabolic intermediates to more stable compounds, and biotransformation, i.e. conversion of pharmacologically active, relatively lipophilic drugs, into inactive, relatively hydrophilic metabolites to facilitate renal or biliary excretion.
DILI is classified into intrinsic and idiosyncratic type based on the mechanism of action of drug. Intrinsic or direct DILI is a predictable event due to toxic drug dosages, while idiosyncratic DILI is an unpredictable event, determined by interaction of environment or host factors with the drug. Idiosyncratic reactions can occur due to metabolic or immunologic idiosyncrasies. The common dermatological drugs causing direct DILI are cyclosporin A (CsA), MTX, highly active antiretroviral therapy, and anabolic steroids, while drugs causing idiosyncratic DILI include isoniazid, ketoconazole, amoxicillin-clavulanate, cephalosporins, minocycline, fluoroquinolones, and terbinafine.
DILI is attributed to the presence of reactive metabolic intermediates and a defect in the cellular detoxification systems, leading to the persistence of these reactive intermediates. Glutathione (GSH) is part of scavenging system which contributes to detoxification by binding to electrophilic compounds. GSH can be depleted with heavy load of reactive intermediates as with drug overdosages and is further depleted by excessive alcohol consumption, HIV infection, and malnutrition, thus increasing a risk of DILI in these settings. DILI can also result from inhibition of the bile salt export pump (BSEP), leading to increased intracellular concentrations of bile salts, which can damage mitochondria causing cytotoxicity and liver injury. Potent BSEP inhibitors including CsA can lead to drug-induced cholestasis. DILI can also be classified according to the pattern of liver injury based on abnormalities in liver function tests (LFTs), as hepatocellular, cholestatic, or mixed [Table 1]. Hepatocellular type of DILI is more likely to be associated with a poor outcome and a higher mortality compared to other variants. Specific phenotypes of DILI seen with dermatological drugs are summarized in [Table 2].
|Table 1: Patterns of drug-induced liver injury based on liver function tests abnormalities|
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| Risk Factors for Drug-Induced Liver Injury|| |
In a susceptible patient, various patient- and drug-related factors work synchronously causing DILI as summarized in [Table 3]. Early phases of DILI are more drug-specific and are influenced by drug variables such as dosing and duration, whereas later phases are determined by the patient’s response to toxic stress.
| Clinical Features|| |
The clinical manifestations of DILI are heterogeneous mimicking acute and chronic liver diseases of various etiologies, ranging from asymptomatic biochemical alterations to ALF and chronic liver damage. Serum enzyme elevations without clinical symptoms constitute the most common pattern of direct DILI. Nonspecific symptoms such as fever, fatigue, nausea, vomiting, jaundice, dark urine, pruritus, and right upper quadrant pain may be present and have been associated with worse outcome. In severe cases, signs of hepatic failure such as ascites, coagulopathy, hyperammonemia, encephalopathy, or coma arise within days. Sinusoidal obstruction syndrome can present as hepatomegaly, abdominal pain, and weight gain, followed by jaundice, and may progress rapidly to hepatic failure.
| Drug-Induced Liver Injury with Skin Reactions|| |
Concomitant DILI and drug-induced skin injury have been reported in 10%–28% of patients in DILI registries. Liver injury typically manifests concurrent or subsequent to skin injury and only rarely (<10%) does it precede skin manifestations. Clinical features of hypersensitivity reactions drug rash with eosinophilia and systemic symptoms (DRESS) may include fever, nonspecific morbilliform rash or blisters, eosinophilia, lymphadenopathy, and mucositis. Antiepileptic drugs, sulfonamides, allopurinol, antibiotics, and nevirapine are the top five causes of concomitant liver and skin injury. The type of liver injury depends on the implicated drug and timing of presentation; however, cholestatic or mixed hepatitis is more common than hepatocellular pattern in DRESS. Atypical erythema multiforme-like eruption is associated with severe hepatic involvement and higher mortality. More severe liver dysfunction has been found in association with DRESS compared to milder liver dysfunction with Steven Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN) and acute generalised exanthematous pustulosis. Vanishing bile duct syndrome may rarely occur as a complication of liver injury in SJS/TEN.
| Diagnosis|| |
Diagnosis of DILI requires a detailed clinical history and cautious documentation of drugs including HDS, along with liver biochemistry, biomarkers, imaging, and in rare cases, liver biopsy. For a vast majority of dermatology drugs, serum aminotransferases alanine transaminase/aspartate transaminase (ALT/AST), alkaline phosphatase ALP, and total bilirubin levels remain mainstay for detecting and classifying liver damage. Serial testing of liver biochemistries should be done in patients with DILI until complete normalization. A steady decline of aminotransferases supports the diagnosis, whereas slow or incomplete resolution suggests other etiologies or chronic outcome. Liver imaging is routinely used at baseline in all suspected DILI patients, with abdominal ultrasonography used to exclude biliary obstruction and focal lesions. Since DILI is a diagnosis of exclusion, other causes of liver injury must be excluded. The panel of tests used in the evaluation of suspected DILI is summarized in [Table 4]. Common dermatological drugs implicated in liver injury along with hepatic monitoring guidelines are highlighted in [Table 5].
|Table 5: Dermatological drugs, liver injury, and hepatic monitoring guidelines|
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| Management|| |
The goal of management of DILI is similar to other adverse drug reactions where a balance has to be maintained between preventing target organ damage and continuing essential drugs. Minor increases in ALT or AST should be treated with reduction in the drug dose and careful follow-up of the transaminases, while increase more than threefold should prompt indefinite discontinuation of the likely culprit drug, unless an alternative etiology is detected.
- Discontinue the implicated agent or all nonessential drugs if culprit drug is unclear. Causality assessment can be done using tools such as Roussel Uclaf Causality Assessment Method
- Monitor LFT closely
- Seek appropriate consultation with a hepatologist when the patient has persistent elevation of transaminases or signs of ALF
- Institute supportive care.
In the large majority of DILI, spontaneous recovery occurs, without the need for any treatment or specific measure. In fact, spontaneous recovery after discontinuation of the offending drug is an important criterion in the causality assessment. Old age, dyslipidemia, and the severity of the acute episode are the risk factors for chronic DILI, which is defined as persistence of biochemical abnormality for more than 1 year. Deliberate re-challenge with the causative drug is not advocated, as it can cause more severe hepatotoxicity with a higher risk of mortality. However, re-challenge with lower dosage can be done under close monitoring in lifesaving drugs such as antitubercular drugs.
Pharmacotherapy has variable level of efficacy and should be used in specific circumstances with the hepatologist consultation.
- i. Cholestyramine: Bile acid resin such as cholestyramine (4 g every 6 h for 2 weeks) has been recommended to speed up drug clearance. Cholestyramine in association with antihistamines has been reported to accelerate the improvement of chronic cholestasis induced by terbinafine and leflunomide
- ii. N-acetyl cysteine (NAC): Besides its use in paracetamol intoxication, NAC has been occasionally used as a treatment for other types of DILI
- iii. Steroids: Systemic corticosteroids are the first-line agents for severe cutaneous and hepatic toxicity features DRESS. Corticosteroids are also used frequently in patients with ALF and autoimmune hepatitis or to treat hepatotoxicity due to immune-checkpoint inhibitors along with other immunosuppressants such as mycophenolate mofetil
- iv. Ursodeoxycholic acid (UDCA): Chronic cholestasis following DILI is often treated with UDCA
- v. Carnitine: L-carnitine with its antioxidant activity has been found to have a protective effect in antitubercular-induced liver injury and alcoholic liver disease.
| Conclusion|| |
Knowledge of DILI can help prevent unnecessary morbidity and rare deaths from systemic drugs, while maximizing the overall safety and efficacy of important systemic drugs used in dermatology. The awareness of hepatotoxic nature of commonly used drug in practice, protocol for baseline and follow-up liver biochemistry, advising patients against excessive alcohol intake, and use of HDS will go a long way in ensuring successful dermatologic pharmacotherapy with minimal risk of DILI.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]