Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications

Dara, Lily; Liu, Zhang–Xu; Kaplowitz, Neil

doi:10.1111/liv.12988

Cited by 110 publications

(82 citation statements)

References 61 publications

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“…Isolated liver enzyme levels on treatment could reflect hepatic adaptation to the medication, wherein transient LBT abnormalities resolve even with continued exposure to the drug and the patient remains clinically well throughout [23]. One large cohort study of over 11,000 patients receiving isoniazid preventive therapy observed symptoms and signs of hepatotoxicity in only 0.15% of patients completing therapy [24], suggesting that the rates of DILI/enzyme elevations requiring intervention are actually very low with monotherapy and, by extension, with standard TB therapy as well.…”

Section: Discussionmentioning

confidence: 99%

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Tweed

Wills

Crook

et al. 2018

BMC Med

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BackgroundDrug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment.MethodsPatients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements.ResultsA total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14–56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008).ConclusionsOur results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1033-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Tweed

Wills

Crook

et al. 2018

BMC Med

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“…A hypersensitivity syndrome with fever and rash as clinical manifestations, as well as with autoantibodies and eosinophilia, and a short latency period (1-6 weeks) point to a predominantly immunoallergic pathophysiological mechanism [43], whereas a lack of hypersensitivity syndrome and a longer latency period (i.e. 1 month to 1 year) points to an idiosyncratic metabolic mechanism [44].…”

Section: Hepatotoxicity and Hypersensitivity Reactionsmentioning

confidence: 99%

The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature

Carvalho

Sharma²,

Brunoni³

et al. 2016

Psychother Psychosom

508

324

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Newer generation antidepressant drugs (ADs) are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents. In this critical review, we evaluated the literature on adverse events, tolerability and safety of selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, bupropion, mirtazapine, trazodone, agomelatine, vilazodone, levomilnacipran and vortioxetine. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms (nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances (heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system disturbances (lowering of seizure threshold, extrapyramidal side effects, cognitive disturbances), sweating, sleep disturbances, affective disturbances (apathy, switches, paradoxical effects), ophthalmic manifestations (glaucoma, cataract) and hyperprolactinemia. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. Other areas of concern involve suicidality, safety in overdose, discontinuation syndromes, risks during pregnancy and breast feeding, as well as risk of malignancies. Thus, the rational selection of ADs should consider the potential benefits and risks, likelihood of responsiveness to the treatment option and vulnerability to adverse events. The findings of this review should alert the physician to carefully review the appropriateness of AD prescription on an individual basis and to consider alternative treatments if available.

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“…Metushi et al42 recently reported the treatment of PD‐1 –/– mice with amodiaqine and anticytotoxic T lymphocyte antigen 4 led to liver injury similar to human iDILI. This model suggested that immune tolerance would have an important role in the development of iDILI 43. Other genetic and drug metabolism markers, such as N‐acetyltransferase 2 or uridine diphosphate glucuronosyltransferase 2B7, also show promise.…”

Section: Future Perspectives On Idilimentioning

confidence: 99%

Idiosyncratic drug‐induced liver injury: A short review

Yamashita

Imai

Mima

et al. 2017

Hepatology Communications

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Idiosyncratic drug‐induced liver injury (iDILI) is a rare adverse drug reaction that occasionally leads to acute liver failure or even death. An aging population that uses more drugs, a constant influx of newly developed drugs, and a growing risk from herbal and dietary supplements of uncertain quality can lead to an increase in iDILI. Antimicrobials, central nervous system agents, and herbal and dietary supplements are the most common causes of iDILI in developed countries. iDILI is still a diagnosis of exclusion, and thus careful history taking and thorough work‐ups for competing etiologies, such as acute viral hepatitis, autoimmune hepatitis, and others, are essential. The pathogenesis of iDILI is not clear and includes a mix of host reactions, drug metabolites, and environmental factors. Immediate cessation of the suspected offending drug is key to preventing or minimizing progressive damage. No definitive therapies for iDILI are available, and the treatments remain largely supportive. (Hepatology Communications 2017;1:494–500)

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Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications

Cited by 110 publications

References 61 publications

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study

The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature

Idiosyncratic drug‐induced liver injury: A short review

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