Drug-Induced Liver Injury: Current Approaches to Diagnosis and Management

  Drug-Induced Liver Injury: Current Approaches to Diagnosis and Management

 Dr Neeraj manikath ; claude.ai

Abstract

Drug-induced liver injury (DILI) represents a significant clinical challenge with diverse presentations ranging from asymptomatic elevation of liver enzymes to acute liver failure. The diagnosis remains one of exclusion, requiring careful evaluation of medication history, temporal relationships, and exclusion of alternative etiologies. This review focuses on current diagnostic approaches, with emphasis on clinical presentation, biomarkers, histopathological features, causality assessment tools, and genetic factors. We also discuss management strategies, including immediate drug withdrawal, supportive care, specific interventions for particular drug classes, and liver transplantation in severe cases. Special consideration is given to DILI in hematologic patients, who often receive multiple hepatotoxic medications and may have complicating factors such as bone marrow transplantation, graft-versus-host disease, or underlying malignancies. Recent advances in biomarker development, pharmacogenomics, and artificial intelligence hold promise for more accurate and timely diagnosis of DILI. This comprehensive overview aims to enhance clinicians' understanding and management of this challenging condition, particularly in the context of hematologic diseases and their treatments.

 Keywords: Drug-induced liver injury; DILI; Hepatotoxicity; Diagnosis; Management; Hematology; Biomarkers; Pharmacogenomics

 

 Introduction

Drug-induced liver injury (DILI) remains a major challenge in clinical practice and a leading cause of acute liver failure in developed countries [1,2]. The annual incidence of DILI is estimated at 14-19 cases per 100,000 individuals, though this likely underestimates the true prevalence due to underreporting and diagnostic challenges [3]. DILI accounts for approximately 10% of all cases of acute hepatitis and is the most common reason for regulatory actions against drug approval and market withdrawal [4].

In hematologic practice, DILI presents unique challenges due to the frequent use of potentially hepatotoxic medications, complex treatment regimens, and patients' compromised immune systems [5]. Hematologic patients often receive multiple medications simultaneously, including chemotherapeutic agents, immunosuppressants, antimicrobials, and supportive medications, all of which can cause liver injury through various mechanisms [6]. Additionally, comorbidities such as viral infections, sepsis, veno-occlusive disease, and graft-versus-host disease (GVHD) can mimic or exacerbate DILI, making diagnosis particularly challenging in this population [7].

This review aims to provide a comprehensive overview of current approaches to diagnosis and management of DILI, with special emphasis on considerations relevant to hematologic practice. We will discuss clinical presentations, diagnostic strategies, causality assessment tools, role of biomarkers, histopathological features, genetic factors, and management principles.

  Classification and Mechanisms of DILI

 

 Classification Based on Clinical Presentation

 DILI is traditionally classified into intrinsic (predictable) and idiosyncratic (unpredictable) types [8]:

 1. Intrinsic DILI: Dose-dependent and predictable, typically occurring within a short time frame after exposure. Acetaminophen toxicity is the prototypical example, causing direct hepatocellular damage through its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) [9].

 2. Idiosyncratic DILI: Not clearly dose-dependent, unpredictable, and with variable latency periods ranging from days to months. Idiosyncratic DILI is further classified as:

 

   - Allergic (immunoallergic): Associated with features of hypersensitivity such as fever, rash, eosinophilia, and short latency upon rechallenge. Examples include phenytoin and sulfonamides [10].

 

   - Non-allergic: Lacks hypersensitivity features but may involve genetic susceptibility factors and metabolic idiosyncrasies. Examples include isoniazid and diclofenac [11].

 Classification Based on Pattern of Liver Injury

DILI is also classified according to the pattern of liver enzyme elevation [12]:

 1. Hepatocellular: Characterized by predominant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT is typically ≥3 times the upper limit of normal (ULN), and the ratio of ALT to alkaline phosphatase (R value) is ≥5.

 2. Cholestatic: Characterized by predominant elevation of alkaline phosphatase (ALP) ≥2 times ULN, with R value ≤2.

3. Mixed: Features of both hepatocellular and cholestatic injury, with R value between 2 and 5.

 The R value is calculated as (ALT/ULN)/(ALP/ULN) [13].

 Mechanisms of Hepatotoxicity

 Multiple mechanisms contribute to DILI, including [14,15]:

1. Direct hepatotoxicity: Through reactive metabolites, oxidative stress, mitochondrial dysfunction, or inhibition of cellular functions.

2. Immune-mediated injury: Involving haptenization of drugs or metabolites with cellular proteins, direct stimulation of T cells, or immune checkpoint inhibition.

 3. Mitochondrial dysfunction: Through inhibition of mitochondrial respiration, depletion of mitochondrial DNA, or disruption of β-oxidation.

 4. Bile salt export pump (BSEP) inhibition: Leading to intrahepatic accumulation of toxic bile acids.

 5. Activation of cell death pathways: Including apoptosis, necrosis, necroptosis, and pyroptosis.

 

 In hematologic patients, these mechanisms may be exacerbated by underlying conditions, comorbidities, or concomitant medications, increasing susceptibility to DILI [16].

 

 Clinical Presentation and Risk Factors

 Clinical Presentation

DILI can present with a wide spectrum of clinical manifestations, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure [17]. Common presentations include:

 1. Asymptomatic transaminase elevation: Detected incidentally on routine laboratory testing.

 2. Acute hepatitis-like syndrome: Characterized by malaise, fatigue, right upper quadrant pain, jaundice, dark urine, and pruritus.

 3. Cholestatic hepatitis: Presenting with jaundice, pruritus, pale stools, and predominant alkaline phosphatase elevation.

 4. Acute liver failure: Characterized by jaundice, coagulopathy (INR ≥1.5), and hepatic encephalopathy developing within 26 weeks in a patient without preexisting liver disease [18].

 5. Chronic DILI: Persistent liver biochemical abnormalities beyond 3-6 months after drug discontinuation, occurring in approximately 15-20% of DILI cases [19].

 6. DILI with autoimmune features: Presenting with features resembling autoimmune hepatitis, including positive autoantibodies and elevated immunoglobulin G [20].

 

In hematologic patients, these presentations may be confounded by other causes of liver injury, including hepatic infiltration by malignant cells, veno-occlusive disease, GVHD, or opportunistic infections [21].

 Risk Factors

Multiple factors influence susceptibility to DILI, including [22,23]:

1. Drug-related factors:

   - Daily dose (>50-100 mg/day)

   - Lipophilicity

   - Extensive hepatic metabolism

   - Formation of reactive metabolites

   - BSEP inhibition potential

   - Mitochondrial toxicity

 

 2. Host-related factors:

   - Age (elderly patients at higher risk)

  - Female sex (for certain drugs)

   - Genetic polymorphisms in drug-metabolizing enzymes, transporters, or HLA alleles

   - Preexisting liver disease

   - HIV infection

   - Obesity and diabetes

   - Malnutrition

   - Alcohol consumption

 In hematologic patients, additional risk factors include [24,25]:

   - Hematopoietic stem cell transplantation

   - Total body irradiation

   - High-dose chemotherapy

   - Concurrent hepatotoxic medications

   - Underlying malignancy with hepatic involvement

  - Compromised immune function

 

 Diagnostic Approaches

The diagnosis of DILI remains challenging due to the lack of specific biomarkers and the need to exclude alternative causes of liver injury. A systematic approach is essential, including detailed medication history, temporal relationship assessment, exclusion of other etiologies, and application of causality assessment tools [26].

 Clinical Evaluation

A comprehensive clinical evaluation includes [27]:

1. Detailed medication history: All prescription medications, over-the-counter drugs, herbal supplements, and dietary supplements, including timing of initiation and discontinuation.

 2. Temporal relationship: Latency period between drug initiation and onset of liver injury, and course of liver tests after drug discontinuation.

 3. Exclusion of alternative causes: Viral hepatitis, autoimmune liver diseases, alcohol-related liver disease, biliary tract disease, hemodynamic disturbances, metabolic liver diseases, and other drug-related liver injuries.

 4. Pattern of liver injury: Hepatocellular, cholestatic, or mixed.

 5. Presence of extrahepatic manifestations: Fever, rash, eosinophilia, lymphadenopathy, or kidney injury, which may suggest immune-mediated DILI.

 Laboratory Investigations

Standard laboratory investigations include [28]:

 1. Liver biochemistry: ALT, AST, ALP, gamma-glutamyl transferase (GGT), total and direct bilirubin.

 2. Synthetic function assessment: International normalized ratio (INR), albumin.

3. Complete blood count: To evaluate for eosinophilia, neutrophilia, or cytopenias.

 4. Viral hepatitis serologies: Hepatitis A, B, C, E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus.

5. Autoimmune markers: Antinuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, immunoglobulin G.

 6. Metabolic and genetic testing: Ceruloplasmin, alpha-1 antitrypsin, ferritin, iron studies, genetic testing for Wilson's disease or hereditary hemochromatosis when clinically indicated.

 

In hematologic patients, additional investigations may include viral studies for adenovirus, human herpesvirus 6, or other opportunistic infections, evaluation for veno-occlusive disease, and assessment for GVHD [29].

 Imaging Studies

Imaging studies help exclude alternative diagnoses and include [30]:

 

1. Ultrasound: To evaluate for biliary obstruction, vascular abnormalities, infiltrative diseases, or focal lesions.

 2. Computed tomography (CT) or magnetic resonance imaging (MRI): For further characterization of abnormalities detected on ultrasound or when clinical suspicion of alternate diagnoses remains high.

 3. Magnetic resonance cholangiopancreatography (MRCP): When biliary obstruction or sclerosing cholangitis is suspected.

 4. Transient elastography (FibroScan): To assess liver stiffness and degree of fibrosis, particularly useful in monitoring chronic DILI.

 Liver Biopsy

 

Liver biopsy is not routinely required for DILI diagnosis but may be valuable in specific situations [31]:

 1. Persistent liver enzyme elevation despite drug discontinuation

 2. Suspicion of autoimmune hepatitis triggered by drugs

 3. Features suggesting chronic liver disease

 4. Failure to identify a clear culprit medication

 5. Suspected concomitant liver disease

 Histopathological patterns in DILI are diverse and include [32]:

1. Acute hepatitis: Characterized by lobular inflammation, hepatocellular necrosis, and Kupffer cell hyperplasia.

2. Cholestatic hepatitis: Showing canalicular and hepatocellular cholestasis, portal inflammation, and bile duct injury.

 3. Granulomatous hepatitis: Featuring non-caseating granulomas in portal tracts or lobules.

 4. Steatohepatitis: Resembling alcoholic or non-alcoholic steatohepatitis with steatosis, ballooning degeneration, and Mallory-Denk bodies.

 5. Vascular injury: Including sinusoidal obstruction syndrome, peliosis hepatis, or nodular regenerative hyperplasia.

 In hematologic patients, histological interpretation may be complicated by overlapping features of DILI, GVHD, viral infections, or hepatic involvement by underlying malignancy [33].

 

 Causality Assessment Tools

 Several causality assessment tools have been developed to standardize the diagnosis of DILI [34]:

 1. Roussel Uclaf Causality Assessment Method (RUCAM): A structured, quantitative system that assigns points based on temporal relationship, course after drug cessation, risk factors, concomitant drugs, alternative causes, previous hepatotoxicity of the drug, and response to rechallenge. Scores categorize causality as highly probable, probable, possible, unlikely, or excluded [35].

2. Maria & Victorino (M&V) Scale: Similar to RUCAM but placing greater emphasis on extrahepatic manifestations of hypersensitivity [36].

 3. Drug-Induced Liver Injury Network (DILIN) Expert Opinion Process: A structured expert consensus opinion categorizing causality as definite, highly likely, probable, possible, or unlikely [37].

4. WHO-UMC System: A general causality assessment system not specific to liver injury but applicable to all adverse drug reactions [38].

RUCAM is the most widely used and validated tool, despite limitations including moderate interobserver reliability and complexity of scoring [39].

  Emerging Biomarkers

 Traditional biomarkers (ALT, AST, ALP, bilirubin) lack specificity for DILI. Several promising biomarkers are being investigated [40,41]:

1. MicroRNAs: Circulating miR-122, miR-192, and miR-193 have shown potential for early detection of DILI, with higher sensitivity and specificity than traditional markers.

 2. High-mobility group box 1 (HMGB1): A damage-associated molecular pattern that may distinguish between different forms of cell death in DILI.

 3. Keratin-18 (K18): Full-length and caspase-cleaved fragments serve as markers of necrosis and apoptosis, respectively.

 4. Glutamate dehydrogenase (GLDH): A mitochondrial enzyme that may indicate mitochondrial dysfunction in DILI.

5. Macrophage colony-stimulating factor receptor (M-CSF receptor): A potential marker of immune activation in DILI.

6. Osteopontin: Elevated in cases of DILI with biliary involvement.

 7. Cytokeratin-18, MCSFR, HMGB1, and osteopontin combined: Have shown improved predictive ability for DILI compared to ALT alone.

 These biomarkers require further validation in large, prospective studies before widespread clinical implementation [42].

Management Strategies

 General Principles

The cornerstone of DILI management includes [43]:

 1. Prompt discontinuation of the suspected drug(s): Essential to prevent progression of liver injury.

 2. Supportive care: Including close monitoring of liver function, coagulation parameters, and clinical status.

 3. Avoidance of other potentially hepatotoxic agents: Including alcohol and certain herbal supplements.

 4. Patient education: Regarding drug avoidance in the future and alerting healthcare providers about the DILI history.

 Specific Interventions

 For certain types of DILI, specific interventions may be beneficial [44]:

 1. Acetaminophen toxicity: N-acetylcysteine administration, preferably within 8-10 hours of ingestion but may be beneficial even in late presenters [45].

 2. DILI with autoimmune features: Corticosteroids may be considered, particularly when autoimmune features predominate or recovery is delayed [46].

 3. Cholestatic DILI: Ursodeoxycholic acid (UDCA) at 13-15 mg/kg/day may improve bile flow and reduce pruritus, although evidence is limited [47].

 4. Valproate-induced hyperammonemia: L-carnitine supplementation may be beneficial in reducing ammonia levels [48].

5. Isoniazid-induced liver injury: Pyridoxine supplementation, although primarily for preventing neurological complications rather than liver injury [49].

  Management in Severe Cases

 In cases of severe or progressive DILI, additional measures include [50]:

1. Transfer to a tertiary center with liver transplantation capabilities: For patients with acute liver failure or signs of severe liver injury (jaundice, coagulopathy).

2. Intensive monitoring: Including serial liver function tests, coagulation parameters, and hepatic encephalopathy assessment.

3. Nutritional support: Ensuring adequate caloric and protein intake while avoiding excess protein in encephalopathic patients.

4. Prevention and management of complications: Including hepatic encephalopathy, coagulopathy, ascites, infections, and renal dysfunction.

5. Liver transplantation evaluation: For patients meeting criteria for acute liver failure with poor prognostic indicators.

The King's College Criteria and the Model for End-Stage Liver Disease (MELD) score are commonly used to assess prognosis and guide transplantation decisions in DILI-related acute liver failure [51].

 

 Management in Hematologic Patients

Management of DILI in hematologic patients presents unique challenges [52]:

1. Balancing the risks and benefits of continuing essential medications: Particularly challenging in patients receiving life-saving treatments for malignancies or post-transplantation.

2. Dose adjustment or alternative regimens: When complete discontinuation is not feasible.

3. Close monitoring: More frequent assessment of liver function in high-risk patients or those receiving potentially hepatotoxic medications.

4. Prophylactic strategies: Including ursodeoxycholic acid for prevention of veno-occlusive disease in stem cell transplantation [53].

5. Treatment of underlying conditions: That may exacerbate DILI, such as infections or GVHD.

6. Antimicrobial stewardship: Judicious use of antimicrobials and close monitoring when multiple hepatotoxic antimicrobials are necessary.

 

 Special Considerations in Hematologic Practice

 Chemotherapy-Associated Liver Injury

Chemotherapeutic agents cause liver injury through various mechanisms [54]:

1. Direct hepatotoxicity: Common with methotrexate, 6-mercaptopurine, cytarabine, and asparaginase.

 2. Sinusoidal obstruction syndrome: Associated with gemtuzumab ozogamicin, oxaliplatin, and dacarbazine.

 3. Steatosis and steatohepatitis: Linked to irinotecan, 5-fluorouracil, and platinum compounds.

4. Nodular regenerative hyperplasia: Reported with thiopurines and oxaliplatin.

5. Idiosyncratic hepatotoxicity: Observed with multiple agents, including tyrosine kinase inhibitors and immune checkpoint inhibitors.

 

Management includes dose adjustment based on liver function, monitoring liver enzymes during treatment, and prophylactic measures in high-risk patients [55].

 Hematopoietic Stem Cell Transplantation (HSCT)

Liver injury after HSCT may result from multiple causes, including [56]:

1. Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD): Characterized by weight gain, painful hepatomegaly, ascites, and hyperbilirubinemia, typically within 21 days post-transplantation. Risk factors include prior hepatic injury, busulfan or cyclophosphamide conditioning, and total body irradiation [57].

2. Graft-versus-host disease (GVHD): Acute GVHD typically presents within 100 days post-transplantation with elevated liver enzymes and hyperbilirubinemia. Chronic GVHD can present as a cholestatic syndrome resembling primary biliary cholangitis [58].

3. Drug-induced liver injury: From antimicrobials, immunosuppressants, and other medications used post-transplantation.

 4. Infections: Including viral hepatitis reactivation, cytomegalovirus, adenovirus, and fungal infections.

 5. Iron overload: Due to multiple transfusions and increased intestinal absorption.

Distinguishing between these etiologies is crucial for appropriate management and often requires liver biopsy [59].

  Anticoagulation-Related Liver Injury

 Anticoagulants commonly used in hematologic practice can cause liver injury through various mechanisms [60]:

1. Heparins: Rarely associated with transaminase elevations, typically asymptomatic and resolving with continued therapy.

2. Low molecular weight heparins: Less frequently associated with liver injury than unfractionated heparin.

3. Direct oral anticoagulants (DOACs): Rivaroxaban has been associated with hepatocellular injury, while dabigatran and apixaban have lower reported rates of hepatotoxicity.

4. Vitamin K antagonists: Warfarin rarely causes clinically significant liver injury.

 Management includes selecting agents with lower hepatotoxicity risk in patients with preexisting liver disease and monitoring liver function during therapy [61].

 

 DILI in the Context of Underlying Liver Disease

 Patients with preexisting liver disease present special challenges [62]:

1. Altered drug metabolism: Due to reduced hepatic blood flow, decreased albumin production, or reduced activity of drug-metabolizing enzymes.

 2. Increased susceptibility to DILI: Due to impaired adaptive responses and regenerative capacity.

 3. Difficulty distinguishing DILI from disease flares: Particularly in autoimmune hepatitis or chronic viral hepatitis.

4. Dosing adjustments: Required for many drugs used in hematologic practice.

Guidelines for drug use in liver disease emphasize individual assessment of risk-benefit ratio, close monitoring, and dose adjustments based on Child-Pugh classification or MELD score [63].

  Recent Advances and Future Directions

Pharmacogenomic Advances

Genetic factors significantly influence susceptibility to DILI [64]:

 

1. HLA associations: Numerous HLA alleles have been linked to DILI from specific drugs:

 

   - HLA-B*57:01 with flucloxacillin-induced DILI

 

   - HLA-B*35:02 with minocycline-induced DILI

 

   - HLA-A*33:01 with terbinafine and multiple other drugs

 

   - HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions

 

2. Drug metabolism polymorphisms: Variations in genes encoding drug-metabolizing enzymes affect susceptibility:

 

   - N-acetyltransferase 2 (NAT2) slow acetylator status with isoniazid hepatotoxicity

 

   - CYP2E1 variants with anti-tuberculosis drug hepatotoxicity

 

   - UGT1A1 polymorphisms with irinotecan toxicity

 3. Mitochondrial variants: Polymorphisms in mitochondrial DNA may predispose to valproate hepatotoxicity and other mitochondrial toxins.

4. Transporters: Variants in ABCB11 (encoding BSEP) and other transporters may influence susceptibility to cholestatic DILI.

Pre-treatment genetic testing is becoming increasingly available for certain drug-gene pairs with strong evidence, potentially allowing personalized risk assessment [65].

 Artificial Intelligence and Machine Learning

Emerging applications of artificial intelligence in DILI include [66]:

1. Prediction models: Integrating clinical, laboratory, genetic, and drug information to predict DILI risk before drug exposure.

2. Pattern recognition: Identifying subtle patterns in laboratory values or temporal trends associated with early DILI.

3. Drug development: Screening compounds for hepatotoxicity potential during preclinical phases.

4. Causality assessment: Supporting more objective assessment of suspected DILI cases.

5. Natural language processing: Extracting relevant information from electronic health records to identify potential DILI cases or risk factors.

These approaches show promise but require further validation in prospective studies [67].

 

 Novel Therapeutic Approaches

Emerging therapeutic strategies include [68]:

1. Targeted antioxidants: To mitigate oxidative stress from reactive metabolites or mitochondrial dysfunction.

2. Pan-caspase inhibitors: To reduce apoptotic cell death in DILI.

3. Farnesoid X receptor (FXR) agonists: To enhance bile acid homeostasis in cholestatic DILI.

4. Inhibitors of sterile inflammation: Targeting damage-associated molecular patterns and inflammatory pathways.

5. Extracorporeal liver support systems: For temporary support in severe DILI until liver regeneration occurs.

6. Cell-based therapies: Including hepatocyte transplantation and mesenchymal stem cell therapy.

These approaches remain investigational but represent promising directions for future therapeutic interventions [69].

 Conclusion

Drug-induced liver injury remains a significant challenge in clinical practice, particularly in hematologic patients who often receive multiple potentially hepatotoxic medications in the context of complex underlying diseases. Diagnosis requires a systematic approach, including detailed medication history, exclusion of alternative causes, and application of causality assessment tools. Management centers on prompt discontinuation of the suspected agent, supportive care, and specific interventions when indicated. In hematologic practice, balancing the risks of DILI against the benefits of continuing essential medications requires careful consideration.

Recent advances in biomarker development, pharmacogenomics, and artificial intelligence offer promise for more accurate diagnosis, risk stratification, and personalized management of DILI. Further research is needed to validate these approaches in diverse patient populations, particularly in hematologic patients with multiple complicating factors. A multidisciplinary approach involving hematologists, hepatologists, and clinical pharmacologists is essential for optimal management of this challenging condition.

 

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