Drug Induced Liver Injury (DILI) Aisling Considine- Consultant Hepatology Pharmacist. King s College Hospital NHS Foundation Trust aislingconsidine@nhs.net
Drug Induced Liver Injury /Disease Acute Liver Failure N Engl J Med 2013;369:2525-34
Type of Drug Reactions Intrinsic Predictable Dose Dependent Tend to occur rapidly e.g. within hours Tend to cause necrosis, acute Liver failure e.g. Paracetamol overdose Idiosyncratic Not predictable Not dose dependent Tend to take longer to occur weeks to months Can result from metabolic idiosyncrasy or immunoallergic reaction Can cause any type of Liver injury e.g. increased LFTs, jaundice, fever, rash E.g. NSAIDS (metabolic), Carbamazepine
Drug Induced Liver Disease Risk factors which may pre-dispose to DILD: Gender (tends to be more common in females) Age Genetics Concurrent diseases e.g. obesity, diabetes, co-infection with HIV Polypharmacy
Is it a Drug Induced Liver Injury? Expert judgement 1. Is there a relationship between symptoms & drug 2. Are there pre existing reports of DILI with drug 3. Did symptoms initially improve on stopping drug Probabilistic approaches Algorithms or scales No gold standard Council for International Organizations of Medical Sciences (CIOMS) scale, also referred to as the Roussel Uclaf Causality Assessment Method (RUCAM) The scale applies numerical weighting to key features in seven different domains: 1. chronology,risk factors, concomitant 2. drug use, search for other aetiologies, 3. existing information on the drug s hepatotoxic potential, 4. response to rechallenge In cases of acute or severe fulminant hepatitis -liver biopsy Journal of Hepatology 2011 vol. 55 j 683 691
DILD Acute Liver Failure (ALF) ALF is a syndrome defined by a rapid decline in hepatic function characterized by; 1. jaundice 2. coagulopathy (INR >1.5) 3. hepatic encephalopathy in patients with no evidence of prior liver disease Management will depend on specific case DILI is traditionally defined as an; 1. increase in alanine aminotransferase (ALT) 5 times ULN; 2. alkaline phosphatase (ALP) 2 times ULN or a; 3. combination of ALT 3 times ULN and bilirubin 2 times above the ULN Clin Liver Dis 21 (2017) 35 54
Case 1 herbal remedy Patient -60yr old Caucasian female PmHx -Migraine, Hypothyroidism Meds on Admission Propranolol 20mg od Levothyroxine 100mcg od Black Cohosh (Traubensilberkerze) 2 tabs bd ( 4 weeks of treatment now stopped) No allergies Presenting Complaint General Practitioner review pruritus and dark urine Of Note No risk factors for viral hepatitis No family history No alcohol
Black Cohosh (Traubensilberkerze) Derived from a plant of the buttercup family Claims to have estrogen-like effects Used for relief of symptoms of menopause Linked to > fifty instances of clinically apparent liver injury including death Clinical presentation -typically with jaundice and with liver biopsy histology resembling acute viral hepatitis
Potential Hepatotoxic Herbal Remedies A helpful resource that is available to clinicians trying to ascertain whether a drug or supplement may be hepatotoxic www.livertox.nih.gov.
Bloods Case 1
Imaging Case 1 Patients abdominal CT
Diagnosis Acute liver failure secondary to DILI (black cohosh) Plan: Liver Transplantation
Management Case 1 STOP THE DRUG IN QUESTION i.e. Black Cohosh Infection Antimicrobials broad spectrum Renal replacement (hyperammonia and lactic acidosis) Filtration Glucose Control Dextrose 30% continuous infusion Pressure Control & Cardiac Output Fluids and pressors (noradrenaline & vasopressin) Antioxidant N-acetylcysteine
Liver Transplantation Immunosuppression Tacrolimus, Mycophenolate, Azathioprine, Ciclosporin, steroids Antimicrobials Broad Spectrum Analgesia Paracetamol and opiates when required
6000 5000 4000 3000 3,5 3 2,5 2 1,5 2000 1000 Bilirubin umol/l AST IU/L 1 0,5 INR 0 0
Case 2 Paracetamol Overdose Patient -27 year old male PmHx - Depression (severe), excess alcohol (40-50 units/week ~ 5 bottles/week of "Schwäbischen Wein ), smoker, cannabis, cocaine use Meds on Admission Nil regular No allergies No herbal remedies Presenting Complaint Staggered paracetamol overdose over 2 days Took 48 x 500mg tablets paracetamol and 32 x 200mg ibuprofen Presented to A&E vomiting and lactic acidosis High ammonia Of Note No risk factors for viral hepatitis No family history Action Transferred to intensive care Br J Clin Pharmacol / 73:2 / 285 294 / 285
* About 5 15% of a dose of paracetamol is hepatically metabolized to a highly reactive hepatotoxic metabolite.the half-life of paracetamol can be nearly doubled in hepatic impairment. Still used in severe hepatic impairment with appropriate caution *
Diagnosis and Action ALF secondary to paracetamol and ibuprofen induced liver injury Acute renal failure likely corticol necrosis due to ibuprofen Background evaluation Anxiety managed by GP, no previous deliberate self harm Overdose secondary to relationship breakdown Alcohol excess Action 28/7/17 listed for liver transplant 1/8/17 delisted due to no longer fulfilling national criteria Managed as per case 1 anti-microbials, filtration, pressors,nacetylcysteine
Bloods Case 2
Recovery Case 2 Spent 4 weeks on intensive care Stepped down to ward Irreversible damage to kidneys dialysis dependent (DILI not always reversible) Liver recovery to baseline Ongoing severe depression
Case 3 Dimethyl Fumarate Patient -43yr old Caucasian female PmHx Multiple sclerosis Meds on Admission Dimethyl Fumarate - started 12 weeks prior to admission Paracetamol when required No allergies Presenting Complaint Admitted to hospital with confusion and jaundice Of Note No risk factors for viral hepatitis No family history No alcohol
Product Characteristics Drug-induced liver injury, including liver enzyme increase ( 3 ULN) and elevation of total bilirubin levels ( 2 ULN) can result from treatment with Tecfidera. The time to onset can be directly, several weeks or longer. Resolution of the adverse events has been observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. ALT, AST) and total bilirubin levels are recommended prior to treatment initiation and during treatment as clinically indicated. www.medicines.org.uk/emc accessed 28/4/17
Diagnosis Acute Liver failure secondary to DILI secondary to Dimethyl Fumarate Date Biochemistry Result Range On presentation Day 1 Bilirubin 320umol/L 5-20 Alanine Transaminase Aspartate Transaminase INR /PT Ammonia 1180 1400IU/L 10-50 1.57 /22.6seconds 140umol/L Viral Screen Hepatitis A,B,C,E negative EBV,CMV,Autoantibodies negative Imaging CT scan Shrunken liver, no malignancy Paracetamol Level negative
Imaging
Patient died Clinical Course Patient fulfilled listing criteria for urgent liver transplant and was treated as per case 1 & 2 Day 4 on intensive care blood pressure dropped not responding to increased support Sepsis pseudomonas on BAL Worsening lactic acidosis By day 6 thought to be too unwell to undergo liver transplantation Broad-spectrum antibiotic therapy was changed However, she continued to deteriorate and ultimately displayed rapid decline in her cardiac and metabolic status
Bloods Case 3 All patients with liver disease will have raised transaminase enzymes? True /False
Bloods Case 3
Summary DILI &Usefulness of LFTs to Guide Prescribing Drug metabolism very complex and not fully understood. Albumin, INR, PT and Bilirubin are considered the best predictors (synthetic and excretory function) Liver will carry out drug metabolism even in cirrhotic patients Difficult to predict PK changes in individual patients Consider route elimination renal, biliary etc Limited studies in the area of DILI dependant on reports In theory any drug has the potential to cause a DILI Patient specific background, environmental factors etc.