If at first you don’t succeed, try and try again Clinical Case Conference David Goldberg October...
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Transcript of If at first you don’t succeed, try and try again Clinical Case Conference David Goldberg October...
If at first you don’t succeed, try and try again
Clinical Case ConferenceDavid Goldberg
October 27, 2010
History• Cc: Jaundice, elevated liver enzymes• HPI:– 48 year-old male with PMH HTN, HLD– 10 days prior to admission ate pig brain– Following AM
• Diffuse maculopapular rash• Fevers up to 103
– Over 48 hours took 20 ES tylenol– After 48 hours prescribed Levaquin– Went to OSH after 10 days– No recent travel, sick contacts, IV drug use
History• PMH: HTN, hyperlipidemia• PSH: None• Medications: – Lotrel (amlodipine and benazepril)– Gemfibrozil– On both medications for >1 year
• ROS: (+) fevers, lethargy, chills, weakness, diffuse maculopapular rash (started diffusely)
• SH: No EtOH, illicits, tobacco, herbal medications. Married with three children. From Colombia, works as truck driver
Outside Hospital
• Outside Hospital Labs– Albumin-4.1– Bilirubin-0.4– AST-41– ALT-76– ALk phos-152– GGT-480– Over course of week, LAEs rose to bilirubin of 16,
AST/ALT/alk phos in the 400s.• Percutaneous liver biopsy performed• Progressive AKI->initiated HD
Presentation to Penn
• Vitals: BP: 130s/80s, P-100s, Tmax-103• Gen: Appeared uncomfortable, putting cold compress on
head• Neck: No LAD• CV: Tachycardic, nl s1/s2, no murmurs• Pulm: CTABl• Abd: (+)BS, mildly distended with diffuse tenderness to
palpation, no rebound or guarding. Some flank dullness. • Skin: Diffuse erythematous maculopapular rash. No spider
angiomata.• Neuro: Alert and conversant. No asterixis.
Labs at Penn• AST-578• ALT-609• Alk Phos-1121• Bilirubin-16.0 (10.7 direct)• CK-44• BUN/Cr: 64/6.5• Protein-4.2, Albumin-2.1• WBC: 14.0 (50% PMNs 14% lymphs, 34% eos) • Hb-9.1 (MCV-85)• Plt-176• Ferritin-6067• INR-1.8• U/S: Slightly echogenic liver• Moderate abdominal ascites
Questions
• What is your differential diagnosis?• What would you do next?
Data
• Hepatitis A, B, C, and E serologies negative• ANA, ASMA, anti-LKM, AMA, HIV negative• Normal iron saturation, ceruloplasmin• Liver biopsy:
– Granulomatous hepatitis – Extensive portal inflammation and cholestasis– Drug reaction vs. infection
• Skin biopsy– Superficial perivascular mixed inflammatory cell infiltrate with many
eosinophils– Drug reaction with eosinophila and systemic symptoms vs. other
hypersentivity reactions
• What do you now think the diagnosis is?• What would you do next to work it up?
Hospital Course• HD #2: Interviewed patient for 3rd time regarding medications
– New “gout medication”– Called pharmacy and reviewed home pill bottles– Allopurinol started on 7/12 (patient’s symptoms started around 8/10)
• Started on 100mg solumedrol• Discharge Labs 1 week later• WBC 5.6 (5% eos)• AST-65• ALT-155• Alk-430• Bili-4.7• INR-1.3• Creatinine-2.1
Outline
• Briefly discuss DILI• Define and briefly discuss DRESS syndrome• Discuss specifically allopurinol-induced DRESS
syndrome
Drug-Induced Liver Injury• Per report from Hepatology, August 2010: Standardization of
Nomenclature and Causality Assessment in Drug-Induced Liver Injury: Summary of a Clinical Research Workshop
• Diagnosis of exclusion• Relies on history, labs, clinical course• Key Diagnostic Elements
– Time to onset– Clinical features– Time and course of recovery– Specific risk factors– Exclusion other diagnoses– Previous reports implicating agents– Additionally
• Rechallenge• Liver biopsy
Drug-Induced Liver Injury
• Time to onset– First day medication->symptoms or lab
abnormalities– Difficult to assess– Can be days to weeks after medication stopped– Depends on mechanism of liver injury
Drug-Induced Liver Injury
• Clinical and laboratory features– Hepatocellular, cholestatic, or mixed
– R ratio• AST/ALK>5=hepatocellular• AST/ALK<2=cholestatic
– Fatigue, nausea, abdominal pain– Pruritus
• Early in cholestatic• Late, if at all, in hepatocellular
– Rash, fever, facial edema, LAD• Hypersensitivity cause• Anticonvulsants, sulfonamides, allopurinol
Drug-Induced Liver Injury
• Time course after cessation of drug– Usually improves with drug withdrawal– Not always predictable– Chronic injury won’t improve
Drug-Induced Liver Injury
• Risk factors• Risk factors not helpful in individual case– Age->INH– Younger->Valproate and Reye’s– Women->? Worse outcomes– Blacks->Anticonvulsant hypersensitivity– Whites->Abacavir and flucloxacillin– Genetics
• HLA B*5701->abacavir and flucloxacillin• ATP-binding cassette B11 (bile salt export pump)->estrogen-induced
cholestasis• Mitochondrial polyemrase gamma->valproate
Drug-Induced Liver Injury
• Exclusion of other causes– Little standardization– Hepatitis A, B, and C– Hepatobiliary imaging– Alcohol use– Prior hypotension, heart failure, hypoxia– TPN use
Drug-Induced Liver Injury• Previous reports– Some medications with characteristic time course,
R ratio (enzyme elevations)– Much data is missing
Drug-Induced Liver Injury
• Rechallenge– Intentional or inadvertent re-exposure to drug– Rarely done– May attempt if:• Initial injury without hypersensitivity• Initial injury not severe• Agent considered essential
– I.e. chemo, HIV meds, anti-Tb meds
– Shorter latency and greater severity
Drug-Induced Liver Injury
• Liver biopsy– Unclear role– Eosinophils– Granulomas– Zonal or massive necrosis– Cholestasis with hepatitis– No confirmatory pathologic criteria
DRESS Syndrome
• DRESS syndrome (aka drug hypersensitivity syndrome)– Drug rash
• Infiltrated maculopapular eruption• Facial edema, marked in periorbital region
– Eosinophilia– Systemic symptoms
• Fever• Lymph node enlargement
– Within 8 weeks initiation of therapy
DRESS Syndrome• Commonly associated with:
– Aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine) (1 in 1,000)
– Sulphonamides (1 in 10,000)• Immunological pathophysiology
– HLA subtypes– HHV 6 active infection
• DDX– Stevens-Johnson/TEN– Hypereosinophilic syndrome– Kawasaki – Still’s disease– Viral infections (HIV, EBC, CMV, influenza)
Allopurinol-Induced DRESS Syndrome
• Allopurinol– Xanthine oxidase inhibitor– Drug and its metabolite inhibit conversion of
hypoxanthine->xanthine->uric acid– Activity related to metabolite oxypurinol– Oxypurinol stays in tissues for long time
• Renally cleared– Most common cause of Stevens-Johnson and TEN in
Europe and Israel1
• 66/379 (17.4%) cases due to allopurinol• OR=18 in case-control study• OR=36 in doses ≥ 200mg/day• Risk restricted to short-term use (≤ 8 weeks)
Halevy S et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2008; 58: 25-32.
Allopurinol-Induced DRESS Sydndrome
• 2% develop mild skin rash• Occurs in 1:260 patients on allopurinol• Syndrome (previously called allopurinol hypersensitivity syndrome)
– Vasculitis– Rash– Eosinophilia– Hepatitis– Progressive renal failure
• 1-8 weeks after first course of therapy• Related to serum levels of oxypurinol
– Renally cleared– 80% cases with baseline renal impairment
– Type III hypersensitivity reaction (immune complex)
Allopurinol-Induced DRESS Sydndrome
• Suggested diagnostic criteria1 – A documented intake of allopurinol– Lack of exposure to other possible drug– 2 major or 1 major and 1 minor
• Major– Worsening renal function (interstitial nephritis)– Acute hepatocellular injury– Rash
» TEN, erythema multiforme, diffuse maculopapular rash, or exfoliative dermatitis
• Minor– Fever, leukocytosis, and eosinophilia
Zinger JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary Morbidity and Mortality. Arthritis Rheum 1986; 29: 82-7.
Allopurinol-Induced DRESS Syndrome
• Clinical presentation– Review of 101 cases1
• Fever: 95.1%• Skin rash: 93.1%• Eosinophilia: 59.7%• Elevated AST (44/50 where AST reported)
– Prognosis• 27/101 (26.7%) cases died (10% in non-allopurinol DRESS)• Higher mortality
– TEN skin rash– AST >500 IU/L– Sepsis
» 15/21 patients with sepsis died» 12/80 without sepsis died
Arellano CG, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother 1993; 27: 337-43.
Allopurinol-Induced DRESS Sydndrome
• Treatment– Withdrawal of drug– Supportive care– Steroids controversial• Abatement of symptoms• Reduce delayed hypersensitivity reaction• Reduce eosinophil accumulation• Rapid improvement in case reports• Higher mortality in steroid recipients in Arellano study
– Sicker patients getting steroids
Conclusions
• Allopurinol commonly causes drug rashes but also can cause severe liver injury
• Important to take detailed medication history• If DILI suspected, advised to contact pharmacy
and go through pill bottles at home