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