Transcript If at first you don*t succeed, try and try again

If at first you don’t succeed, try
and try again
Clinical Case Conference
David 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
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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
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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
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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)
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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
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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
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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)->estrogeninduced 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
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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
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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)
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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
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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
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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