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Liver Failure Case
 

Liver Failure Case

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Liver Failure Case Liver Failure Case Presentation Transcript

  • A Case of Fatal Cholestatic Liver Failure Senior Clinicopathologic Conference Andre Cap, MD, PhD Walter Reed Army Medical Center
  • History of Present Illness
    • 63 y/o white male
    • Recent radical cystoprostatectomy for poorly differentiated urothelial carcinoma
      • 2.5x3 cm bladder mass invading muscle
      • Negative margins, ureters, LND
      • Chronic cystitis
      • T2a N0 Mx
    • One month later, developed symptoms c/w acute cholecystitis and underwent laparoscopic cholecystectomy at civilian hospital
      • Gross pathology reveals bile sludge, no stones, inflammatory changes consistent with chronic cholecystitis
  • History of Present Illness (cont.)
    • Post-op, LFT’s continued to rise in cholestatic pattern and patient developed painless jaundice and pruritis
    • POD#3, patient underwent ERCP
      • No evidence of retained stone or other obstruction
      • Stent placed in distal CBD
    • POD#5, ERCP repeated due to continued rise in LFT’s
      • No evidence of obstruction or retained stone
      • Larger stent placed in CBD and sphincterotomy performed
  • History of Present Illness (cont.)
    • POD#17, HIDA scan performed showing lack of tracer in biliary tree, indicating hepatocellular dysfunction
    • CT scan revealed mild intra-hepatic ductal dilatation
    • Third ERCP revealed patent hepatobiliary tree
    • Laboratory evaluation of cholestasis unrevealing
      • Normal studies: copper, iron, alpha-1 anti-trypsin, ASMA, ANA, AMA, anti LKM, ANCA, Hepatitis A and C
      • Hepatitis B core Ab positive (all other Hepatitis B serologies negative, Hep B DNA PCR negative)
    • Liver biopsy performed and patient sent to WRAMC for further evaluation
  • History of Present Illness (cont.)
    • Admission medications: protonix, lisinopril, anusol, ursodiol, atarax, dolasetron, nystatin ointment
      • Previously treated with Augmentin for 10 day course post-cholecystectomy (unclear how many doses taken)
      • Previously treated with imipramine for incontinence post-prostacystectomy, discontinued prior to episode of cholecystitis
      • Reports 7U PRBC transfusion at civilian hospital, no records
    • Patient denied taking herbals, OTC medications, EtOH, tylenol
    • Workplace toxin exposure: diesel fuel, other petroleum products
    • No family history of liver disease
  • Other Past Medical History
    • Hypertension
    • Right knee surgery January 2005
    • Vasectomy
    • Hernia repair 1968
    • Tonsillectomy in childhood
    • NKDA
    • Prior tobacco use (15 pack-yrs, quit 1981), moderate alcohol consumption (2-3 beers/week, remote history of heavy EtOH abuse)
  • Physical Exam / Labs
    • Afebrile, BP 113/71, HR 80
    • Icteric, otherwise unremarkable exam
    • LFT’s on admission to WRAMC (POD 29):
      • Alkaline phosphatase 1249, AST 135, ALT 154, total bilirubin 25.3, conjugated bilirubin 25.2, total protein 7.5, albumin 3.0, INR 1.3
    • WBC 14.2, H/H 12.3/35.7, PLT 566
    • Creatinine 2.2 (baseline 1.7)
  • Initial Hospital Course
    • MRCP performed
      • No biliary dilatation, complex renal cysts
    • ERCP repeated
      • Beading and minor narrowing of intrahepatic ducts, no CBD stricture/obstruction
    • Exhaustive laboratory evaluation repeated
      • No etiology for cholestasis identified
    • ARF resolved with IV fluids
    • Liver biopsy repeated
  • Biopsy Results
    • Dr. Zachary Goodman, Chief, Hepatopathology, AFIP
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  • Summary Biopsy Results
    • Centrilobular cholestasis, dilated bile canaliculi
    • Acute cholangitis
      • Bile duct injury with PMN infiltration
      • Ductular proliferation
      • Mild portal fibrosis
    • Inflammatory pseudotumor
      • Indicative of obstruction and/or ruptured bile duct
  • Summary Biopsy Results (cont.)
    • Biopsies performed at civilian hospital and WRAMC with similar findings
      • No evidence of malignancy
      • No evidence of chronic inflammatory changes
      • No evidence of cirrhosis
    • Histopathology consistent with obstruction versus drug effect
  • Subsequent Hospital Course (6 weeks)
    • Worsening cholestatic hepatic failure
      • Total bilirubin rising to over 50
      • Coagulopathy developing
      • Encephalopathy
    • Upper GI bleed, multiple episodes
      • Erosion of CBD stent into duodenum
      • Duodenal ulcer, jejunal bleeding
    • Acute renal failure, requiring dialysis
      • Thought to be contrast-induced nephropathy, not hepato-renal syndrome
    • Sepsis (VRE)
    • Death due to sepsis
  • Subsequent Hospital Course (6 weeks)
  • Autopsy Results
    • Dr. Zachary Goodman, Chief, Hepatopathology, AFIP
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  • Autopsy Results
    • Marked cholestatic liver injury (similar to biopsies)
    • Centrilobular hepatocellular necrosis, probably due to hypotension
    • Granulomata in liver with yeast forms consistent with Candida (probably acquired in hospital)
    • Patent extrahepatic biliary tree
    • Normal pancreas
    • Evidence of ATN on exam of renal tissue
  • Differential Diagnosis of Cholestasis
    • Biliary obstruction (intra- or extra-hepatic)
    • Sepsis (inflammatory cascade)
    • Hepatitis (viral, EtOH)
    • PBC, PSC
    • Malignancy (HCC, mets)
    • Granulomatous disease (infection, sarcoid, drugs – allopurinol, quinidine, sulfonamides, sulfonylureas)
    • Pregnancy
    • Genetic
    • GVHD
    • Transplant rejection
    • Paraneoplastic (RCCA -- Stauffer’s syndrome, NHL, HD, prostate)
    • Medication, TPN effect
  • What can we rule out?
    • Biliary obstruction (intra- or extra-hepatic)
      • ERCP X 4 w/o evidence of obstruction
    • Sepsis (inflammatory cascade)
      • Negative blood cultures until late in clinical course
    • Hepatitis (viral, EtOH)
      • Negative serologies, no EtOH consumption as inpatient
    • PBC, PSC
      • Biopsy results and chronicity not c/w these, negative AMA, ERCP not c/w PSC
    • Malignancy (HCC, mets)
      • No evidence of hepatic involvement on biopsy, autopsy
  • What can we rule out?
    • Granulomatous disease (infection, sarcoid, drugs – allopurinol, quinidine, sulfonamides, sulfonylureas)
      • Autopsy reveals few scattered granulomas, not sufficient burden of disease
      • Cholestasis due to fungal infection generally a manifestation of disseminated disease, fulminant process
        • Histoplasma, cryptococcus, blastomycosis, candida
      • Case reports of biliary duct obstruction by fungus ball
      • Fungal infection likely acquired in hospital, negative cultures
        • Case reports of hepatic and pancreatic candidal infections post-ERCP
    • Pregnancy
    • Genetic
    • GVHD
    • Transplant rejection
    • TPN
  • What’s left?
    • Paraneoplastic (RCCA -- Stauffer’s syndrome, NHL, HD, prostate)
      • Poorly understood pathophysiology – inflammatory cascade?
      • Not previously described in urothelial carcinoma
      • No mets identified
      • Up to 50% of patients with T2 or higher stage urothelial carcinoma are eventually found to have metastatic disease
    • Medication effect
      • Our patient exposed to at least 2 medications known to cause cholestasis
  • Drug Induced Liver Injury
    • Dr. Jonathan Koff, Director, WRAMC Liver Clinic
  • Definition
    • Liver injury caused by drugs or other chemicals, including complementary or alternative remedies
    • There is no single diagnostic test
      • Diagnosis requires a high index of suspicion and judicious use of diagnostic lab and imaging tests
    • A diagnosis of exclusion (causality difficult to prove)
  • Incidence
    • One of the most frequent types of adverse reactions to pharmaceuticals and other chemicals
    • 2-5% of patients hospitalized for jaundice
    • More than 40% of “hepatitis” in persons over age 50 years old
    • Major cause of acute liver failure
  • General Mechanisms Underlying Injury Drug (xenobiotic) Stable metabolites, excretion P450 bioactivation Detoxification Reactive metabolite Immune mechanisms Nonimmune mechanisms Cell damage
  • Classification NSAIDs, Statins, Bactrim, Amoxicillin / Clavulanate, phenytoin Acetaminophen Carbon tetrachloride Examples Aberrant metabolite; Hypersensitivity Toxic Metabolite Cause Cholestatic / Mixed Hepatocellular Type of reaction Yes No Genetic No Yes Predictable No Yes Dose - dependent Idiosyncratic Intrinsic Feature
  • Hypersensitivity Reactions
    • Idiosyncratic
    • Production of intermediate metabolite (immunoallergen)
    • Systemic immunologic reaction:
      • Fever
      • Rash
      • Eosinophilia
    • Examples:
      • Phenytoin, Halothane, Sulfonamides
  • Metabolic Idiosyncrasy
    • Drug metabolized to toxic intermediary in small proportion of patients
    • No signs of hypersensitivity
    • Latent period is unpredictable
    • Liver injury can occur 1 week to 1 year after starting medication
    • Prototype drug - isoniazid
  • Risk factors
    • Age:
      • More common in persons > 50 y.o.
      • More severe in persons > 50 y.o.
    • Gender:
      • Women at increased risk v. men
    • Obesity
    • Chronic alcohol use
    • Patients with previous hepatotoxicity
    • Use of multiple drugs
  • Subclinical liver disease
    • Injury reflected by elevation in serum liver enzymes
      • Aminotransferases and Alkaline phosphatase
    • May occur in 5-50% of patients
    • Elevations (<3 times ULN):
      • May resolve spontaneously
      • Drug may be continued if chemistries monitored
  • Aminotransferases
    • Elevations > 3-5 x ULN are associated with significant liver injury when:
      • Observed in > 3% of study population
      • Occur with any elevation in serum bilirubin (10% chance of severe liver injury)
    • Elevations > 10 x ULN rarely occur spontaneously and are highly significant in any patient
  • Pre-existing Liver Disease
    • Does not increase risk of drug toxicity:
      • Most drug reactions – idiosyncratic
      • Related to production of metabolites
    • If toxicity does occur:
      • May be more severe
      • But only with advanced liver disease
    • Exceptions:
      • Methotrexate
      • Chemotherapeutic agents
  • Acute Hepatocellular Cholestatic Chronic Hepatocellular Cholestatic Vascular Neoplastic Steatosis Phospholipidosis Fibrosis Granulomas Spectrum of Injury
  • Hepatocellular v. Cholestatic Reactions < 1 % Up to 10 % Case fatality rate Rare Yes Acute liver failure Yes No Pruritis + + / - + / - Jaundice ALP AST / ALT Enzyme elevations Cholestatic Hepatocellular Feature
  • Acute Liver Failure: Etiology Ostapowitz G et al. Ann Inter Med 2002;137:947
  • Acute Liver Failure: Definition Rapid onset of hepatic encephalopathy with severe coagulopathy occurring within weeks of symptoms or jaundice in a patient without pre-existing liver disease
  • Epidemiology
    • 2000-2500 cases per year in U.S.
    • 300-350 emergency liver transplants for ALF per year
    • Case fatality rate 57% to 80% without transplant
  • Contraindications to Liver Transplantation
    • Medical
      • Hepatic malignancy (too large or too many)
      • Cholangiocarcinoma
      • Extrahepatic malignancy
      • Active sepsis
      • Advanced cardiopulmonary disease
      • Active alcoholism or substance abuse
      • Irreversible brain damage caused by liver failure
    • Surgical
      • Complete thrombosis of portal venous circulation
  • Cholestasis: Medications Floxuridine Intralesional scolicidal agents (2% formaldehyde, 20% hypertonic saline, absolute alcohol, silver nitrate, iodine solution) Chlorpromazine Flucloxacillin and other oxypenicillins Amoxicillin-clavulanic acid     Ampicillin  Amitriptyline   Azathioprine Barbiturates Carbamazepine Chlorthiazide Cotrimoxazole   Clindamycin   Chlorpromazine   Cimetidine   Cyproheptadine   Dicloxacillin   Erythromycin esters Estradiol   Flucloxacillin   Haloperidol   Ibuprofen   Imipramine D-penicillamine   Phenytoin   Norandrostenolone   Prochlorperazine   Tetracycline   Terbinafine   Thiabendazole  Tiopronin  Tolbutamide Methyl testosterone  Dextropropoxyphene Flucoxacillin Carmustine Toxins: paraquat, methylene-dianiline Chlorpromazine Macrolide antibiotics Tricyclic anti-depressants Carbamazepine Amoxicillin-clavulanate Oxypenicillins NSAIDs Azathioprine Estrogens Anabolic steroids Cyclosporine Tamoxifen Azathioprine Sclerosing cholangitis-like Vanishing bile duct syndrome Cholestasis w/ bile duct injury Cholestasis w/ hepatitis Cholestasis w/o hepatitis
  • Critical Exposure?
    • Imipramine
      • Prescribed in the weeks following cystoprostatectomy for incontinence
      • Timing of exposure could account for cholestasis progressing to cholecystitis and subsequent chain of events
    • Amoxicillin-clavulanate
      • Common cause of drug-induced cholestasis
      • At least part of patient’s clinical syndrome seems to have started prior to exposure
      • Unclear how much of drug taken
    • 2 hits?
      • Rare sensitivity to 2 drugs?
  • Literature Review Augmentin-induced Cholestasis
    • First marketed in 1984
      • First case report of cholestatic hepatopathy in 1988
    • Widely prescribed - 1/78209 prescriptions is Augmentin
    • Garcia et al. (1996) estimated risk of significant hepatic injury at 1/100,000 patients exposed
      • 80%+ of cases with a cholestatic injury pattern
      • Also associated with sialadenitis and AIN
    • Retrospective cohort study by Rodriguez et al. found risk of cholestatic liver injury to be 1.7/10,000 patients
      • Found a 5X increased risk of liver injury for Augmentin versus Amoxicillin alone (1.7/10,000 vs 0.3/10,000)
  • Literature Review Augmentin-induced Cholestasis
    • Both studies noted similar trends:
      • At greater risk: males, 60+yo, more than one exposure
      • Latency period: few days to 1 month
      • 75-80% present with cholestatic injury pattern: jaundice, pruritis, less frequent N/V
    • Striker et al., comment on the incidence of unnecessary cholecystectomies performed on patients with Augmentin cholestasis
    • Larrey et al., note association of Augmentin cholestasis and liver biopsies showing granulomatous hepatitis
  • Literature Review Imipramine Cholestasis
    • TCA’s: Imipramine and Amitryptiline
      • Fewer case reports in the literature
        • Probably due to fewer prescriptions, TCAs falling out of favor w/ clinicians due to serious side effect profile
        • Cholestatic injury pattern and hepatocellular necrosis
      • Described as a “chronic cholestasis” process, usually with at least 1 month latency period between use and presentation
      • Self-limited, very rare case reports of fulminant hepatic failure
  • Literature Review: Summary
    • Case series/reports of drug-induced cholestasis causing liver failure and death
      • Most cases are self-limited, resolve with discontinuation of offending agent
      • Rarely, patients can develop progressive disease
      • No clear risk factors for progressive disease identified
    • Idiosyncratic drug reactions comprise almost 12% of all cases of acute liver failure (ALF Study Group)
      • Most ALF w/ hepatocellular injury pattern, not cholestasis
  • Treatment?
    • Discontinuation of offending agent
    • Supportive therapy
    • No definitive therapy if cholestasis is progressive
      • Steroids? Cholestyramine? Ursodeoxycholic Acid?
        • Only O’Brien et al (1996) reported success with ursodeoxycholic acid in treating drug-induced cholestasis
    • Transplant must be considered early for progressing cholestasis
      • Our patient was considered for transplant at Mt. Sinai in NYC, but died before transfer
  • References
    • Garcia Rodriguez, L.A., et al. 1996. Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid. Arch Intern Medicine . 1996;156: 1327-32.
    • Horst, D.A., et al. 1980. Prolonged cholestasis and progressive hepatic fibrosis following imipramine therapy. Gastroenterology . 1980; 80: 550-4.
    • Larrey D., et al. 1992. Hepatitis associated with amoxicillin-clavulanic acid combination: report of 15 cases. Gut . 1992;33: 368-71.
    • Lee, W.M., et al. 2003. Drug induced hepatotoxicity. N Engl J Med . 2003;349: 474-485.
    • O’Brien, C.B., et al. 1996. Drug induced vanishing bile duct syndrome: response to ursodiol. Am J Gastroent . 1996;123: 161-7.
    • Mohi-ud-din, J.H., et al. 2004. Drug-and chemical-induced cholestasis. Clin Liver Dis 2004;8: 95-132.
    • Striker B.H., et al. 1989. Cholestatic hepatitis due to antibacterial combination of amoxicillin and clavulanic acid (Augmentin). Dig Dis Sci . 1989;34: 1576-80.