Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Liver Failure Case

9,623 views

Published on

Published in: Economy & Finance

Liver Failure Case

  1. 1. A Case of Fatal Cholestatic Liver Failure Senior Clinicopathologic Conference Andre Cap, MD, PhD Walter Reed Army Medical Center
  2. 2. History of Present Illness <ul><li>63 y/o white male </li></ul><ul><li>Recent radical cystoprostatectomy for poorly differentiated urothelial carcinoma </li></ul><ul><ul><li>2.5x3 cm bladder mass invading muscle </li></ul></ul><ul><ul><li>Negative margins, ureters, LND </li></ul></ul><ul><ul><li>Chronic cystitis </li></ul></ul><ul><ul><li>T2a N0 Mx </li></ul></ul><ul><li>One month later, developed symptoms c/w acute cholecystitis and underwent laparoscopic cholecystectomy at civilian hospital </li></ul><ul><ul><li>Gross pathology reveals bile sludge, no stones, inflammatory changes consistent with chronic cholecystitis </li></ul></ul>
  3. 3. History of Present Illness (cont.) <ul><li>Post-op, LFT’s continued to rise in cholestatic pattern and patient developed painless jaundice and pruritis </li></ul><ul><li>POD#3, patient underwent ERCP </li></ul><ul><ul><li>No evidence of retained stone or other obstruction </li></ul></ul><ul><ul><li>Stent placed in distal CBD </li></ul></ul><ul><li>POD#5, ERCP repeated due to continued rise in LFT’s </li></ul><ul><ul><li>No evidence of obstruction or retained stone </li></ul></ul><ul><ul><li>Larger stent placed in CBD and sphincterotomy performed </li></ul></ul>
  4. 4. History of Present Illness (cont.) <ul><li>POD#17, HIDA scan performed showing lack of tracer in biliary tree, indicating hepatocellular dysfunction </li></ul><ul><li>CT scan revealed mild intra-hepatic ductal dilatation </li></ul><ul><li>Third ERCP revealed patent hepatobiliary tree </li></ul><ul><li>Laboratory evaluation of cholestasis unrevealing </li></ul><ul><ul><li>Normal studies: copper, iron, alpha-1 anti-trypsin, ASMA, ANA, AMA, anti LKM, ANCA, Hepatitis A and C </li></ul></ul><ul><ul><li>Hepatitis B core Ab positive (all other Hepatitis B serologies negative, Hep B DNA PCR negative) </li></ul></ul><ul><li>Liver biopsy performed and patient sent to WRAMC for further evaluation </li></ul>
  5. 5. History of Present Illness (cont.) <ul><li>Admission medications: protonix, lisinopril, anusol, ursodiol, atarax, dolasetron, nystatin ointment </li></ul><ul><ul><li>Previously treated with Augmentin for 10 day course post-cholecystectomy (unclear how many doses taken) </li></ul></ul><ul><ul><li>Previously treated with imipramine for incontinence post-prostacystectomy, discontinued prior to episode of cholecystitis </li></ul></ul><ul><ul><li>Reports 7U PRBC transfusion at civilian hospital, no records </li></ul></ul><ul><li>Patient denied taking herbals, OTC medications, EtOH, tylenol </li></ul><ul><li>Workplace toxin exposure: diesel fuel, other petroleum products </li></ul><ul><li>No family history of liver disease </li></ul>
  6. 6. Other Past Medical History <ul><li>Hypertension </li></ul><ul><li>Right knee surgery January 2005 </li></ul><ul><li>Vasectomy </li></ul><ul><li>Hernia repair 1968 </li></ul><ul><li>Tonsillectomy in childhood </li></ul><ul><li>NKDA </li></ul><ul><li>Prior tobacco use (15 pack-yrs, quit 1981), moderate alcohol consumption (2-3 beers/week, remote history of heavy EtOH abuse) </li></ul>
  7. 7. Physical Exam / Labs <ul><li>Afebrile, BP 113/71, HR 80 </li></ul><ul><li>Icteric, otherwise unremarkable exam </li></ul><ul><li>LFT’s on admission to WRAMC (POD 29): </li></ul><ul><ul><li>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 </li></ul></ul><ul><li>WBC 14.2, H/H 12.3/35.7, PLT 566 </li></ul><ul><li>Creatinine 2.2 (baseline 1.7) </li></ul>
  8. 8. Initial Hospital Course <ul><li>MRCP performed </li></ul><ul><ul><li>No biliary dilatation, complex renal cysts </li></ul></ul><ul><li>ERCP repeated </li></ul><ul><ul><li>Beading and minor narrowing of intrahepatic ducts, no CBD stricture/obstruction </li></ul></ul><ul><li>Exhaustive laboratory evaluation repeated </li></ul><ul><ul><li>No etiology for cholestasis identified </li></ul></ul><ul><li>ARF resolved with IV fluids </li></ul><ul><li>Liver biopsy repeated </li></ul>
  9. 9. Biopsy Results <ul><li>Dr. Zachary Goodman, Chief, Hepatopathology, AFIP </li></ul>
  10. 21. Summary Biopsy Results <ul><li>Centrilobular cholestasis, dilated bile canaliculi </li></ul><ul><li>Acute cholangitis </li></ul><ul><ul><li>Bile duct injury with PMN infiltration </li></ul></ul><ul><ul><li>Ductular proliferation </li></ul></ul><ul><ul><li>Mild portal fibrosis </li></ul></ul><ul><li>Inflammatory pseudotumor </li></ul><ul><ul><li>Indicative of obstruction and/or ruptured bile duct </li></ul></ul>
  11. 22. Summary Biopsy Results (cont.) <ul><li>Biopsies performed at civilian hospital and WRAMC with similar findings </li></ul><ul><ul><li>No evidence of malignancy </li></ul></ul><ul><ul><li>No evidence of chronic inflammatory changes </li></ul></ul><ul><ul><li>No evidence of cirrhosis </li></ul></ul><ul><li>Histopathology consistent with obstruction versus drug effect </li></ul>
  12. 23. Subsequent Hospital Course (6 weeks) <ul><li>Worsening cholestatic hepatic failure </li></ul><ul><ul><li>Total bilirubin rising to over 50 </li></ul></ul><ul><ul><li>Coagulopathy developing </li></ul></ul><ul><ul><li>Encephalopathy </li></ul></ul><ul><li>Upper GI bleed, multiple episodes </li></ul><ul><ul><li>Erosion of CBD stent into duodenum </li></ul></ul><ul><ul><li>Duodenal ulcer, jejunal bleeding </li></ul></ul><ul><li>Acute renal failure, requiring dialysis </li></ul><ul><ul><li>Thought to be contrast-induced nephropathy, not hepato-renal syndrome </li></ul></ul><ul><li>Sepsis (VRE) </li></ul><ul><li>Death due to sepsis </li></ul>
  13. 24. Subsequent Hospital Course (6 weeks)
  14. 25. Autopsy Results <ul><li>Dr. Zachary Goodman, Chief, Hepatopathology, AFIP </li></ul>
  15. 31. Autopsy Results <ul><li>Marked cholestatic liver injury (similar to biopsies) </li></ul><ul><li>Centrilobular hepatocellular necrosis, probably due to hypotension </li></ul><ul><li>Granulomata in liver with yeast forms consistent with Candida (probably acquired in hospital) </li></ul><ul><li>Patent extrahepatic biliary tree </li></ul><ul><li>Normal pancreas </li></ul><ul><li>Evidence of ATN on exam of renal tissue </li></ul>
  16. 32. Differential Diagnosis of Cholestasis <ul><li>Biliary obstruction (intra- or extra-hepatic) </li></ul><ul><li>Sepsis (inflammatory cascade) </li></ul><ul><li>Hepatitis (viral, EtOH) </li></ul><ul><li>PBC, PSC </li></ul><ul><li>Malignancy (HCC, mets) </li></ul><ul><li>Granulomatous disease (infection, sarcoid, drugs – allopurinol, quinidine, sulfonamides, sulfonylureas) </li></ul><ul><li>Pregnancy </li></ul><ul><li>Genetic </li></ul><ul><li>GVHD </li></ul><ul><li>Transplant rejection </li></ul><ul><li>Paraneoplastic (RCCA -- Stauffer’s syndrome, NHL, HD, prostate) </li></ul><ul><li>Medication, TPN effect </li></ul>
  17. 33. What can we rule out? <ul><li>Biliary obstruction (intra- or extra-hepatic) </li></ul><ul><ul><li>ERCP X 4 w/o evidence of obstruction </li></ul></ul><ul><li>Sepsis (inflammatory cascade) </li></ul><ul><ul><li>Negative blood cultures until late in clinical course </li></ul></ul><ul><li>Hepatitis (viral, EtOH) </li></ul><ul><ul><li>Negative serologies, no EtOH consumption as inpatient </li></ul></ul><ul><li>PBC, PSC </li></ul><ul><ul><li>Biopsy results and chronicity not c/w these, negative AMA, ERCP not c/w PSC </li></ul></ul><ul><li>Malignancy (HCC, mets) </li></ul><ul><ul><li>No evidence of hepatic involvement on biopsy, autopsy </li></ul></ul>
  18. 34. What can we rule out? <ul><li>Granulomatous disease (infection, sarcoid, drugs – allopurinol, quinidine, sulfonamides, sulfonylureas) </li></ul><ul><ul><li>Autopsy reveals few scattered granulomas, not sufficient burden of disease </li></ul></ul><ul><ul><li>Cholestasis due to fungal infection generally a manifestation of disseminated disease, fulminant process </li></ul></ul><ul><ul><ul><li>Histoplasma, cryptococcus, blastomycosis, candida </li></ul></ul></ul><ul><ul><li>Case reports of biliary duct obstruction by fungus ball </li></ul></ul><ul><ul><li>Fungal infection likely acquired in hospital, negative cultures </li></ul></ul><ul><ul><ul><li>Case reports of hepatic and pancreatic candidal infections post-ERCP </li></ul></ul></ul><ul><li>Pregnancy </li></ul><ul><li>Genetic </li></ul><ul><li>GVHD </li></ul><ul><li>Transplant rejection </li></ul><ul><li>TPN </li></ul>
  19. 35. What’s left? <ul><li>Paraneoplastic (RCCA -- Stauffer’s syndrome, NHL, HD, prostate) </li></ul><ul><ul><li>Poorly understood pathophysiology – inflammatory cascade? </li></ul></ul><ul><ul><li>Not previously described in urothelial carcinoma </li></ul></ul><ul><ul><li>No mets identified </li></ul></ul><ul><ul><li>Up to 50% of patients with T2 or higher stage urothelial carcinoma are eventually found to have metastatic disease </li></ul></ul><ul><li>Medication effect </li></ul><ul><ul><li>Our patient exposed to at least 2 medications known to cause cholestasis </li></ul></ul>
  20. 36. Drug Induced Liver Injury <ul><li>Dr. Jonathan Koff, Director, WRAMC Liver Clinic </li></ul>
  21. 37. Definition <ul><li>Liver injury caused by drugs or other chemicals, including complementary or alternative remedies </li></ul><ul><li>There is no single diagnostic test </li></ul><ul><ul><li>Diagnosis requires a high index of suspicion and judicious use of diagnostic lab and imaging tests </li></ul></ul><ul><li>A diagnosis of exclusion (causality difficult to prove) </li></ul>
  22. 38. Incidence <ul><li>One of the most frequent types of adverse reactions to pharmaceuticals and other chemicals </li></ul><ul><li>2-5% of patients hospitalized for jaundice </li></ul><ul><li>More than 40% of “hepatitis” in persons over age 50 years old </li></ul><ul><li>Major cause of acute liver failure </li></ul>
  23. 39. General Mechanisms Underlying Injury Drug (xenobiotic) Stable metabolites, excretion P450 bioactivation Detoxification Reactive metabolite Immune mechanisms Nonimmune mechanisms Cell damage
  24. 40. 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
  25. 41. Hypersensitivity Reactions <ul><li>Idiosyncratic </li></ul><ul><li>Production of intermediate metabolite (immunoallergen) </li></ul><ul><li>Systemic immunologic reaction: </li></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Eosinophilia </li></ul></ul><ul><li>Examples: </li></ul><ul><ul><li>Phenytoin, Halothane, Sulfonamides </li></ul></ul>
  26. 42. Metabolic Idiosyncrasy <ul><li>Drug metabolized to toxic intermediary in small proportion of patients </li></ul><ul><li>No signs of hypersensitivity </li></ul><ul><li>Latent period is unpredictable </li></ul><ul><li>Liver injury can occur 1 week to 1 year after starting medication </li></ul><ul><li>Prototype drug - isoniazid </li></ul>
  27. 43. Risk factors <ul><li>Age: </li></ul><ul><ul><li>More common in persons > 50 y.o. </li></ul></ul><ul><ul><li>More severe in persons > 50 y.o. </li></ul></ul><ul><li>Gender: </li></ul><ul><ul><li>Women at increased risk v. men </li></ul></ul><ul><li>Obesity </li></ul><ul><li>Chronic alcohol use </li></ul><ul><li>Patients with previous hepatotoxicity </li></ul><ul><li>Use of multiple drugs </li></ul>
  28. 44. Subclinical liver disease <ul><li>Injury reflected by elevation in serum liver enzymes </li></ul><ul><ul><li>Aminotransferases and Alkaline phosphatase </li></ul></ul><ul><li>May occur in 5-50% of patients </li></ul><ul><li>Elevations (<3 times ULN): </li></ul><ul><ul><li>May resolve spontaneously </li></ul></ul><ul><ul><li>Drug may be continued if chemistries monitored </li></ul></ul>
  29. 45. Aminotransferases <ul><li>Elevations > 3-5 x ULN are associated with significant liver injury when: </li></ul><ul><ul><li>Observed in > 3% of study population </li></ul></ul><ul><ul><li>Occur with any elevation in serum bilirubin (10% chance of severe liver injury) </li></ul></ul><ul><li>Elevations > 10 x ULN rarely occur spontaneously and are highly significant in any patient </li></ul>
  30. 46. Pre-existing Liver Disease <ul><li>Does not increase risk of drug toxicity: </li></ul><ul><ul><li>Most drug reactions – idiosyncratic </li></ul></ul><ul><ul><li>Related to production of metabolites </li></ul></ul><ul><li>If toxicity does occur: </li></ul><ul><ul><li>May be more severe </li></ul></ul><ul><ul><li>But only with advanced liver disease </li></ul></ul><ul><li>Exceptions: </li></ul><ul><ul><li>Methotrexate </li></ul></ul><ul><ul><li>Chemotherapeutic agents </li></ul></ul>
  31. 47. Acute Hepatocellular Cholestatic Chronic Hepatocellular Cholestatic Vascular Neoplastic Steatosis Phospholipidosis Fibrosis Granulomas Spectrum of Injury
  32. 48. 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
  33. 49. Acute Liver Failure: Etiology Ostapowitz G et al. Ann Inter Med 2002;137:947
  34. 50. 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
  35. 51. Epidemiology <ul><li>2000-2500 cases per year in U.S. </li></ul><ul><li>300-350 emergency liver transplants for ALF per year </li></ul><ul><li>Case fatality rate 57% to 80% without transplant </li></ul>
  36. 52. Contraindications to Liver Transplantation <ul><li>Medical </li></ul><ul><ul><li>Hepatic malignancy (too large or too many) </li></ul></ul><ul><ul><li>Cholangiocarcinoma </li></ul></ul><ul><ul><li>Extrahepatic malignancy </li></ul></ul><ul><ul><li>Active sepsis </li></ul></ul><ul><ul><li>Advanced cardiopulmonary disease </li></ul></ul><ul><ul><li>Active alcoholism or substance abuse </li></ul></ul><ul><ul><li>Irreversible brain damage caused by liver failure </li></ul></ul><ul><li>Surgical </li></ul><ul><ul><li>Complete thrombosis of portal venous circulation </li></ul></ul>
  37. 53. 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
  38. 54. Critical Exposure? <ul><li>Imipramine </li></ul><ul><ul><li>Prescribed in the weeks following cystoprostatectomy for incontinence </li></ul></ul><ul><ul><li>Timing of exposure could account for cholestasis progressing to cholecystitis and subsequent chain of events </li></ul></ul><ul><li>Amoxicillin-clavulanate </li></ul><ul><ul><li>Common cause of drug-induced cholestasis </li></ul></ul><ul><ul><li>At least part of patient’s clinical syndrome seems to have started prior to exposure </li></ul></ul><ul><ul><li>Unclear how much of drug taken </li></ul></ul><ul><li>2 hits? </li></ul><ul><ul><li>Rare sensitivity to 2 drugs? </li></ul></ul>
  39. 55. Literature Review Augmentin-induced Cholestasis <ul><li>First marketed in 1984 </li></ul><ul><ul><li>First case report of cholestatic hepatopathy in 1988 </li></ul></ul><ul><li>Widely prescribed - 1/78209 prescriptions is Augmentin </li></ul><ul><li>Garcia et al. (1996) estimated risk of significant hepatic injury at 1/100,000 patients exposed </li></ul><ul><ul><li>80%+ of cases with a cholestatic injury pattern </li></ul></ul><ul><ul><li>Also associated with sialadenitis and AIN </li></ul></ul><ul><li>Retrospective cohort study by Rodriguez et al. found risk of cholestatic liver injury to be 1.7/10,000 patients </li></ul><ul><ul><li>Found a 5X increased risk of liver injury for Augmentin versus Amoxicillin alone (1.7/10,000 vs 0.3/10,000) </li></ul></ul>
  40. 56. Literature Review Augmentin-induced Cholestasis <ul><li>Both studies noted similar trends: </li></ul><ul><ul><li>At greater risk: males, 60+yo, more than one exposure </li></ul></ul><ul><ul><li>Latency period: few days to 1 month </li></ul></ul><ul><ul><li>75-80% present with cholestatic injury pattern: jaundice, pruritis, less frequent N/V </li></ul></ul><ul><li>Striker et al., comment on the incidence of unnecessary cholecystectomies performed on patients with Augmentin cholestasis </li></ul><ul><li>Larrey et al., note association of Augmentin cholestasis and liver biopsies showing granulomatous hepatitis </li></ul>
  41. 57. Literature Review Imipramine Cholestasis <ul><li>TCA’s: Imipramine and Amitryptiline </li></ul><ul><ul><li>Fewer case reports in the literature </li></ul></ul><ul><ul><ul><li>Probably due to fewer prescriptions, TCAs falling out of favor w/ clinicians due to serious side effect profile </li></ul></ul></ul><ul><ul><ul><li>Cholestatic injury pattern and hepatocellular necrosis </li></ul></ul></ul><ul><ul><li>Described as a “chronic cholestasis” process, usually with at least 1 month latency period between use and presentation </li></ul></ul><ul><ul><li>Self-limited, very rare case reports of fulminant hepatic failure </li></ul></ul>
  42. 58. Literature Review: Summary <ul><li>Case series/reports of drug-induced cholestasis causing liver failure and death </li></ul><ul><ul><li>Most cases are self-limited, resolve with discontinuation of offending agent </li></ul></ul><ul><ul><li>Rarely, patients can develop progressive disease </li></ul></ul><ul><ul><li>No clear risk factors for progressive disease identified </li></ul></ul><ul><li>Idiosyncratic drug reactions comprise almost 12% of all cases of acute liver failure (ALF Study Group) </li></ul><ul><ul><li>Most ALF w/ hepatocellular injury pattern, not cholestasis </li></ul></ul>
  43. 59. Treatment? <ul><li>Discontinuation of offending agent </li></ul><ul><li>Supportive therapy </li></ul><ul><li>No definitive therapy if cholestasis is progressive </li></ul><ul><ul><li>Steroids? Cholestyramine? Ursodeoxycholic Acid? </li></ul></ul><ul><ul><ul><li>Only O’Brien et al (1996) reported success with ursodeoxycholic acid in treating drug-induced cholestasis </li></ul></ul></ul><ul><li>Transplant must be considered early for progressing cholestasis </li></ul><ul><ul><li>Our patient was considered for transplant at Mt. Sinai in NYC, but died before transfer </li></ul></ul>
  44. 60. References <ul><li>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. </li></ul><ul><li>Horst, D.A., et al. 1980. Prolonged cholestasis and progressive hepatic fibrosis following imipramine therapy. Gastroenterology . 1980; 80: 550-4. </li></ul><ul><li>Larrey D., et al. 1992. Hepatitis associated with amoxicillin-clavulanic acid combination: report of 15 cases. Gut . 1992;33: 368-71. </li></ul><ul><li>Lee, W.M., et al. 2003. Drug induced hepatotoxicity. N Engl J Med . 2003;349: 474-485. </li></ul><ul><li>O’Brien, C.B., et al. 1996. Drug induced vanishing bile duct syndrome: response to ursodiol. Am J Gastroent . 1996;123: 161-7. </li></ul><ul><li>Mohi-ud-din, J.H., et al. 2004. Drug-and chemical-induced cholestasis. Clin Liver Dis 2004;8: 95-132. </li></ul><ul><li>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. </li></ul>

×