Acute Liver Failure UCSF Critical Care Medicine and Trauma Meeting June 6, 2008 Tim Davern, MD UCSF Liver Transplant Program

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1 Acute Liver Failure UCSF Critical Care Medicine and Trauma Meeting June 6, 2008 Tim Davern, MD UCSF Liver Transplant Program

2 Acute Liver Failure - Outline - Incidence Definition Etiology Diagnosis Prognosis Complications Treatment Current Future Prevention

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4 Center Adult ALFSG Enrollment Total Cases 2006 cases 2007 cases UCSF Michigan UCLA Washington Pittsburg VCU Nebraska UCD UAB Mayo-R Mt Sinai

5 Adult ALFSG Outcome by Site Center Total Pts Died Spon Surv (%) UCSF % 46 TX- TX- Overall Alive Dead Survival (%) % Michigan % % UCLA % % Washington % % Pittsburg % % VCU % % Nebraska % % UCD % % UAB % % Mayo-R % % Mt Sinai % %

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7 Chronic Liver Disease Acute Liver Disease ~ 2-2 4,000 cases in USA per year ALF

8 Acute Liver Failure -Definition- a a potentially reversible condition, the consequence of severe liver injury with an onset of encephalopathy within 8 weeks of appearance of the first symptoms of the disease and in the absence of pre-existing existing liver disease Trey and Davidson, 1973 Critical Points: A liver-related related illness of short duration ---> no chronic liver disease Coagulopathy (INR > 1.5) Any alteration in mental status (presumed not due to sedation alone) May be subtle Asterixis = stage II

9 Etiology of ALF in the USA: Adult Registry (n = 906) n ACM Drug Hep B Hep A Autoimm Ischemic Wilson's Budd-Chiari Pregnancy Other Indeter Data courtesy W. Lee

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11 Increasing Incidence of APAP-related ALF in US Total ALF cases: Percent of ALF Cases 60% 50% 44% 47% 51% 40% 38% 38% 30% 28% 20% 10% 0% YEAR

12 Suicidal vs. Accidental APAP cases Suicidal Unintentional (n = 101) (n = 109) Female (%) p Value 76 NS APAP (g) NS APAP/day (g) Coma (% > 3) ALT (IU/L) 6,118 3, Spont Surv (%) NS Antidepressant (%) NS APAP/opiate (%)

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14 Adduct+ Indeterminate ALF 3.0 APAP ALF nmol APAP-CYS / mg protein Non-APAP ALF controls APAP OD (no ALF) Adduct- Indeterminate ALF 0.0 A B C D E Patient Group Davern TJ, et al. Gastroenterology 2006;130:687-94

15 ALT (IU/L) ALT (IU/L) Pt A, Admisssion APAP = 90 mg/dl Pt B, Admission APAP = 105 mg/dl Acetaminophen-CYS (umol/l)/mg protein ALT (IU/L) Hospital Day Pt D (Admission APAP = 0 mg/dl) Pt C, Admission APAP = 0 mg/dl Acetaminophen-CYS (umol/l)/mg protein ALT (IU/L) Hospital Day Hospital Day Hospital Day Acetaminophen-CYS (umol/l)/mg protein Acetaminophen-CYS (umol/l)/mg protein

16 Other 30% APAP 30% Occult APAP toxicity Drug 10% Viral Hepatitis 10% Other 30% Indeterminate 20% APAP 30% Approximately 20% of indeterminate ALF cases appear to be related to occult APAP toxicity Approximately 4% of all ALF cases appear to be related to occult APAP toxicity Drug 10% Viral Hepatitis 10% Indeterminate 16% Occult APAP 4%

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18 Acute Liver Failure - Prognosis - King s s College Criteria APAP-induced ALF ph < 7.3 (s/p hydration and irrespective of grade of HE) Or Grade III+ HE and: INR > 6.5 and Creat > 3.4 Survival if: If ph < > > 5% If INR > > > 28% If creat > > > 44% Non-APAP APAP-induced ALF INR > 6.5 (irrespective of HE grade) Or any three of following: Cryptogenic or drug-related related Age <10 and > 40 > 7 days of jaundice prior to HE Bilirubin > 17.5 INR. 3.5 Survival if: One adverse predictor > > 20 % Two -----> > 6%

19 ALF: Prognostic scores King s s College Hosptial (KCH) criteria are reasonably specific for predicting poor outcome but identify only 50-60% of patients who will ultimately die or need tx KCH in US ALFSG ALFSG - unpublished data

20 Key Points in Caring for the ALF Patient Requires multidisciplinary team Transplant hepatologist,, surgeon, social workers, coordinators ICU physicians and nurses Nephrologists Neurosurgeons Rapidly assess for contraindications (medical, psych/social) to liver transplant List ALF patient for transplant as soon as eligible (barring contraindications) Anticipate/prevent/manage complications of ALF Support patients to allow/facilitate hepatic repair/regeneration

21 Etiology-based Medical Therapy for ALF NAC for APAP poisoning Given early (<8 hours) ----> > completely prevents liver injury Given later (?how late) -----> > still may help Charcoal, PCN, silimarin,, NAC for Amanita Delivery for pregnancy-related related ALF Steroids for autoimmune hepatitis Chelation for Wilson Disease * Entecavir for HBV; Acyclovir for HSV; Gancyclovir for CMV Correct hemodynamics for shock Decompressive vascular shunting for BCS * Probably marginal benefit

22 NAC is TPA for the Liver NAC should be given ASAP to patients with suspected APAP overdose We always be suspicious APAP levels are unreliable IV NAC is safe and more reliable than oral NAC in patients with ALF Treat patients with cryptogenic ALF and high aminotransferases with NAC Late administration of NAC appears to be ameliorate APAP toxicity Role for non-apap APAP-related ALF is still unclear

23 Liver Transplant for ALF

24 TRANSPLANT LISTING = LIVER TRANSPLANT Listing is necessary but not sufficient Current UNOS criteria for Status 1 listing: Onset of hepatic encephalopathy (any grade) within 8 weeks of the first symptoms of liver disease» Absence of preexisting (clinically overt?) liver disease is critical Life expectancy of < 7 days In ICU requiring mechanical ventilation, renal support, or with INR > 2.0

25 TRANSPLANT LISTING = LIVER TRANSPLANT Hours (even minutes) can be the difference between life and death If the ALF patient is exhaustively evaluated for LTx prior to listing, he/she is likely to die Listing patients in the field may occasionally be appropriate The decision to proceed with LTx should be made at the time an acceptable organ is identified and represents one of the most difficult decisions that transplant physicians and surgeons must make. Prognostic models are imperfect

26 Two Text Pages on 2/12/08 12:19 PM: Tim, Just FYI, we have a fulminant coming in today, Tylenol OD, with h/o prior suicide attempts. Kaiser patient. No arrival time yet. -Kiran 3:50 PM: Just some f/u on the fulminant. She s s herniating at the outside hospital. Unfortunate situation. -Kiran

27 TRANSPLANT LISTING = LIVER TRANSPLANT Hours (even minutes) can be the difference between life and death If the ALF patient is exhaustively evaluated for LTx prior to listing, he/she is likely to die Listing patients in the field may occasionally be appropriate The decision to proceed with LTx should be made at the time an acceptable organ is identified and represents one of the most difficult decisions that transplant physicians and surgeons must make. Prognostic models are imperfect

28 1033 Patients enrolled 455 (44%) listed Spontaneous survivors n= 465 (45%) Transplanted n= 262 (25%) Died (Not Transplanted) n= 306 (30%) Alive n= 134 (86%) Died n= 38 (14%) Overall survival: n = 695 (67%)

29 Liver Transplant for ALF Right Lobe Graft Left Lobe Graft Photographs courtesy of Bob Brown, Columbia P&S

30 ALF Complications Elevated Intracranial Pressure (ICP)/cerebral edema/cerebral herniation/brain death Multi-organ failure -> > ICU care Renal failure-- --> > continuous dialysis (CVVH) Infection-- --> > culture, empiric abx Hypoglycemia-- --> > glucose Electrolyte problems-- --> > replacement Misc - pancreatitis, aplastic anemia

31 Cerebral edema Poorly understood pathogenesis Arterial NH3 appears to be predictive of complications Role of lactulose and enteric abx undefined Difficult to diagnose accurately on clinical grounds CT insensitive and impractical ICP monitoring is controversial

32 Liver Failure Ammonia Infection Inflammatory Cytokines Glutamate Glutamine Osmotic stress Oxidative stress Inflammation Increased cerebral blood flow Edema Astrocyte swelling

33 Cerebral edema Poorly understood pathogenesis Arterial NH3 appears to be predictive of complications Role of lactulose and enteric abx undefined Difficult to diagnose accurately on clinical grounds CT insensitive and impractical ICP monitoring is controversial

34 Is ICP monitoring worth the risks? Data regarding utility are thin Major complication: bleeding

35 First Do No Harm

36 ICP monitoring via Lumbar Catheter 16 UCSF pts w/ ALF (one with PNF) Robust/dynamic pressure measurements that correlate with CT findings and respond to Rx Safe (so far )

37 Acute Liver Failure - Treatment - Treatment of elevated ICP Goals: : ICP < 20 mm Hg, CPP > 50 mm Hg* Maintain MAP > 60 mm Hg Avoid volume overload (----( ----> > early renal support) Avoid/treat factors that may increase ICP» Fever, seizures, hypertension, vasodilating drugs (e.g., nitroprusside), agitation, jugular venous compression, neck flexion, unnecessary stimulation/suctioning Elevate head of bed to 20 degrees * CPP = MAP - ICP

38 Acute Liver Failure - Treatment - Treatment of elevated ICP Mannitol (20%)» 0.5 to 1 g/kg over 5 min; repeat q hours as necessary until serum osmolarity > mosm/l» Not effective with renal failure (----( ----> > consider renal support early) Barbituate coma > > brain metabolism > > CBF, CBV» Pentobarbital load (3-5 5 mg/kg; maximum 500 mg) over 15 min then continuous infusion ( mg/kg/hr)» Use limited by cardiac depression, hypotension (----( ----> consider PA line early)» Can no longer follow neuro exam, EEG

39 Acute Liver Failure - Treatment - Treatment of elevated ICP Moderate Hypothermia» degrees Celsius» Decreases ICP in uncontrolled studies» Decreases liver injury in mouse models» Side effects - shivering, infection, PLT dysfunction, impaired hepatic regeneration?» ALFSG study planned

40 Novel medical therapies are desperately needed We need better medical therapies aimed at limiting liver injury and enhancing liver repair/regeneration We need better therapies to prevent and treat cerebral edema a a potentially reversible condition,, the consequence of severe liver injury with an onset of encephalopathy within 8 weeks of appearance of the first symptoms of the disease and in the absence of pre-existing existing liver disease Trey and Davidson, 1973

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42 Is ALF Preventable? Mass vaccination for viral hepatitis A and B Appropriate food handling and preparation Education for mushroom pickers Safer drugs Drug Induced Liver Injury Network (DILIN) Limitation of package size for acetaminophen Uncoupling acetaminophen/opiate combinations Who came up with the idea of mixing a dose-dependant dependant toxin with a highly addictive drug?

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44 Is ALF Preventable? Mass vaccination for viral hepatitis A and B Appropriate food handling and preparation Education for mushroom pickers Safer drugs Drug Induced Liver Injury Network (DILIN) Limitation of package size for acetaminophen Uncoupling acetaminophen/opiate combinations Who came up with the idea of mixing a dose-dependant dependant hepatotoxin with a highly addictive drug?

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46 Is ALF Preventable? Mass vaccination for viral hepatitis A and B Appropriate food handling and preparation Education for mushroom pickers Safer drugs Drug Induced Liver Injury Network (DILIN) Limitation of package size for acetaminophen Uncoupling acetaminophen/opiate combinations Who came up with the idea of mixing a dose-dependant dependant hepatotoxin with a highly addictive drug?

47 Slide courtesy of Will Lee

48 Magnitude of DILI Problem DILI is most common cause of ALF in US DILI is the most common reason for drug withdrawal or restriction of prescription Enormous $ for pharmaceutical and regulatory industries Many patients may be denied access to good drugs Primum non nocere DILI is iatrogenic Mediocolegal implications

49 If you have seen cases of DILI, please contact us. We need your help!

50 Is ALF Preventable? Mass vaccination for viral hepatitis A and B Appropriate food handling and preparation Education for mushroom pickers Safer drugs Drug Induced Liver Injury Network (DILIN) Limitation of package size for acetaminophen Uncoupling acetaminophen/opiate combinations Who came up with the idea of mixing a dose-dependant dependant hepatotoxin with a highly addictive drug?

51 Etiology of ALF in the USA: Adult Registry (n = 906) n % 203 Unintentional % Using APAP/Opiate ACM Drug Hep B Hep A Autoimm Ischemic Wilson's Budd-Chiari Pregnancy Other Indeter Data courtesy W. Lee

52 APAP-Opiate Combinations An ill-conceived idea Like mixing candy and poison No good medical reason the drugs can not be prescribed separately Uncoupling APAP-opiate combinations would likely save more lives than all of our efforts to reduce idiosyncratic DILI and would be far less $ (e.g., than pharmacogenomics) Regulatory action to uncouple APAP-opiates is needed

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54 APAP-Opiate Combinations An ill-conceived idea Like mixing candy and poison No good medical reason the drugs can not be prescribed separately Uncoupling APAP-opiate combinations would likely save more lives than all of our efforts to reduce idiosyncratic DILI and would be far less $ (e.g., than pharmacogenomics) Regulatory action to uncouple APAP-opiates is needed APAP-opiate combinations (e.g., Vicodin R ) should be removed from the market

55 ALF: Evaluation and Management - Summary - ALF is a rare but important syndrome Multiple etiologies may cause ALF but APAP toxicity is the most common cause of ALF in the US Some cases of ALF from APAP may be occult If etiology is at all in doubt, treat with NAC (quickly) Prognostic models for ALF are imperfect Early listing of the ALF patient is potentially life saving ALF patients appear to benefit from a multidisciplinary approach to care > refer to transplant center early! We need better medical therapies aimed at limiting liver injury and enhancing liver repair/regeneration Uncoupling APAP-opiates may decrease the incidence of ALF by over 10% in the US

56 Questions? my office UCSF Liver Transplant Answering Service