Acute Liver FailureNeil Shah, MD

UNC School of MedicineHigh-Impact HepatologySaturday, Dec 8th, 2018

Disclosures

None

Outline

• Overview of ALF• Management of ALF• Diagnosis of ALF• Treatments and Support

• Acute on Chronic Liver Failure (ACLF)

Acute Liver Failure (ALF)

• Definition: Onset of coagulopathy (INR > 1.5) and encephalopathywithin 8 (to 26) weeks in a patient without prior liver disease*• *Exceptions: Wilson’s Disease, HBV or AIH

• Clinical decompensation can be rapid• Cerebral edema and infection are leading causes of death• 30-40% spontaneous survival with ICU care

• Relatively rare: ~2000 cases annually• Liver Transplantation leads to good survival• 1-Year à 80%• 5-Year à 75%

Etiology and Outcomes in the US

Etiology % AffectedAcetaminophen 39%

DILI 13%

Hepatitis A 4%

Hepatitis B 7%

Ischemic Hepatitis 6%

Autoimmune 4%

Wilson Disease 3%

Budd-Chiari 2%

Indeterminate 17%

Ostapowicz, MD et al. Ann Intern Med. 2002

Look for Etiology Early and TreatTreatableAcetaminophen N-Acetylcysteine, Lavage, CharcoalAmanita Mushroom PenGAutoimmune Hepatitis IV steroidsBudd-Chiari Anticoagulation, TIPSHepatitis B TDF/TAF, EntecavirHerpes Simplex IV AcyclovirAcute Fatty Liver of Pregnancy DeliveryWilson’s Disease TRANSPLANTTransplant ContraindicatedInfiltrating Cancer

Test Sensitivity Specificity Likelihood ratioALP : Bilirubin < 4 94% 96% 23

AST : ALT > 2.2 94% 86% 7

Both tests 100% 100% ∞Korman JD Hepatology. 2008

Initial and General Management

• Early Recognition!

• INR not often checked with labs

• Grade I-II Encephalopathy: Transfer

• Grade III-IV Encephalopathy: Intubate and Transfer

• Monitor blood tests every 8-12 hours

• Liver enzymes, INR, electrolytes

• Renal Function à CVVHD?

• ABG Ammonia à > 200 with poor prognosis

• Blood glucose à D10 gtt?

• Liver Biopsy not necessary

• May lead to fluid overload in attempts to correct coagulopathy

Specific Management

• Circulatory• Colloid preferred, MAP > 75 mmHg• Vasopressin controversial à ↑ ICP• CVVHD > iHD

• Infection• No data for prophylaxis• Surveillance cultures recommended

• Coagulopathy• IV Vitamin K• FFP or PLT only for active bleeding• H2 Blocker for GI ppx

• Encephalopathy• HOB Elevation• Propofol preferred for sedation• Lactulose – Pros/Cons• Seizures? à Phenytoin

• Cerebral Edema• Hyperventilate: PaCO2 goal 25 mmHg• IV mannitol• Hypertonic saline• Phenobarbital infusion• ICP Monitoring: Center dependent

Lee WM et al. Hepatology Sept 2011

Benefit of NAC in Non-Tylenol ALF

Lee WM, Gastroenterology. 2009 Sep

High-Volume Plasma Exchange in ALF

• Randomized: SMT (n=17) vs HVPE (n=16)• More vasopressor use in SMT;

more renal failure in HVPE• Higher transplant-free survival in

HVPE group (75% vs 38%)• Improved NH3 clearance in HVPE

group à unclear significance

Maiwall et al, Abstract 288, Liver Meeting 2018

We Are Getting Better at Treating ALF

Reuben et al. Ann Intern Med. 2016Slide Adapted from Dr. Paul Hayashi

Overall

Transplant-FreeSurvival

Transplant-FreeSurvival; Listed

Patients

67.1%75.3%

56.2%

45.1%

19.2% 35.7%

Why Are We Better?

Reuben et al. Ann Intern Med. 2016

End of study period for NAC in non-APAP failure

Gastro paperpublished

Acute on Chronic Liver Failure (ACLF)

• Largest prospective database by CANIONIC investigators à EASL

• Described as acute decompensation of cirrhosis associated with organ failure (OF) and high short-term mortality (28-day mortality ≥15%)• Affects ~30% of hospitalized patients with cirrhosis• 28-Day Mortality: 33% | 90-Day Mortality: 51%

• Can develop in outpatients, risk factors include:• High MELD, anemia, presence of ascites and low MAP

Hernaez R, et al. Gut 2017Moreau R, et al. Gastroenterology. 2013

Prognostic Models for ACLF

Jalan et al. J Hepatol. 2014Hernaez R, et al. Gut 2017

CLIF-SOFA

“Grayed out” à Defines organ failure

CLIF-C ACLF Score Calculator

https://www.clifresearch.com/ToolsCalculators.aspx

ACLF Grades and Mortality

Grades of ACLF Clinical characteristics

No ACLF No organ failure, or single non-kidney organ failure, creatinine <1.5 mg/dl, no HE

ACLF Ia Single renal failure

ACLF Ib Single non-kidney organ failure, creatinine 1.5–1.9 mg/dl and/or HE grade 1–2

ACLF II Two organ failuresACLF III Three or more organ failures

Hernaez R, et al. Gut 2017

ACLF is Dynamic

Initial Grade

Final GradeNo ACLF (n = 165)

ACLF-1 (n = 70)

ACLF-2 (n = 59)

ACLF-3 (n = 94)

ACLF-1 (%)Prevalence (n = 202)

110 (54.5) 49 (24.3) 18 (8.9) 25 (12.4)

ACLF-2 (%)Prevalence (n = 136)

47 (34.6) 19 (14.0) 35 (25.7) 35 (25.7)

ACLF-3 (%)Prevalence (n = 50)

8 (16.0) 2 (4.0) 6 (12) 34 (68)

Gustot et al Hepatology. 2015

ACLF Grade at Days 3-7 after diagnosis predicted 28-day and 90-day mortality more accurately than ACLF at diagnosis

Early Change in Score Predicts Survival

• 48 patients with ACLF admitted

to ICU with CLIF-SOFA scores

calculated at D0, D2, D5 and D7

• Change in CLIF-SOFA between

D2 and D5 or D7 best indicator

of survival

Kotha et al. Abstract 291, Liver Meeting 2018

Precipitants of ACLF

Bacterial Infection 32%

GI Bleeding 13%

Active Alcoholism (within 3 months) 25%

Other* 9%

None Identifiable 44%

More Than One 14%

Moreau R, et al. Gastroenterology. 2013

*TIPS, Surgery, LVP without Albumin, HBV/AIH Flare

Rising Burden of EtOH in ACLF

Axley PD et al, Abstract 282, Liver Meeting 2018

• EtOH abuse disproportionately affects youth• Reviewed 112,174 admissions

over 8 years (2006-2014) and analyzed in two age groups (< 35 and > 35)• Alcoholic Hepatitis: 40.6% vs

16.5%• ACLF-2: 26.8% vs 21.8%• ACLF-3: 7.2% vs 3.4%

Management of ACLF

• Supportive care, similar to that of ALF• Infectious workup and low threshold for Abx• Circulatory support with albumin +/- vasopressors• HRS treatment +/- CVVHD• Avoid unnecessary transfusions of FFP and PLT

• Adrenal insufficiency commonly seen• Specific Management• G-CSF à improves short-term survival, but only studied in ACLF-1 patients• Extracorporeal liver support systems (ECAD) à MARS• Liver Transplantation

Arroyo et al, Nature Reviews Disease Primers June 2016

ECAD for ACLF?

• Open Albumin Dialysis (OPAL) previously described to be better than MARS (Charcoal-based)• Cross-over study of 30 patients

with ACLF• OPAL better at removing bile acids

and “toxin load”• OPAL better at improving

encephalopathy too• No report of clinical outcomes

• 62 patients with ACLF• Majority were alcohol (62%)

• Survival à 1 mo: 56%, 3 mo 47%• Overall transplant-free survival 28%

• Those with ACLF-3 had lowest survival à deemed futile

Stange et al, Abstract 293, The Liver Meeting 2018Saliba et al, Abstract 286, The Liver Meeting 2018

Liver Transplantation for ACLF

Arroyo et al, Nature Reviews Disease Primers June 2016

5-year post-OLT Survival > 80%

…But only feasible in < 25% of patients

Can aid with prognosis/goals of care discussion

Good Post-OLT Survival for ACLF-3

• UNOS database: 6,010 patients identified with ACLF-3• 1-year post-OLT survival• ACLF-3 81.1% vs 88.4% and 91.7%

in ACLF-2 and ACLF-1

• Risk factors for mortality:• Respiratory failure• High Donor Risk Index

Sundaram et al, Abstract 2349, The Liver Meeting 2018

Summary

• Early detection and treatment of ALF is key• “Let the kidneys go” and initiate CVVHD if needed• Minimize unnecessary transfusions for coaguloapathy

• Acute on chronic liver failure is a distinct entity from “simple decompensation”• CLIF-SOFA score and subsequent ACLF grade correlates better than MELD for

prognosis and can help with prognosis• Alcohol decompensations are on the rise• Liver transplant works, but window is small, so transfer early