Approach to Acute liver Failure

Bader Alenezi, MD Chairman of Internal Medicine Jahra Hospital Consultant Gastroenterolgy & Hepatology

Outlines

• • • • • • • Definition Acute Liver failure common causes of ALF Acetaminophen toxicity Diagnosis and Initial Evaluation ALF Manage complications of ALF Identify prognostic criteria Future therapy in ALF

Acute liver Failure (ALF)

• • • • Rare Represent the most sever form of liver injury Hard to treat Difficult to study

Acute liver Failure

• Fulminant hepatitis • Fulminant hepatic failure • Subfulminant liver failure • Subacute hepatic necrosis • Subacute liver failure • Hyperacute liver failure

ALF: Definition

• • The original term “fulminant hepatic failure” “a severe liver injury, potentially reversible in nature and with onset of hepatic encephalopathy within 8 weeks of the first symptoms in the absence of pre-existing liver disease,” • Trey C , Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970;3:282-98

ALF: Definition

• The most widely accepted definition of ALF: • Coagulation abnormality, usually an INR >1.5, and any degree of mental alteration (encephalopathy) without preexisting cirrhosis and with an illness of <26 weeks duration.

• • AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD

Defining Acute Liver Failure

• • • INR > 1.5

Altered mental status Illness of < 26 weeks duration • • • Hyperacute < 7 days Acute 7-21 days Subacute > 21 days and < 26 weeks • Fulminant (2 wks) vs subfulminant (2-12 wks)

ALF: Causes

• • • •

Acetaminophen 39% Indeterminite 17% Idiosynchratic drug rxns 13% Viral hepatitis 12%

–

HBV > HAV > HEV, HSV

• • • • • Autoimmune 4-5% Wilson’s Disease 2-3% Mushroom Poisoning Herbal Medications Vascular – Bud-Chiarri – Ischemic – Hepatic Vein Thrombosis • • • Reye’s Syndrome Fatty Liver of Pregnancy HELLP

U.S. ALF STUDY GROUP 2002 (308 Patients, 73% Women

)

40 35 30 25 20 15 10 5 0 ACM HBV HAV Indet Other

ALF: Causes

• • • ALF in developed world << developing world developing world viral infections (hepatitis A, B, and E) are the predominant causes.

Western world drug-induced liver injury is the most common cause of acute liver failure

ALF CAUSES: Viruses

• • • • Globally, hepatitis A and E infections are probably responsible for the majority of cases of ALF ALF may occur after hepatitis B infection, Asian and Mediterranean countries. Reactivation of HBV without established chronic liver disease treatment-induced immunosuppression during or after therapy for cancer Antiviral prophylaxis before the initiation of chemotherapy, immunotherapy, or glucocorticoid therapy are effective in prevention

ALF CAUSES: Other Viruses

• • • • • rare viral causes of acute liver failure : Herpes simplex virus CMV Epstein–Barr virus Parvoviruses • Ichai P, Samuel D. Etiology and prog- nosis of fulminant hepatitis in adults. Liver Transpl 2008;14:Suppl 2:S67-S79.

Drug-Induced Liver Injury (DILI)

Drug-Induced Liver Injury (DILI)

• • • • • • • • DILI is responsible for approximately 50% of cases of ALF in United States Can be dose- dependent and predictable, as exemplified by acetaminophen-induced hepatotoxicity Or may be idiosyncratic, unpredictable, and independent of dose idiosyncratic drug hepatotoxicity usually within the first 6 months after drug initiation. A potentially hepatotoxic medication used continually 1 to 2 years is unlikely to cause de novo liver damage. Certain herbal preparations, weight loss agents and other nutritional supplements  need complete medication history.

Ostapowicz G,et al. Ann Intern Med 2002 .

Acetaminophen Hepatotoxicity

• • • • • • Dose-related Dose leading to ALF exceed 10 gm/day (>150 mg/kg) Doses as low as 3-4 gm/day rarely causes ALF Very high aminotransferase levels Serum levels exceeding 3,500 IU/L are highly correlated with acetaminophen poisoning low or absent levels do not rule out hepatotoxicity (remote ingestion or over several days)

Rumack-Matthew Nomogram

• • • Used to interpret plasma acetaminophen values to assess hepatotoxicity risk after a single, acute ingestion Nomogram tracking begins 4 hours after ingestion (time when acetaminophen absorption is likely to be complete) and ends 24 hours after ingestion About 60% of patients with values above the "probable" line develop hepatotoxicity

Rumack-Matthew Nomogram

• • • • • The standard acetaminophen toxicity nomogram may aid in determining the likelihood of serious liver damage can not be used if: 1- multiple doses over time 2- when the time of ingestion is unknown 3- When altered metabolism occurs such as in the alcoholic or fasting patient Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis. 2007;11: 525-48.

Lee WM. Drug-Induced Hepatotoxicity. N Engl J Med 2003;349: 474-485.

Treatment of Acetaminophen Hepatotoxicity

• • Activated charcoal for gastrointestinal decontamination best if given within 1hr of ingestion may be of benefit as long as 3 to 4 hours after ingestion. Administration of activated charcoal (standard dose 1 gm/kg orally) just prior to administration of N-acetylcysteine does not reduce the effect of N-acetylcysteine.

• Sato RL,et al Efficacy of superactivated charcoal administration late (3 hours) after acetaminophen overdose. Am J Emerg Med 2003;21:189-191.

Treatment: N-acetylcysteine (NAC)

• • • • N-acetylcysteine (NAC), the antidote for acetaminophen poisoning  effective and NAC should be given as early as possible NAC is nearly 100% hepato protective when it is given within 8 hours but may still be of value 48 hours or more after ingestion

N-acetylcysteine (NAC)

• • NAC orally (140 mg/kg by mouth or nasogastric tube diluted to 5% solution, followed by 70 mg/kg by mouth q 4 h x 17 doses) Oral administration has largely been replaced by intravenous administration (loading dose is 150 mg/kg in 5% dextrose over 15 minutes; maintenance dose is 50 mg/kg given over 4 hours followed by 100 mg/kg administered over 16 hours or 6 mg/kg/hr)

N-acetylcysteine (NAC)

• • • • • • Use of the IV formulation of NAC is preferred in the following situations: Altered mental status GI bleeding and/or obstruction A history of caustic ingestion Potential fetal acetaminophen toxicity in a pregnant woman Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics

Wilson disease

• • • • uncommon cause of ALF (2% to 3% of cases in the U.S.

Early identification is critical because the fulminant presentation of Wilson disease is considered to be uniformly fatal without transplantation young patients with Coombs negative hemolytic anemia with serum bilirubin levels >20 mg/dL Kayser-Fleischer rings are present in about 50% of patients

Wilson disease

• • • • Serum ceruloplasmin is typically low, but may be normal in up to 15% of cases and is reduced in ~50% of other forms of ALF.

High plasma and urinary copper levels as well as hepatic copper measurement will confirm the diagnosis.

Very low serum alkaline phosphatase or uric acid levels A high bilirubin to alkaline phosphatase ratio (>2.0) is a rapid, reliable indicator of Wilson disease

Wilson disease

• • • • •

Rx:

penicillamine is not recommended in ALF due to risk of hypersensitivity recovery is very rare absent transplantation.

Patients must be promptly considered for liver transplantation (AASLD recommendation 2011 )

Autoimmune Hepatitis

• • • • • unrecognized preexisting chronic disease and yet still be considered as having ALF. AIH patients that develop ALF represent the most severe form of the disease.

Autoantibodies absent (up to 30% of cases) Liver biopsy should be considered if autoimmune hepatitis is suspected and autoantibodies are negative Recommended to receive corticosteroid therapy

ALF in Pregnancy

• • • • • • Acute Fatty Liver of Pregnancy/HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) Syndrome Near the end of pregnancy will develop rapidly progressive hepatocyte failure.

Increased fetal or maternal mortality.

Triad of jaundice, coagulopathy, and low platelets Hypoglycemia and Features of pre-eclampsia are common Transplantation may need to be considered if hepatic failure does not resolve quickly following delivery

Budd-Chiari Syndrome

• • • • • Acute hepatic vein thrombosis Abdominal pain, ascites and striking hepatomegaly Diagnosis confirmed with hepatic imaging studies (computed tomography, Doppler ultrasonography, venography, magnetic resonance venography) Prognosis is poor Liver transplantation is indicated, provided underlying malignancy is excluded

Budd-Chiari Syndrome

Ischemic Hepatitis and ALF

• • • • • Liver cell necrosis - massive Cardiac tamponade Acute heart failure Pulmonary embolus Hepatic artery thrombosis

Poisoning and ALF

• • • • • • Amanita mushrooms (amanatoxins) - LD = 50 gms (3 mushrooms) - Toxins not destroyed by cooking - Rapid onset of HE in 4-8 days following severe emesis and diarrhea • Solvents - chlorinated hydrocarbons • Herbal remedies • Yellow phosphorus

Diagnosis and Initial Evaluation ALF

• • • In all patients with clinical or laboratory of acute hepatitis PT and careful evaluation for subtle alterations in mentation should done If PT is prolonged by ~4-6 seconds or more (INR >1.5) and there is any evidence of altered sensorium, the diagnosis of ALF is established and hospital admission is mandatory.

Transfer to intensive care unit (ICU) and contact with a transplant center if indicated

Diagnosis and Initial Evaluation ALF

• • • • Physical Exam: Determine presence or absence of pre-existing liver disease Hepatic tenderness Hepatic decompensation

Diagnosis and Initial Evaluation ALF

• HISTORY: • • • • • • Family members with liver disease?

Recent cold sores Onset of jaundice Work environment- toxic agents Hobbies Herbal products/dietary supplements

Initial Laboratory Analysis

• • • • • •

Prothrombin time/INR Chemistries Liver enzymes Arterial blood gas Acetaminophen level

Toxicology screen

Viral hepatitis serologies

HBsAg, anti-HBc IgM, anti-HEV, anti-HCV, HCV RNA , HSV1 IgM, VZV) (anti-HAV IgM,

Initial Laboratory Analysis

• • • Ceruloplasmin level • Pregnancy test (females) Ammonia (arterial if possible) Autoimmune Markers (ANA, ASMA, Immunoglobulin levels ) Liver Biopsy reserved for diagnostic dilemma (Transjugular approach)

Liver biopsy in ALF

Complications of Acute Liver Failure:

• • • • • • CNS disturbances – Hepatic encephalopathy – Cerebral edema Hemodynamic Collapse Infections Coagulopathy and bleeding Renal failure Metabolic derangements

Cerebral Edema

• • • • • There is increasing evidence that ammonia plays an important role in the pathogenesis of cerebral edema/ ICH arterial ammonia level >200 ug/dL rarely if <75 ug/dL  cerebral herniation; Degree of encephalopathy correlates w/ cerebral edema – Grade I-II: rare – Grade III: 25-35% risk risk – Grade IV: 65-75% risk Uncal herniation Compromises cerebral blood flow  hypoxic brain injury

Intracranial Pressure

CPP = MAP – ICP CPP > 60mmHg ICP < 20mmHg

Intracranial Pressure

CPP = MAP – ICP CPP< 60mmHg ICP < 20mmHg

Cerebral Edema/Intracranial Hypertension

• • • • Grade I/II Encephalopathy Consider transfer to liver transplant facility and listing for transplantation Brain CT: rule out other Avoid stimulation; avoid sedation if possible Antibiotics: surveillance and treatment of infection required; prophylaxis possibly helpful Lactulose, possibly helpful

Grade III/IV Encephalopathy

• • • • • • • Intubate trachea Elevate head of bed Consider placement of ICP monitoring device Immediate treatment of seizures required; prophylaxis of unclear value Mannitol: use for severe elevation of ICP or first clinical signs of herniation Hypertonic saline to raise serum sodium to 145-155 mmol/L Hyperventilation: effects short-lived; may use for impending herniation

Infection

• Surveillance for and prompt antimicrobial treatment of infection required • • Antibiotic prophylaxis possibly helpful but not proven Prophylactic antibiotics and antifungals have not been shown to improve overall outcomes in ALF

Coagulopathy

• • • • • Vitamin K: give at least one dose FFP: give only for invasive procedures or active bleeding Platelets: give only for invasive procedures or active bleeding Recombinant activated factor VII: possibly effective for invasive procedures Prophylaxis for stress ulceration: give H2 blocker or PPI

Hemodynamics/Renal Failure

• • • • • Volume replacement Pressor support (dopamine, epinephrine, norepinephrine) as needed to maintain adequate mean arterial pressure Avoid nephrotoxic agents Continuous modes of hemodialysis if needed Vasopressin recommended in hypotension refractory to volume resuscitation and norepinephrine

Metabolic Concerns

• • Follow closely: glucose, potassium, magnesium, phosphate Consider nutrition: enteral feedings if possible or total parenteral nutrition

What are the potential outcomes?

• 1. Recovery because of a successful intervention – NAC for acetaminophen toxicity – Antivirals for acute hepatitis B • • 2. Spontaneous recovery with supportive care 3. Death • 4. Rescue by liver transplant

•

Predicting Outcomes in Acute Lifer Failure

Most important predictive factors: – Degree of encephalopathy • Suggested laboratory markers: – Factor V – AFP – – Serum Phosphate VII/V ratio > 30 – Gc globulin • Clinical algorithms: – King’s College Criteria – APACHE II

Prognosis and Transplantation

• • • overall mortality has improved to between 30 40% Transplant free-survival was >50% in acetaminophen, hepatitis A, shock liver, or pregnancy-related disease.

other etiologies showed <25% transplant-free survival.

Poor Prognosis in Patients With ALF (Etiology)

• • • • • • • Idiosyncratic drug injury Acute hepatitis B (and other non-hepatitis A viral infections) Autoimmune hepatitis Mushroompoisoning Wilson disease Budd-Chiari syndrome Indeterminate cause

King’s College Criteria

• • • • • • • • •

Acetaminophen-Induced ALF:

Strongly consider OLT listing if: arterial lactate >3.5 mmol/L after early fluid resuscitation List for OLT if: pH<7.3 Or arterial lactate >3.0 mmol/L after adequate fluid resuscitation List for OLT if all 3 occur within a 24-hour period: 1- presence of grade 3 or 4 hepatic encephalopathy 2- INR >6.5 3- Creatinine >3.4 mg/dL

King’s College Criteria

• • •

Non-acetaminophen

: INR > 6.5 OR Any 3 of the following 5: – Age < 10 or > 40 – Serum bilirubin > 18 – Jaundice to encephalopathy interval > 7 days – INR > 3.5

– Unfavorable Etiology • Non-A, non-B hepatitis, halothane, idiosyncratic drug reaction, Wilson’s

AASLD Recommendation

• Currently available prognostic scoring systems do not adequately predict outcome and determine candidacy for liver transplantation. Reliance entirely upon these guidelines is thus not recommended.(III) • AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD

Liver Transplantation

• • Urgent hepatic transplantation is indicated in acute liver failure where prognostic indicators sug- gest a high likelihood of death (II-3).

Living donor or auxiliary liver transplantation may be considered in the setting of limited organ supply, but its use remains controversial • AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD

Future therapy

Future therapy

• • • • • • extracorporeal liver-assist devices: Nonbiologic dialysis-based systems for systemic detoxification Bioartificial devices that incorporate hepatic cells of porcine or human origin to replace both detoxification and synthetic functions.

A multicenter RCT showed no survival benefit.

Saliba F, et al. Ann Intern Med 2013;159:522-31

Future therapy

• • Liver Support Systems: Currently available liver support systems are not recommended outside of clinical trials; their future in the management of acute liver failure remains unclear

Future therapy

• • • • • Hepatocyte transplantation Intraportal & intraperitoneal infusion of isolated human hepatocytes Some success in neonates and children with inborn errors of metabolism Limited experience in pediatric acute liver failure Remains experimental.

• Hughes RD,et al Current status of hepatocyte transplantation. Transplantation 2012;93:342-7.

Summary

• • • • Management of ALF is real challenge for the treating team ALF should be treated in ICU Treatments for specific etiologies Consideration of transplantation should be under-taken urgently