Acute Liver Failure

Acute Liver Failure - Vishal Baldua : 

Acute Liver Failure - Vishal Baldua Mumbai, India

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Definitions and Etiologies of ALF Clinical Features & Investigations Complications and their treatment Treatment of ALF – etiology specific and liver supports Prognosis and prognosticating factors

CASE SCENARIO: : 

CASE CASE SCENARIO: History : 6yr old boy , . Progressive jaundice -- 4 days Altered sensorium -- 1 day No fever, no medications. O/E – Drowsy , Icteric, Hepatomegaly, NG brown aspirates HGT- 36 ?? Diagnosis

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Immediate management: A , B, C Dextrose Further labs Vitamin K Watch for CNS, bleeding ,vitals

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Acute Liver Failure

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Definitions and Etiologies of ALF

Acute Liver Failure: 

Acute Liver Failure Pediatric Acute Liver Failure Study Group (PALFSG) consensus:ALF Biochemical evidence of liver injury No history of known chronic liver disease Coagulopathy not corrected by vitamin K administration INR greater than 1.5 if patient had encephalopathy or greater than 2.0 if patient does not have encephalopathy

Definitions- ALF: 

Definitions- ALF Classic definition: Fulminant hepatic failure : --hepatic encephalopathy within 8 weeks of jaundice Classification: Time interval from jaundice onset to development of encephalopathy Hyperacute LF - within 1 week Acute LF - within 2-4 weeks Subacute LF - between 5 - 28 weeks

Etiologies…: 

Etiologies… Infections Drug related Metabolic– IEM, Mitochondrial Ischemic Autoimmune Indeterminate

Why etiology is important ?: 

Why etiology is important ?

Infectious ALF : 

Infectious ALF Viruses Neonates & Infants--- HSV, Echovirus, Adenoviruses Hepatitis A , E Non-typable Viruses Malaria, Leptospirosis

Drug induced liver failure : 

Drug induced liver failure Idiosyncratic - due to polymorphisms of proteins Acetaminophen : Dose dependent Highly reactive metabolite NAPQI Anticonvulsants : severe rash and eosinophilia Stimulating autoantibody formation to liver microsomes

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Autoimmune Hepatitis : Steroids can be life saving Metabolic Causes : Lactic acidosis , ammonia, CSF lactate Systemic features , F2T Ischemic Hepatitis : Centrilobular necrosis Enzymes >5-10,000

Metabolic disorders : 

Metabolic disorders Wilsons Disease – Serum copper > 200 mics/dl Urinary copper > 200 mics /24 hours Renal insufficiency ? Ceruloplasmin Heriditary Tyrosenemia Mutation of hydrolase enzyme ALF with poor weight gain and renal tubular acidosis

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Clinical Features & Investigations

Clinical Features: 

Clinical Features Icterus Encephalopathic--- irritable  comatosed Bleeding manifestations Etiology Specific May present with features of Infections or MODS

Investigations :: 

Investigations :

Investigations: 

Investigations Baseline biochem and hemat ---including Coags Viral serologies Toxic screen and drug levels Metabolic workup – blood, urine, CSF USG abdomen with Doppler CT scan Biopsy

Further investigations:: 

Further investigations: ABG – Unremarkable , Lactate 2.1 SGPT > 1400 INR>3 Sr Ammonia 146 Negative viral panel , metabolic work-up --- Ferritin, TG , Urine- awaited USG – hepatomegaly with altered echotexture

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How do we treat this child ?

Specific treatments ? : 

Specific treatments ? Acetaminophen : NAC Activated charcoal Viral hepatitis – neonatal herpes Viral hep B -- risk of infection in the transplanted liver AIH—Methylprednisolone

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Wilsons :Albumin dialysis – Copper Penicillamine –risk of hypersensitivity Neonatal hemochromatosis – Selenium, Vitamin A,E , NAC, Deferroxamine

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No etiology yet in our patient ?

Slide 28: 

Journal of Hepatology, ALF Study group , 2007

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…NAC -- in all forms of ALF --- though survival benefit only for acetaminophen toxicity Current Opinion in Critical Care 2009, 15:163

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So NAC Infusion commenced 150mg/kg loading over 60 mins – f/b 50 mg /kg over next 4 hours f/b 100 mg/kg – till next 16 hours Therafter, ?? 150mg/kg/d – next 3-5 days

Over the next 24 hours: 

Over the next 24 hours Worsening Encephalopathy INR > 6 inspite of FFP Thrombocytopenia < 24000

Complications ……..: 

Complications …….. Neurological – hepatic encephalopathy and cerebral edema Coagulopathy

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Failure of detoxification . . Hepatic encephalopathy

Slide 34: 

High NH3 , HYPONATREMIA , CYTOKINES aquaporin 4 pores in BBB & Astrocytes NH3 stimulates Production of Glutamine I Swelling of astrocyte Via H2o influx I Nitric oxide CO Production Free radical production Cytotoxic edema + Brain Hyperemia

EEG Grading: HE: 

EEG Grading: HE Stage I : (1-6 Hz) with a reactive or inconsistently reactive EEG pattern. Stage II: Slow (3-4 Hz): absent EEG reactivity. Stage III: (1-3 Hz). Stage IV: (<1 Hz) pattern Stage V : Progressive disappearance of EEG activity.

Raised ICP ……………………: 

Raised ICP …………………… Risk factors : Grade 3-4 HE- --Loss of cerebral autoregulation subclinical seizures NH3 > 150-200 SIRS , Vasopressor usage , Renal failure , ↓Na , hyperglycemia

CNS symptoms : 

CNS symptoms Altered sensorium Convulsions s/o ↑ ICP D/D—Metabolic encephalopathies, ICH , post-ictal state, Key Investigations – Ammonia + Glucose levels CT scan

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Treatment for Neurological Manifestations

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ICP Bedside care – position, pain relief Avoid precipitating factors Intubation--- !! r/o herniation Sedation & Analgesia Acute ICP increases ICP catheter– debatable use

For Encephalopathy: 

For Encephalopathy Therapeutic hypothermia: 32-33 degrees Celsius brain metabolism & NCSE delivery of ammonia CVVH Seizure management-- Phenytoin

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Therapies without proven benefit ……….. Flumazenil To lower ammonia : Lactulose –– Neomycin – Rifamyxin--- LOS L ornithine l aspartate –detoxification of ammonia within the muscles Benzoate

Complications: 

Complications Neurological - Hepatic Encephalopathy & cerebra Edema Coagulopathy

Coagulopathy : : 

Coagulopathy : Worst coagulopathy --Hep B, Acetamoinophen overdose ,Wilsons and Budd Chiari M/C – gastric erosions +/- DIC DIC - if factor VIII levels & INR > 5 is not being corrected by FFP

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FFP—Not Prophylactically ! As infusion Factor VII-------- If PT elevated inspite of FFP Cryoprecipitate---- If Fibrinogen levels < 100 mg /dl ----If fluid overload Prophylaxis for GI bleed , Vitamin K Thrombopenia - DIC - Infection/SIRS/CVVHDF --Functional Maintain Hgb > 8

So …: 

So … Intubated CT- Edema, no bleed EEG—STAGE III- minimal reactivity FFP, Platelets

Over next 48 hours : 

Over next 48 hours INR- 5-6 with Cryoppt. & FFP Hypotension Decrease in U/O Hypoglycemia Sodium 130

Complications ___: 

Complications ___ Shock Renal Failure Infections Nutrition Metabolic

Shock : : 

Shock : Low systemic vascular resistance Norepinephrine preferred Vasopressin/Terlipressin avoided

Renal failure: 

Renal failure Prerenal ATN direct copper related tubultopathy in Wilsons , Hepatorenal syndrome Rx – vasopressin /terlipressin -?? CVVHDF - also removes Ammonia

Infectious Disease Concerns :: 

Infectious Disease Concerns : Commonly lungs , G U and blood Prophylactic antibiotics- - rapidly progressive encephalopathy, refractory hypotension or evidence of sepsis /SIRS Piptazo + Metronidazole Antifungals

Nutrition : 

Nutrition Hypoglycemia –refractory may herald imminent death May need 5-8mg/kg/min of GIR Avoid Hyperglycemia Protein intake of 0.5 – 1 g/kg/day Energy intake– 150%

Metabolic issues: : 

Metabolic issues: Hyponatremia – Renal failure , SIADH , Iatrogenic Hypernatremeia – Aldosterone , Iatrogenic Hypokalemia –Diuretics, Aldosterone Hypophosphatemia : urinary losses Metabolic acidosis : shock IEM

Further ….: 

Further …. Coagulopathy persisted ICP swings – poorly responsive to medical management EEG;;;;CONTI Repeat CT scan –s/o herniation Parents counselled about poor prognosis Eventually died

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Help around the corner ?

Liver support :: 

Liver support : Cell free artificial systems : Plasmapheresis CVVH Albumin or charcoal based dialysis MARS – ammonia--- same mortality --- copper in Wilsons disease Bioartificial systems – human or porcine hepatocytes ---risk of antibody formation Liver Transplant – Total or Auxillary

MARS: 

MARS

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Liver Transplant

Liver transplantation: 

Liver transplantation Indications : low grade encephalopathy seizures , ascites , Bili more than 23, fibrinogen less than 100mg/dl, ammonia more than 150 mmol/L

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Types: Living/Deceased Full Organ Auxillary orthotopic liver transplant better for PCM or viral related ESLD , hyperacute with no MODS

Post-op complications :: 

Post-op complications : Vascular thrombosis Extensibe bleeding Biliary sludging IAH, Sepsis , renal failure

Contraindications to transplantation include:: 

Contraindications to transplantation include: : uncontrolled systemic sepsis, irreversible neurologic injury. refractory hypotension

Predictors of poor outcomes :: 

Predictors of poor outcomes : Kings college criteria --- INR, Creat Etiology-wise INR > 5 SGPT > 2400 IU/L Encephalopathy >7 d after onset ofsymptoms

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