Management of fulminant hepatic failure final

Management of fulminant hepatic failure

Dr. Mohd. ArifPediatric Resident

IOM

Index

1. Definition2. Problem Statement3. Pathophysiology4. History and Examination5. Complications6. Treatment7. Prognosis8. Keypoints

DEFINITIONHepatic Failure is characterized by

• Jaundice• Coagulopathy• Altered sensorium (hepatic encephalopathy)• Acute hepatic failure is dramatic clinical

syndrome in which previously healthy children rapidly lose hepatic function and become critically ill in few days

(Squires R, Shneider B, Bucuvalas J. J Pediatr 2006, 148: 652-8 )

DEFINITION

• Fulminant hepatic failure: Fulminant hepatic failure is a clinical syndrome resulting from massive necrosis of hepatocytes or from severe functional impairment of hepatocytes.

• Synthetic, excretory, and detoxifying functions of the liver are all severely impaired.

Nelson Textbook of Ped 19th Edn• Recent literatures recommend use of ‘’acute liver

failure’’

DEFINITIONThe currently accepted definition in children includes: • biochemical evidence of acute liver injury (usually <8 wk

duration); • no evidence of chronic liver disease; and • hepatic-based coagulopathy defined as

Prothrombin time (PT) >15 sec or International normalized ratio (INR) >1.5 not corrected by vitamin

K in the presence of clinical hepatic encephalopathy, or PT >20 sec or INR >2 regardless of the presence of clinical hepatic

encephalopathy.Nelson Textbook of paed 19th Edn

DEFINITION• Hyperacute liver failure- Onset of symptoms within 10 days of liver injury• Acute liver failure - coagulopathy due to acute liver

dysfunction > 10 days, but < 30 days . Encephalopathy absent or impossible to recognize, esp younger patients.

• Subacute liver failure - coagulopathy due to acute liver dysfunction > 31 days, but < 6 months. Jaundice almost always present, encephalopathy often marks preterminal deterioration. Eg. Wilson disease, autoimmune liver disease, postmedications.

• Chronic liver failure - Occurrence of signs of liver failure such as hepatic encephalopathy and/or ascites at least 6 months after the onset of hepatic illness.

(Tandon BN, Bernauau J, O’Grady J, et al: J Gastroenterol Hepatol 1999;14:403-404 )

Problem statement

• No reliable data published about incidence of acute liver failure

• 6% of death accounting for liver disease• Mortality rate of 85% without transplantation• One year survival rates between 60-80%• 2000 death per year due to ALF related to

hepatitis in USA( Hoofnagle Jh, Carithers RL, Jr., Shapiro C, Ascher N.Fulminant hepatic

failure ;summary of a workshop ,Hepatology 1995;21;240-252)

ALF in Nepal• Acute hepatitis is common in Nepal with peak

incidence in rainy season• Most common cause is hepatitis E virus (56%)• Hepatitis A, B & C accounts for only 3%(Shrestha SM, Shrestha S, Tsuda F. et al. Molecular investigation of hepatitis E virus infection in

patients with acute hepatitis in Kathmandu, Nepal. J Med Virol 2003;69:207-214.)

• Hepatitis A is least common infection in Nepal(Shrestha SM. Immune status of Nepali ,population against hepatitis A virus. J Inst Med 1986;283-

290)

• Hepatitis-B is decreasing due to vaccination• Hepatitis- C is confined to IV drug users

Pathogenesis

• Critical level of liver cell death not adequately decompensated by hepatocellular regenerative activity

• Death pathways1. Apoptosis- viral hepatitis, Wilson’s disease,

ischemic reperfusion injury2. Necrosis- Acitaminophen overdose

Apotosis

• TrigerI. ExtrinsicII. Intrinsic• Death ligands- TNF-α, Fas ligand, CD95, TGF-

β and TRAIL• Capsase 8 and 9• Beta 1 integrin

Necrosis

• Marked oxidative stress• Inhibition of proapototic capsase• Oteopontin (OPN)

ETIOLOGY • Viral agents- Hepatitis-A, B,C ,D & E Epstein-Barr virus Adenovirus Enterovirus Cytomegalovirus Parvovirus B19V Varicella-zoster infections herpes simplex virus

ETIOLOGY

Toxins associated with dose-related toxicity AcetaminophenAmanita phalloides

mushroom toxin Bacillus cereus toxin Cyanobacteria toxin Organic solvents (eg,

carbon tetrachloride) Yellow phosphorus

Drugs Idiosyncratic reaction

PhenytoinValproic acidINHSalicylates (Reye

syndrome) Halothane

ETIOLOGY

Illicit drugs Ecstasy (3,4-

methylenedioxymethamphetamine [MDMA])

Cocaine (may be the result of hepatic ischemia)

Herbal or alternative medicines Ginseng Pennyroyal oil Teucrium polium Chaparral or

germander tea Kawakawa

ETIOLOGY

Vascular causes Hepatic vein thrombosis (Budd-Chiari syndrome) Hepatic veno-occlusive disease Portal vein thrombosis Ischemic hepatitis

ETIOLOGY

Metabolic DiseaseWilson’s diseaseReye’s syndromeGalactosemiaAlpha-1 antitrypsin

deficiency Hereditary fructose

intolerance Mitochondrial electron

transport chain defects Hemochromatosis Tyrosinemia

ETIOLOGY

Autoimmune hepatitisMalignancyAn idiopathic form of fulminant hepatic failure

accounts for 40–50% of cases in children.

J Pediatr. 2006 May; 148(5): 652–658Acute Liver Failure in Children: The First 348 Patients in The Pediatric Acute Liver

Failure Study GroupRobert H. Squires, Jr et al.

Etiology and Prognosis of Acute Liver Failure in Children, Anil DhawanPaediatric Liver Centre, King’s College London School of Medicine, King’s College Hospital, London, United KingdomLiver Transplantation, Vol 14, No 10, Suppl 2 (October), 2008: pp S80-S84

METHODSo Retrospective analysis of cases admitted with a

diagnosis of acute liver failure between April 2003 to March 2010 in Liver Unit of Bir hospital and Norvic International hospital.

o Definition and classification of acute liver failure was followed as per Trey and Davidson (1970) and O'Grady et al. (1993).

o Patients admission chart with all relevant investigations were reviewed.

o Survival measured as final outcome.

Acute liver failure in tertiary care center in Nepal (Sudhamshu K.C., Dilip Sharma, Sandip Khadka, Anil K Mishra,Bir Hospital

RESULTSEtiology of ALF

Etiology Male (72) Female (20)

HEV 44 15 (10 pregnant)

HEV + PCM 1 0

HAV 11 2 (1 pregnant)

HBV 4 0

ATT 4 1

Wilson’s disease 1 0

Mushroom 1 1

Cryptogenic 6 1 (pregnant)

Male Female

Hyperacute 22 11

Acute 38 7

Sub acute 12 2

Types of failure at presentation

HISTORY

• H/O onset of jaundice• H/O decrease alertness or altered sensorium• H/O fever• Constitutional symptoms e.g vomiting• Similar illness in the family or community• H/O herbal medication in last one year• H/O i.v drug abuse• H/O Mushroom eating, Fireworks exposure or solvent

ingestion• H/O bleeding• H/O decreased urinary output

History contd..

• Past History- ATT intake Anticonvulsants intake• Developmental history- Failure to thrive Developmental delay Neuromuscular weakness• Family history- Consanguinity Early infant death Liver disease

PHYSICAL EXAMINATION

• General Physical examination – Level of consciousness Jaundice Spider navei Palmer erythema Caput medusae Asterixis Gynaecomastia ENT examination

• Vitals. BP P/R R/R with pattern Temperature

• Per abdominal examination- liver size Presence of ascites Liver tenderness Ascites• CNS examination- Detail CNS examination with level of

alertness Abducent palsy Reflexes

Investigations

• CBC• Prothombin time/INR• S.aminotransferase• S.billirubin• S.ammonia• S.Lactate• Arterial blood gas analysis• B.sugar

• S.creatinine• S. Phosphate• Blood C/S• S.ceruloplasmin level Viral studies:• HBV- serum IgM anti-HBcAg or HBsAg• HAV- serum anti-HAV IgM.• HCV -serum anti-HCV antibody or HCV RNA.• HDV - serum anti-HDV RNA

INVESTIGATION

Autoimmune markers: ANASoluble liver antigenAnti LKM antibodiesSerum IgG level

Acetaminophen level

Drug screen: IV drug abuser.

Imaging StudiesLiver ultrasound (Doppler) ,CT/MRI- abdomen, brain

INVESTIGATION

Liver biopsy: Helpful in autoimmune hepatitis, metastatic liver

disease, lymphoma, or herpes simplex hepatitis is suspected.

• Perivenular ( centrilobular ) necrosis– shock like states, drugs – acetaminophen, valproate,

reyes syndrome.

• Periportal ( peripheral ) necrosis – viral hepatits

COMMON COMPLICATIONS

Encephalopathy Cerebral edema- Less common in grade I &II, 25-35% in

grade III and 65-75% in grade IV Hemorrhage, DIC, Coagulopathy- platelets counts <

15000 (50-75%) Cardiac & circulatory instability Pulmonary failure Renal failure, Hepatorenal syndrome Hypoglycemia Acid-base/electrolytes derangements Sepsis

Stages of Hepatic Encephalopthy (Nelson text book 19th edn)

Stage I• Symptoms- periods of

lethargy, euphoria; reversal of day-night sleeping; may be alert

• Signs- trouble drawing figures, performing mental tasks

• EEG- normal

Stage II• Symptoms-drowsiness,

inappropriate behavior, agitation, wide mood swings, disorientation

• Signs- asterixis, fetor hepaticus, incontinence.

• EEG-generalized slowing, theta waves

Stages of Hepatic Encephalopthy (Nelson text book 18th edn)

Stage III• Symptoms- stupor but

arousable, confused, incoherent speech

• Signs- Asterixis, hyperreflexia, extensor reflexes, rigidity

• EEG - markedly abnormal, triphasic waves

Stage IV• Symptoms- coma

– IVa responds to noxious stimuli

– IV b no response

• Signs- no asterixis, areflexia, flacidity

• EEG - markedly abnormal b/l slowing, delta waves, electric-cortical silence.

Hepatorenal syndrome• Functional renal failure• Renal vasoconstriction• Systemic vasodilation• Oligouria (<1ml/kg)• Urinary sodium < 10 mEq/L• F E Na <1%• Urine:plasma creatinine ratio <10• Normal urinary sediment

Clinical and Biochemical Profile of Acute Liver Failure with Hepatic Encephalopathy in Children from Eastern NepalShah GS, Singh MK, Shah D: J. Nepal Paediatr. Soc, May-August, 2011/Vol 31/Issue 2

AASLD Position Paper: The Management ofAcute Liver Failure: Update 2011

1.General treatment

• Patients with ALF should be hospitalized and monitored frequently ,preferably in an ICU ( level-3)

• Contact with transplant centre for suitable candidate ( level -3)

• Precise etiology should guide the further management ( level -3)

2.Hemodynamics

• Fluid resuscitation with normal saline( level-3)• Maintenance fluid should be half normal

saline with dextrose (level-3)• If acidosis, 75mEq/lt of NaHCo3• Maintain MAP at 75mmHg or CPP at 60-80

mmHg (level-2)• Norepinephrine is the agent of choice• Vasopressin and analogue for refractory cases

but should be used cautiously in raised ICP ( level-2A)

3.Renal perfusion

• Adequate hemoperfusion• Avoid aminoglycosides and NSAIDs• Continuous mode of hemodialysis as compare

to intermittent mode (level-1)• Avoid i.v. contrast agents• NO role of NAC and prostoglandins• Dopamine can be a alternative

4.Metabolic concerns

• Careful monitoring of Metabolic homeostasis in all ALF patients

• Hypoglycemia• Hypokalemia• Hypomagnesemia• Hypophosphatemia

5.Feeding

• Start early enteral feeding early• Severe restriction of protein is avoided• 1gm/day, max upto 60gm/day of protein• Branch amino acid• Parenteral nutrition• Gastrointestinal bleeding

6. Prevention & management of raised ICP

• ?? Lactulose• Patients with Grade III and IV encephalopathy

should go intubation ( level-3)• Seizure should be control with phenytoin and

BZD .prophylactic phenytoin is not recommended( level- 3)

• Intracranial pressure monitoring or neurological examination on hourly basis ( level-3)

• For raised ICP mannitol bolus (1gm/kg). Prophylactic mannitol is not recommended ( level 2A)

• Patients having higher risk of edema ( serum ammonia > 150 µM, grade ¾ encephlalopathy, acute renal failure, on vasopressors) ,prophylactic induction of hypernatremia with HS to a level of 145-155 mEq/L. ( level-1)

• Short acting barbiturates and hypothermia of 34-35 degree C in refractory cases ( level-2C)

• Corticosteroids should not be used for edema ( level-1)

7.infection

• Bacterial infections (80%) and candidiasis (32%)• Staph., CONS, Steprtococi, E.coli & Pesudomonas• Antibiotics should be started in any sign of acute

infection , progression to high grade encephalopathy or elements of SIRS ( level-3)

• Prophylactic antibiotics fail to show any improvement in overall outcome and hence recommended ( level-3)

8.Cogulopathy

• NO correction of INR ,in the absence of bleeding• Plasma transfusion• Vitamin –K- • Plasmapheresis• rFVIIa • Platelets• Replacement therapy for thrombocytopenia

and/or prolonged PT ,only in setting of hemorrhage or invasive procedure.( level-3)

• Prophylaxis with H2 blockers or PPI (level-1)

Specific treatmentAcetaminophen poisoning• Toxicity level.• Activated charcoal – 1 gm/kg.useful with in 4

hr of ingestion. Do not hamper the action of NAC( level-1).

• Begin NAC promptly in all patients of acitaminophen ingestion ( level -2A)

• NAC in all cases where there is possibility of acetaminophen ingestion OR doubtful history OR aminotransferase level suggestive of acetaminophen ingestion

NAC dosages

• As early as possible• After 48 hours• N- acetylcysteine – 140 mg/kg PO loading ,then 70 mg/kg q 4 hr for a

total of 17 doses. – IV 150mg/kg infusion over 15 min, then 50mg/kg

IV over 4hrs, then 100mg/kg over 16 hrs or 6 mg/kg/hr

Role of NAC in non-acetaminnophen acute liver failure• AIMS: N-acetylcysteine (NAC), an antidote for acetaminophen poisoning,

might benefit patients with non-acetaminophen-related acute liver failure.• METHODS: In a prospective, double-blind trial, acute liver failure patients

without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.

• RESULTS: A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043).

• CONCLUSIONS: Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

(Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. Epub 2009 Jun 12.Intravenous N-acetylcysteine improves transplant-free survival in early stage non

acetaminophen acute liver failure. Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, Davern TJ 2nd, Murray NG, McCashland T, Reisch JS, Robuck PR; Acute Liver Failure Study Group.)

Amanita phalloids poisoning

• Urgent gastric lavage-oral charcoal.

• Benzyl penicillin (1,000,000units /kg/day ) with NAC (level-3)

• Silibinin, a water-soluble derivative of silymarin, may be administered orally.(30-40 mg/kg/day)

Specific treatment

Drug induced liver injury• In the setting of ALF due to drug injury, discontinue all but essential medications.(level-3)• NAC is beneficial in setting of ALF due to drug injury .( level-1)

Autoimmune Hepatitis

• Liver biopsy in suspected cases where autoantibodies are negative(level-3)

• Prednisolone 2mg/kg/d (decrease mortality rate in early phase of disease); given over a period of 3 -12 months in the setting of cogulopathy and mile encephalopathy( level-3)

• Azathioprine 1-2 mg/kg/d 1-2 yrs.• Tacrolimus , cyclosporine , MTX may be useful in poorly

responsive cases.

Specific treatment

Specific treatment

Viral hepatitis• Viral hepatitis A and E is treated with supportive

care( level-3)• Nucleoside analogue should be considered in

hepatitis –B ALF and prevention of recurrence in post transplant ( level-3)

• Herpes and CMV- acyclovir @5-10 mg/kg i.v. 8 hourly ( level-3)

Specific treatment

Metabolic disorders• Omiting offending metabolits (galactose, fructose)

diminish further insults.

• Iron chelation , anti- oxidant therapy in Neonatal hemachromatosis .

• Copper Chelation in Wilson’s disease with d-penicillamine, zinc.

Prognosis• Etiology-1. Idiosyncratic drug injury2. Acute hepatitis-B3. Autoimmune hepatitis4. Wilson disease5. Budd-chiari syndrome6. Indeterminate cause• Coma grade III or IV on admission

Criteria for liver transplantation in Acute liver Failure

(king’s college Hospital criteria for LTx in FHF):Acetaminophens patients pH < 7.3 ( irrespective of

grade of encephalopathy) Or All of the following present

at same time; PT > 100sec (INR > 6) , S.creatinine >3.4 mg/dl (300mmol/L) , Grade III or IV encephalopathy.

Non- Acetaminophens patients

pH < 7.3 ( irrespective of grade of encephalopathy)

Or Any 3 of the following

irrespective of grade of encephalopathy ;Age >10 ,jaundice to encephalopathy > 7days, etiology: Non A to E hepatitis, halothane. ideosyncratic drug rxn PT > 50sec (INR >3.5) S bilirubin >300mmol/L (> 17.5 mg/dl).

Liver Transplantation

Orthotopic liver transplantation (OLT)All children are potential candidates.May be life saving.One year survival rate is poor

Auxillary orthotopic liver transplantation (AOLT)

Technique where part of native liver is removed and replaced with either the respective left or right lobe of reduced graft.

• Living donar liver transplantation- 2 % cases Risk factors and ethical issues

Liver support system

• Artificial support- Molecular absorbent recirculation system

• Bioartificial support- HeaptAssist ELAD ( extra corporeal liver support device) MELS ( modular extra corporeal liver support) BLSS ( bioartificial liver support system) AMC ( Amsterdam medical center bioartificial liver)

Summary• Acitamenophen overdose in the main cause of ALF

in pediatric age group• Hepatitis causing ALF is showing downtrends• Continuous monitoring and prompt correction of

metabolic derangement is mainstay of treatment• Treatment for specific etiologies and consideration

for transplantation should be done in ALF with encephalopathy

Thank you