3. Introduction
• Acute liver failure is a rare clinical syndrome resulting from
massive necrosis of hepatocytes or from severe functional
impairment of hepatocytes.
• The synthetic, excretory, and detoxifying functions of the liver
are all severely impaired.
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5. Definition
• Biochemical evidence of acute liver injury (usually <8 wk
duration); no evidence of chronic liver disease; and
• Prothrombin time (PT) >15 sec or (INR) >1.5 not corrected by
vitamin K in the presence of clinical hepatic encephalopathy, or
• A PT >20 sec or INR >2 regardless of hepatic encephalopathy
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6. Definition
• Liver failure in the perinatal period can be associated with prenatal
liver injury and even cirrhosis.
• Examples include gestational alloimmune liver disease(GALD),
tyrosinemia, familial hemophagocytic lymphohistiocytosis (HLH),
and some cases of congenital viral (herpes simplex virus [HSV])
infection
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8. Definition
• Acute-on-chronic liver failure can occur when a patient with an
underlying liver disease such as biliary atresia develops hepatic
decompensation after viral or drug-induced hepatic injury
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10. Infection
• An unusually high rate of fulminant hepatic failure occurs in young
people who have combined infections with the hepatitis B virus (HBV)
and hepatitis D
• HBV is also responsible for some cases of fulminant liver failure in the
absence of serologic markers of HBV infection but with HBV DNA found
in the liver.
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11. Infection
• Patients with chronic hepatitis C are at risk if they have
superinfection with hepatitis A virus
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12. Non-viral infectious hepatitis
• Very rarely ALF is a rare complication of congenital syphilis &
Leptospirosis.
• In endemic areas, brucellosis and Coxiella burnetii (Qfever), Plasmodium
falciparum, and Entamoeba histolytica infections have presented as ALF.
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13. Autoimmune Hepatitis
• Approximately 5% of cases have a positive autoimmune marker
antinuclear antibody
anti–smooth muscle antibody
liver-kidney microsomal antibody, or soluble liver antigen) and
an elevated serum IgG level.
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14. Autoimmune Hepatitis
• If a biopsy can be performed, liver histology often demonstrates
interface hepatitis and a plasma cell infiltrate
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16. Neoplasm
• Acute liver failure can occur with malignancies including
leukemia, lymphoma, and familial HLH
• ALF is a common feature of HLH caused by several gene
defects, infections by mostly viruses of the herpes group.
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17. Gestational Alloimmune Liver Disease
• GALD is the most common cause of acute liver failure in the
neonate.
• In this alloimmune process, maternal immunoglobulin (Ig) G
antibodies bind to fetal liver antigens and activate the terminal
complement cascade resulting in hepatocyte injury and death.
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18. Gestational Alloimmune Liver Disease
• Infants with GALD present with low/normal aminotransferases
that are out of proportion to their degree of liver failure.
• They may have significant hypoglycemia, jaundice,
coagulopathy, and
hypoalbuminemia.
• Alpha fetoprotein levels are typically high as are serum ferritin
levels
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21. Vascular
• Ischemia and hypoxia resulting from hepatic vascular occlusion
• severe heart failure
• cyanotic congenital heart disease or
• circulatory shock
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22. Idiopathic Acute Liver Failure
• Accounts for 40–50% of acute hepatic failure cases in children.
• The disease occurs sporadically and usually without the risk factors
for common causes of viral hepatitis.
• It is likely that the etiology of these cases is heterogeneous, including
unidentified or variant viruses, excessive immune activation, and
undiagnosed genetic or metabolic disorders
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23. Pathology
• Liver biopsy usually reveals patchy or confluent massive necrosis
of
hepatocytes.
• There may be little or no regeneration of hepatocytes.
• A zonal pattern of necrosis may be observed with certain insults.
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24. Pathology
• Centrilobular damage is associated with acetaminophen
hepatotoxicity or with circulatory shock.
• Evidence of severe hepatocyte dysfunction rather than cell
necrosis is occasionally the predominant histologic finding.
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25. Pathogenesis
• The mechanisms that lead to acute hepatic failure are poorly
understood. It is unknown why only approximately 1–2% of
patients with viral hepatitis experience liver failure.
• Massive destruction of hepatocytes might represent both
a direct cytotoxic effect of the virus and an immune response to
the viral antigens.
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26. Pathogenesis
• Of patients with HBV-induced liver failure,(1/3-1/2) become
negative for serum hepatitis B surface antigen within a few days
of presentation and often have no detectable HBV antigen or
HBV DNA in serum
• These findings suggest a hyperimmune response to the virus that
underlies the massive liver necrosis.
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27. Pathogenesis
• Whatever the initial cause of hepatocyte injury, various factors can
contribute to the pathogenesis of liver failure
including impaired hepatocyte regeneration
altered parenchymal perfusion
endotoxemia and
decreased hepatic reticuloendothelial function
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29. Clinical Manifestations
• ALF can be the presenting feature of liver disease or it can
complicate previously known liver disease (acute-on-chronic
liver failure).
• A history of developmental delay and/or neuromuscular
dysfunction can indicate an underlying mitochondrial or β-
oxidation defect.
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30. Clinical Manifestations
• A child with ALF has usually been previously healthy and most
often has no risk factors for liver disease such as exposure to
toxins or blood products.
• Progressive jaundice, fetor hepaticus, fever, anorexia, vomiting,
and abdominal pain are common.
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31. Clinical Manifestations
• A rapid decrease in liver size without clinical improvement is an
ominous sign.
• A hemorrhagic diathesis and ascites can develop
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32. Clinical Manifestations
• Patients should be closely observed for hepatic encephalopathy,
which is initially characterized by minor disturbances of
consciousness or motor function.
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33. Clinical Manifestations
• Irritability, poor feeding, and a change in sleep rhythm may be
the only findings in infants
• Asterixis may be demonstrable in older children
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34. Clinical Manifestations
• Patients are often somnolent, confused, or combative on
arousal and can eventually become responsive only to painful
stimuli.
• Patients can rapidly progress to deeper stages of coma in which
extensor responses and decerebrate and decorticate posturing
appear.
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37. Hepatic encephalopathy
• The pathogenesis is likely related to
increased serum levels of ammonia
false neurotransmitters amines
increased γ-aminobutyric acid receptor activity, or
increased circulating levels of endogenous benzodiazepine-like
compounds.
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38. HE
• The mechanisms responsible for cerebral edema and intracranial
hypertension in acute liver failure (ALF) suggest both cytotoxic and
vasogenic injury.
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39. HE
• There is increasing evidence for an inflammatory response
(synthesis and release of inflammatory factors from activated
microglia and endothelial cells) which acts in synergy with
hyperammonemia to cause severe astrocyte swelling/brain
edema.
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43. Laboratory Findings
• Serum direct and indirect bilirubin levels and serum
aminotransferase activities may be markedly elevated.
• The blood ammonia concentration is usually increased, but
hepatic coma can occur in patients with a normal blood
ammonia level.
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44. Laboratory Findings
• PT and the INR are prolonged and often do not improve after
parenteral administration of vitamin K.
• Hypoglycemia can occur, particularly in infants.
• Hypokalemia, hyponatremia, metabolic acidosis or respiratory
alkalosis can also develop.
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45. Treatment
• Specific therapies for identifiable causes of acute liver failure
include
N -acetylcysteine (acetaminophen)
acyclovir (herpes simplex virus)
penicillin(Amanita mushrooms)
nucleos(t)ide analogs such as entecavir (hepatitis B
virus[HBV]), and
prednisone (autoimmune hepatitis)
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46. Treatment of GALD
• combination of double-volume exchange transfusion to remove
existing reactive antibody followed immediately by administration
of high-dose intravenous immunoglobulin (IVIG) (1 g/kg) to block
antibody induced complement activation.
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47. Treatment
• Management of other types of acute hepatic failure is
supportive.
• No therapy is known to reverse hepatocyte injury or to promote
hepatic regeneration.
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48. Treatment
• Endotracheal intubation may be required to prevent aspiration, to
reduce cerebral edema by hyperventilation, and to facilitate
pulmonary toilet.
• Mechanical ventilation and supplemental oxygen are often
necessary in advanced coma..
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49. Treatment
• Sedatives should be avoided unless needed in the intubated
patient because these agents can aggravate or precipitate
encephalopathy Opiates may be better tolerated than BDZ.
• Prophylactic use of proton pump inhibitors should be considered
because of the high risk of gastrointestinal bleeding.
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50. Treatment
• Hypovolemia should be avoided and treated with cautious
infusions of isotonic fluids and blood products.
• Renal dysfunction can result from dehydration, acute tubular
necrosis, or functional renal failure (hepatorenal syndrome).
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51. Treatment
• Electrolyte and glucose solutions should be administered IV to
maintain urine output, to correct or prevent hypoglycemia, and to
maintain normal serum potassium concentrations.
• Hyponatremia is common and should be avoided; it is usually
dilutional and not a result of sodium depletion
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52. Treatment
• Coagulopathy should be treated with IV vitamin K.
• Fresh-frozen plasma, cryoprecipitate, platelets, activated factor VII,
or prothrombin complex concentrates can be used to treat clinically
significant bleeding
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53. Treatment
• Patients should be monitored closely for infection, including sepsis,
pneumonia, peritonitis, and urinary tract infections.
• At least 50% of patients experience serious infection.
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54. Treatment
• Gram-positive organisms (Staphylococcus aureus,
Staphylococcus epidermidis) are the most common pathogens,
but Gram negative and fungal infections are also observed.
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55. Precipitant of encephalopathy
• Gastrointestinal hemorrhage
• infection
• constipation
• Sedatives
• electrolyte imbalance and hypovolemia should be identified and
corrected
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56. Precipitant of encephalopathy
• Protein intake should be initially restricted, Not >1g/kg/day or
eliminated, depending on the degree of encephalopathy.
• If encephalopathy or hyperammonemia develops, lactulose
(0.4-0.5 gm/kg/2hrs) or rifaximin can be administered.
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57. Precipitant of encephalopathy
• Cerebral edema is an extremely serious complication of hepatic
encephalopathy that responds poorly to measures such as
corticosteroid administration and osmotic diuresis
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58. Management of cerebral edema
• Maintain Spo2 > 95%
• Restrict Total daily fluid requirement to 85-90 %
• Decrease agitation
• Head elevation to 20-30 degree
• Administration broad spectrum antibiotics
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60. Liver transplantation
• Orthotopic liver transplantation can be lifesaving in patients who
reach advanced stages (III, IV) of hepatic coma.
• Reduced-size allografts and living donor transplantation have
been important advances in the treatment of infants with hepatic
failure.
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63. Liver transplantation
• Partial auxiliary orthotopic or heterotopic liver transplantation is
successful in a small number of children, and
• in some cases it has allowed regeneration of the native liver and
eventual withdrawal of immunosuppression.
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64. Prognosis
• Children with acute hepatic failure fare better than adults.
• Improved survival can be attributed to careful intensive care and
if necessary liver transplantation.
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65. Prognosis
• In the largest prospective PALFS 709 children were assessed at
21 days
50.3% of patients survived with supportive care alone
36.2% survived after liver transplantation, and
13.4% died.
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66. Prognosis
• A scoring system based on peak values of total serum
bilirubin, PT, and plasma ammonia concentration predicted
transplant-free survival. (Liver Injury Unit,LIU)
• Prognosis varies considerably with the cause of liver failure and
stage of hepatic encephalopathy.
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67. Prognosis
• Survival rates with supportive care may be as high as 90% in
acetaminophen overdose and with fulminant hepatitis A.
• Up to 40% of patients with liver failure caused by the idiopathic
(indeterminate) form of acute liver failure or an acute onset of
Wilson disease.
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68. Poor prognosis
• Mitochondrial deficits
• Hemophagocytic syndromes
• Herpes simplex disease
• Idiosyncratic drug reactions and
• Liver necrosis and multiorgan failure
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69. Poor prognosis
• Stage IV coma the prognosis is extremely poor.
• Brain stem herniation is the most common cause of death.
• Major complications such as sepsis, severe hemorrhage, or
renal failure increase the mortality.
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70. Increased mortality
• Age <1 yr.
• Stage 4 encephalopathy
• INR > 4
• PT >90 sec
• low factor V levels, and the need for dialysis before
transplantation
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71. Increased mortality
• A plasma ammonia concentration >200 µmol/L is associated with
a 5-fold increased risk of death.
• Children with acute hepatic failure are more likely to die while on
the waiting list compared to children with other liver transplant
requiring diagnoses.
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72. 6 mo post–liver transplantation survival
• 75% for acute liver failure
• 90% for chronic liver disease.
• Patients who recover from fulminant hepatic failure with only
supportive care do not usually develop cirrhosis or chronic liver
disease
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73. Recommendations
• The hospital laboratory should avail coagulation profile and serum
electrolyte ,total and direct bilirubin consistently
• Early identification and referral is of paramount importance
• The department shall have a Pediatric Gastroenterologist, as a place
of excellence
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74. REFERENCES
• Frederick j. suchy, amy g. feldman ,acute hepatic failure ,Nelsons textbook of
pediatrics 2019(391):p8432-8442
• UpToDate 2018
• Naresh P. Shanmugam and Anil Dhawan ,Acute Liver Failure in Children,
Textbook of Pediatric Gastroenterology, Hepatology and Nutrition A
Comprehensive Guide to Practice, Second Edition 2022(73):P995-1003
5/31/2022 74
17/100 000/yr in usa in all age groups the incidence in pediatric is unknown
*HAV < 0.8 % in developed and 80% in developing
*HBV in endemic area accounts for up to 20% of PALF
*HEV=INCIDENCE NOT KNOWN BUT in pregnant CFR=10-20%
*HSV=NEWBORNS AND INFANTS
*EBV=In areas where HBV & HAV are not endemic
death of hepatocytes at the interface of parenchyma and the connective tissue of the portal zone, accompanied by a variable degree of inflammation and fibrosis
Metabolic disorders presenting as ALF is common in young children. Galactosemia and tyrosinemia 1 are the most common cause of neonatal liver failure, presenting with hepatomegaly, jaundice, and coagulopathy. Classical galactosemia is an autosomal recessive condition resulting in the mutation in galactose-1-phosphate uridyl transferase gene located on chromosome 9p13. Liver failure in this condition is thought to be due to accumulation on galactitol. Neonates presenting with hepatitis or ALF should be started on a galactose-free formula until galactosemia. Galactose-free diet coupled with supportive management helps the liver to recover, but some may still progress and need a liver transplant
=is a malignant disorder of the hematopoietic system where there is uncontrolled proliferation of activated lymphocytes and macrophages
= fever, splenomegaly, cytopenias, high triglyceride levels, very high ferritin levels, low natural killer cell activity, high soluble CD25 levels;
they may also have hemophagocytosis on bone marrow or liver biopsy and a variety of other conditions including organ transplantation and malignancies
Pathophysiological alterations of liver physiology in CHD are often related to hemodynamic derangements, either resulting from backward failure of the subpulmonary ventricle (venous congestion), from forward failure of the systemic ventricle, or from hypoxemia in cyanotic CHD.
Multilobular or bridging necrosis can be associated with collapse of the reticulin framework of the liver.
Onset is not known unless its pcm overdose
A rapid decrease in liver size without clinical improvement is an ominous sign.
Patients are often somnolent, confused, or combative on arousal and can eventually become responsive only to painful stimuli.
Irritability, poor feeding, and a change in sleep rhythm may be the only findings in infants; asterixis may be demonstrable in older children.
Decreased hepatic clearance of these substances can produce marked central nervous system dysfunction.
SEPSIS
FLUID ,BLOOD AND BLOOD PRODUCTS ADMINSTRATION
Serum aminotransferase activities do not correlate well with the severity of the illness and can decrease as a patient deteriorates.
Sedation could be maintained with a combination of an opiate such as morphine or fentanyl and a hypnotic such as midazolam
Hypokalemia 2 to renal retention of NH3 in exchange for K, and urinary K loss
Decrease hepatic cellular K uptake espite insulin hypersecretion
=Parenteral supplementation with calcium, phosphorus, and magnesium may be required
Replacement of these blood products is only recommended prior to invasive procedures or in the setting of hemorrhage [9]. However, plasma infusion might not be adequate to correct severe coagulopathy and might risk volume overload. Use of recombinant factor VIIa (rFVIIa) has been found to be transiently effective in managing the coagulopathy and facilitates performance of invasive procedures and management of spontaneous hemorrhage without increasing the risk of volume overload [66]. This may be especially important in the setting of renal insufficiency. However, rFVIIa should be used cautiously mainly due to its high cost and reports of serious thromboembolic events associated with its administration
*Vitamin K deficiency is present in about 18–24% of adults with ALF and administration of IV vitamin K is recommended
* Data regarding SIRS or infection-related outcomes in PALF are currently lacking .
The guidelines regarding use of prophylactic antimicrobials or antifungals remain unclear [9, 17].
* There are several adult studies investigating the role of prophylactic antibiotics in ALF, but the results remain inconclusive
The idea of protein restriction to limit the possibility of HE has now been disregarded and adequate calories should be provided. A plant protein-based diet which has more of branched-chain amino acid (BCAA) is preferred over animal protein which has more of aromatic amino acid (AAA).
Goal serum Na 145-150 meq/l
Serum osm 300-320 mosm /lA
*rapid bolus of 0.5 g/kg as a 20% solution over a 15-min period is recommended, and the dose can be repeated if the serum osmolarity is less than 320 mOsm/L
In adults and PCM overdose
CR=3.3 Mg/dl
he Pediatric End-stage Liver Disease (PELD) score, incorporating albumin, bilirubin, INR, growth failure, and age (< 1 year), has been used as a predictor of mortality in children with chronic liver disease listed for transplantation, but it has not been extensively studied for use in PALF [76].
Another pediatric scoring system, pediatric Liver Injury Unit (LIU) score, may prove to be a helpful dynamic tool for prediction of outcomes in PALF. It uses peak values of total bilirubin and PT/INR during hospitalization to assess the risk of death or need of liver transplantation in PALF
PR transplantation serum bilirubin concentration or the height of hepatic enzymes is not predictive of post transplantation survival.
Long-term survivors demonstrate average IQ and visual spatial ability but greater than expected impairments in motor skills, attention, executive function, and health related quality of life.
