ACUTE LIVER FAILURE 2. by Dr Ruchi Rajashree Panda , resident

Acute livrer failure presentation

1. Presenter: Dr.Saranya (2 nd YR PG) Moderator: Dr . A.Vasundhara mam ( Professor and HOD ) ACUTE LIVER FAILURE(ALF)/ FULMINANT HEPATIC FAILURE(FHF)

2. CONTENTS 1)CRITERIA 2)ETIOLOGY 3 )PATHOGENESIS 4 )PATHOLOGY 5 )CLINICAL FEATURES

3. CRITERIA FOR ALF/FHF The Pediatric Acute Liver Failure (PALF) study group suggests the following entry criteria to define ALF in children. Children with no known evidence of chronic liver disease, B iochemical evidence of acute liver injury, and H epatic-based coagulopathy defined as PT (Prothrombin Time ) 15 seconds or international normalized ratio (INR) 1.5 not corrected by vitamin K in the presence of clinical HE or a PT 20 seconds or INR 2.0 regardless of the presence or absence of clinical HE .

4. ETIOLOGY OF ALF I nfective Infiltrative Autoimmune Drugs and toxins Metabolic Vascular

5. INFECTIVE-MOST COMMON CAUSE 1)VIRAL Viral hepatitis A, B, B + D,C, E Non-A–E hepatitis (seronegative hepatitis) NON HEPATOTROPIC VIRUS : Adenovirus, Epstein-Barr virus, Herpes simplex, Cytomegalovirus , Echovirus ,Varicella, Measles ,Yellow fever Rarely, Lassa, Ebola, Marburg virus, Dengue , Toga virus

6. 2)BACTERIAL: Gram negative infections such as Salmonellosis, Shigella , Pseudomonas, E.Coli septicemia. Others such as Tuberculosis,Brucellosis , Q fever , Leptospirosis, Meningococcemia, Congenital syphilis.

7. Hepatic dysfunction in sepsis is the result of decreased hepatic perfusion, hypoxia, and lactic acidosis. Bacterial cell wall products (endotoxin and lipoteichoic acid) and cytokines (tumor necrosis factor, interleukin-1, and interferons) induce the production of nitric oxide. The elevated levels of inducible nitric oxide are toxic to liver cells.

8. 3)PROTOZOA: Malaria Bartonella

9. DRUGS Acetaminophen –Most coomon drug implicated in ALF ( Centrilobular necrosis) Halothane Isoniazid Nonsteroidal anti-inflammatory drugs Phenytoin , Sodium valproate , Carbamazepine Ecstasy (3 METOXY 3 METHAMPHETAMINE)

10. MECHANISM OF PCM INDUCED FHF

11. DRUGS Troglitazone Antibiotics (Penicillin , Erythromycin , T etracyclines , Sulfonamides , Quinolones ) Allopurinol , Propylthiouracil Amiodarone Ketoconazole Antiretroviral drugs

12. The most common liver injury pattern owing to drugs is hepatitic (hepatocellular necrosis), accounting for about 90% of cases. Others could be cholestatic (biliary damage), mixed (both hepatitic and cholestatic ), or steatosis

13. TOXINS Amanita phalloides (mushroom poisoning) . Herbal medicines Carbon tetrachloride Yellow phosphorus Industrial solvents Chlorobenzenes

14. METABOLIC Galactosemia Tyrosinemia Hereditary fructose intolerance Fatty acid oxidation defects Niemann –Pick disease type C Wilson disease Congenital disorders of glycosylation Acute fatty liver of pregnancy

15. MITOCHONDRIAL DISORDERS Pearson syndrome (Mitochondrial DNA deletion) Alpers disease (Mitochondrial DNA mutation) Symptoms include dementia, increased muscle tone, seizures, exaggerated reflexes.

16. AUTOIMMUNE Type 1 autoimmune hepatitis ( antinuclear/smooth muscle antibody positive ) Type 2 autoimmune hepatitis ( LKM Ab positive.) Neonatal Hemochromatosis (NH)

17. VASCULAR / ISCHEMIC Budd–Chiari syndrome Acute circulatory failure Heat stroke Acute cardiac failure Cardiomyopathies

18. INFILTRATIVE Leukemia Lymphoma HLH( Hemophagocytic Lympho Histicytosis )

19. CAUSES OF NEONATAL ALF Perinatal HSV infection Neonatal hemochromatosis Galactosemia Tyrosinemia HLH Septicemia Mitochondrial cytopathies Congenital disorders of glycosylation Birth asphyxia

20. PATHOGENESIS OF FHF Factors that are involved in FHF: Injury to the hepatocyte plasma membrane Organelle dysfunction Disturbances of hepatic circulation Regenerative capacity of liver.

21. INJURY TO THE HEPATOCYTE PLASMA MEMBRANE The plasma membrane maybe damaged by the immune mediated attacks of virus and drugs This causes loss of electrolytes, enzymes , co-enzymes from the cells, and entry of calcium into the cells, causing cell death. The loss of hepatocyte mass is an important cause of FHF.

22. ORGANELLE DYSFUNCTION It is the major lesion responsible for the FHF in metabolic diseases like W ilson’s disease, Galactosemia etc. The other examples are: 1)Drugs maybe activated to toxic metabolites by the microsomal enzyme system and these damage the vital macromolecules of the cells. Similarly, free radicals may be produced that damage cellular lipids and proteins. 2)The toxins of amanita phalloides mushroom may injure the endoplasmic reticulum, causing FHF.

23. DISTURBANCES OF HEPATIC CIRCULATION The hepatic circulation is compromised in FHF by two factors : a)Porto systemic shunting b)Impaired sinusoidal microcirculation . These factors deprive the hepatocytes of adequate nutrients so that they are not able to remove circulating toxins contributing to FHF.

24. REGENERATIVE CAPACITY OF LIVER If regeneration is less than degeneration, FHF results and this is due to the following factors: If the injurious process is prolonged, hepatocellular regeneration is affected. The aetiologic factor is also important: regeneration is more in FHF due to hepatitis A virus, than that due to B or C virus. Role of hepatotropic factors: Insulin, glucagon and epidermal growth factor may help in the regeneration of hepatocytes. Hence their deficiency will aggravate degeneration.

25. PATHOLOGY Jones classification of FHF Type lesion 1 Type lesion 2 Type lesion 3

26. Type 1 lesion This is the most common lesion in FHF and is characterized by necrosis and loss of hepatocytes. This is seen in: a)Viral hepatitis b)Toxic hepatitis ( aflatoxin,Amantia phalloides ) c) Ischaemic hepatitis d)Metabolic hepatitis (Wilson’s disease,neonatal haemochromatosis).

27. Serum bilirubin varies from 10-60mg%. The damaged hepatocytes can take up and conjugate bilirubin initially, but cannot excrete it into the bile, as it is an energy-dependent process, thereby resulting in conjugated hyperbilirubinaemia . However, as the damage increases , the uptake of bilirubin is also affected, resulting in increase of unconjugated bilirubin also.

28. TYPE 2 LESION This is characterized by the presence of microvesicular fatty infiltration . The burnt of the damage is on the mitochondria and hepato -cellular necrosis is insignificant. Hence, jaundice is minimal and the transaminases are only slightly elevated. If the patient survives, the histologic recovery is complete . The picture is seen in: a)Reye syndrome b)Valproate toxicity c)Acute fatty liver of pregnancy

29. TYPE 3 LESION This is characterized by swelling of hepatocytes and condensation of organelles and cytoplasmic elements. Serum bilirubin and transaminases are moderately elevated, the levels being between those of type 1 and type 2 lesions. T his picture is seen in: a)Hereditary Fructose I ntolerance b)Type 1 T yrosinaemia .

30. CLINICAL FEATURES OF FHF The typical patient is a previously healthy , school aged child, with absolutely no major medical problems. The initial symptoms mimic an ordinary viral hepatitis with fever, nausea, anorexia and vomiting, jaundice. The child is given the usual treatment for hepatitis.

31. However, the child does not seem to improve and develops progressive lethargy and occasionally hallucination. He will be desperately sick, with deep jaundice and fetor hepaticus . The liver span may be markedly decreased and there may be bleeding from puncture sites, nose or the GI tract. Lastly child may develop encephalopathy.

32. STAGES OF HEPATIC ENEPHALOPATHY

33. INFECTIVE Patients usually present with icterus and markedly raised serum transaminase levels. In patients who spontaneously recover, serum bilirubin, INR, and serum transaminases gradually decline, whereas a continued rise in bilirubin levels and INR; despite declining serum transaminase levels;, indicates massive hepatocyte necrosis and a poor prognosis.

34. VIRUS RISK OF ALF HAV 0.1-0.4% HBV 1-4% HEV 0.6-2.8%

35. Herpes simplex virus (HSV) , should be suspected in any neonate with or without vesicular rash who is unwell with dramatically high transaminases and coagulopathy . cytomegalovirus , Epstein–Barr virus, and varicella-zoster virus, and members of the herpes virus family can cause severe hepatic necrosis, particularly in immunocompromised patients and neonates . Echovirus (type 20) and Coxsackie viruses have been reported to cause ALF, especially in neonates.

36. METABOLIC

37. METABOLIC Galactosemia and T yrosinemia 1 are the most common cause of neonatal liver failure. Galactosemia ,it is an AR disorder usually associated with hypoglycemia and gram negative septicemia . Tyrosinemia presents with severe coagulopathy, mild jaundice, hepatomegay and rickets. Hereditary fructose intolerance is rare, but a history of administration of fructose, as in fruits, sugar, or honey, may coincide with clinical symptoms.

38. WILSONS DISEASE Wilson’s disease, an autosomal recessive disorder, may present as ALF in an older child. The acute hepatic presentation is characterized by the presence of liver failure, Coombs-negative hemolytic anemia, and low alkaline phosphatase. Demonstration of Kayser –Fleischer rings is diagnostic of Wilson’s disease in a patient who presents with ALF. Serum C eruloplasmin is usually LOW, and serum-free copper concentration can be increased or normal.

39. MITOCHONDRIAL Presenting symptoms could be hypotonia , feeding difficulties , seizures , hypoglycemia, vomiting , coagulopathy, acidosis, and increased lactate , deranged LFTs. The presence of high serum lactate in the mother and a history of sibling deaths are suggestive of this condition. Diagnosis involves quantitative assessment of the respiratory chain enzyme complexes in the affected tissues

40. MUSHROOM POISONING The usual presentation is severe diarrhea with or without vomiting, commencing about five or more hours after ingestion .

41. NH / GALD Neonatal hemochromatosis (NH) is the single most common cause of ALF during first month of life , where there is massive iron deposition in liver and extrahepatic tissues, but with sparing of the reticuloendothelial system . NH is now referred as gestational allo immune liver disease (GALD), as maternal antibody is directed towards fetal liver antigen resulting in activation of fetal complement leading to the formation of membrane attack complex (MAC) resulting in hepatocyte loss .

42. This hypothesis is supported by successful prevention of severe disease by antenatal and postnatal treatment with intravenous Ig. GALD presents with jaundice, coagulopathy, moderately elevated alanine aminotransferase, high ferritin, and raised iron saturation levels. High ferritin is seen in other cause of neonatal liver failure and no single biochemical test is diagnostic of NH.

43. HLH Hemophagocytic lymphohistiocytosis (HLH) is a malignant disorder of hemopoietic system where there is uncontrolled proliferation of activated lymphocytes and macrophages and could present as ALF, particularly during infancy. HLH could be inherited or acquired following infection due to over activation of natural killer cells and of CD8+ T cell lymphocytes, invariably leading to clinical and hematologic alterations. It is associated with defective apoptosis and reduced cytotoxic activity .

44. It is of 2 types familial (primary) HLH and secondary HLH. Familial HLH is an autosomal recessive disease seen mostly in infancy and early childhood . Familial HLH occurs due to mutations in P erforin gene. Secondary HLH usually occurs after systemic infection or immunodeficiency, which can affect people at any age and may subside spontaneously.

45. HLH presents with fever, cutaneous rash, hepatosplenomegaly , pancytopenia,bleeding from vene puncture sites due to coagulopathy and, in severe cases, with ALF . Usual associated features are high alkaline phosphatase , high lactate dehydrogenase, and abnormalities on peripheral blood film.

46. DIAGNOSTIC CRITERIA FOR HLH

47. REFERENCES 1.A RIYAZ.TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY AND HEPATOLOGY:FULMINANT HEPATIC FAILURE .3 RD EDITION PG NO 451-458. 2.NELSON.TEXTBOOK OF PEDIATRICS:ACUTE HEPATIC FAILURE.21 EDITION.VOLUME 2 .PG NO 2133-2150. 3.KLEINMAN ET AL.WALKERS PEDIATRIC GASTROINTESTINAL DISEASE.ACUTE LIVER FAILURE(CHAPTER 37).6 TH EDITION . VOLUME 2. PG NO 4342-4354 4.STEPHANO GUANDALINI ET AL. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY,HEPATOLOGY AND NUTRITION.ACUTE LIVER FAILURE IN CHILDREN (CHAPTER 70).VOLUME 2.PG NO 831-842 . 5.HELI BHATT ET AL.,MANAGEMENT OF ACUTE LIVER FAILURE: A PEDIATRIC PERSPECTIVE,CURRENT PEDIATRICS REPORTS (2018)6:246-257