Acute ,,,,,,,,,,,,,,MMMMMMMLiver Failure.pptx

GFGHGJ

1. ACUTE LIVER FAILURE Presenter: Dr. Awatif Bashir M.D (R1) Moderator: Dr. Mamaru M.D (Internist Consultant)

2. OUTLINE 1 Introduction & Epidemiology 2 3 4 Etiology, Pathogenesis, & Classification Presentation & Diagnosis Management, Complications, & Prognosis

3. Introduction & Epidemiology

4. INTRODUCTION Definition: ALF is a clinical entity diagnosed by Acute Live Injury (Abnormal LFTs) manifested by presence of Hepatic Encephalopathy and Coagulopathy (INR >1.5) in persons with no pre-existing liver disease or cirrhosis with the duration of illness not exceeding <26 weeks To Break down the definition, To diagnose ALF you must have: Abnormal LFTs, Hepatic Encephalopathy, and Coagulopathy No prior liver disease or cirrhosis Illness duration <26 week The exception to this is in patients with: Wilsons Disease Hepatitis B Re-activation Autoimmune Hepatitis In these conditions ALF can be considered despite the possibility of Cirrhosis development if their disease has been recognized <26 weeks.

5. INTRODUCTION Acute Liver failure is a rare life- threatening, severe disruption of Liver Function that may lead to severe complications and mostly carries a poor prognosis It was formerly known as many other names including: Fulminant Hepatitis Fulminant Hepatic Failure Hepatic Necrosis The term Acute Liver Failure gives a better description of the disease process and it broadly includes the above mentioned entities

6. EPIDEMIOLOGY Globally speaking, ALF is a rare disease with low incidence worldwide In the US and Most Developed countries, the incidence of Alf is around 2000 cases annually or <10 cases per million. among these cases, the majority is caused by Acetaminophen Toxicity accounting for >42% of cases In developing countries although statistics aren’t as thorough, the incidence remains low. However, in these countries the leading cause is Intra-Hepatic rather then drug toxicities Hepatitis E virus is associated with higher incidence in pregnant women

7. Etiology Pathogenesis & Classification

8. PATHOPHYSIOLOGY The hallmark and major pathologic process in ALF is the development of Cerebral Edema which is a major morbidity and mortality cause The pathogenesis however isn’t fully understood and is thought to be multifactorial including: Hyperammoniemia leading to Cytotoxic Edema Vasogenic Edema Multisystem Organ Failure Acetaminophen Hepatotoxicity Other associated factors include: Elevated levels of cytokines TNF alpha, IL-1, IL-6 and many others.

9. PATHOPHYSIOLOGY Cytotoxic Edema This is due to impaired cellular osmoregulation in the brain leading to astrocyte edema which is the result of excess ammonia (Hyperammoniemia) Ammonia is detoxified to Glutamine by Glutamine Synthesate . Glutamine is then taking by astrocyte and works as osmotic agent causing water shift to astrocytes. In normal conditions there is a balance in the brain glutamine content and thus no damage occurs. However, in Hyperammoniemia cases, excess conversion to glutamine and subsequent excess uptake of glutamine by astrocytes results in their swelling leading to Brain Edema.

10. PATHOPHYSIOLOGY 2. Vasogenic Edema This is caused by impaired or disrupted cerebral blood flow autoregulation leading to significant increase in cerebral blood flow leading to increased intracranial blood volume as well as intracranial pressure. This is thought to be mediated by the actions of elevated serum nitric oxide concentrations which acts as a potent vasodilator.

11. PATHOPHYSIOLOGY 3. Multisystem Organ Failure This is a cause of complications more then it being a cause of ALF to develop. It’s mostly observed in Hyperdynamic Circulatory State that leads to circulatory insufficiency (low systemic vascular resistance) leading to poor organ perfusion. This causes failure of multiple organs but also affects the liver causing hypoperfusion and further increasing the damage to the failing liver.

12. PATHOPHYSIOLOGY 4. Acetaminophen Hepatotoxicity Acetaminophen in it self isn’t a harmful substance, however it undergoes it’s metabolism in the liver into a highly reactive, hepatotoxic metabolite called N-Acetyl-P-Benzoquinone-imine (NAPQI) which binds with cellular proteins This metabolite is further metabolized by Glutathione into a NAPAM which is excreted and doesn’t react with cellular protein thus not causing any damage. This regular mechanism fails in two scenarios which end up causing toxicity and liver Injury

13. PATHOPHYSIOLOGY 4. Acetaminophen Hepatotoxicity Drug Overdose Accidental or Intentional taking of doses >10g in a day causes toxicity by exhausting the liver Glutathione stores thus allowing large amounts of active toxic metabolites to escape metabolism Alcoholics In people who regularly consume alcohol (even in mild amounts) it causes depletion of glutathione stores in the liver and puts these people at risk of life-threatening hepatotoxicity at lower and sometimes normal doses (Maximum total daily dose 4g\d)

14. CLASSIFICATIONS There are multiple Classification systems for ALF based on onset and duration of symptoms, mostly between onset of jaundice and HE

15. ETIOLOGY

16. ETIOLOGY Numerous different etiologies leads to ALF, and they can be grouped as Vascular Causes Budd-Chiari Syndrome Hepatic Veno -Occlusive Disease Portal Vein Thrombosis Ischemia (Shock Liver) Sepsis Hypovolemic Shock Obstructive Shock Cardiogenic Shock Cardiac Arrest Toxin Related Causes Amanita Phalloides Mushroom Toxin Bacillus Cereus Toxin Organic Solvents Cyanobacteria Toxin Infiltrative Causes Wilsons Disease HLH ( Hemophagocytic Lymphohistiocytosis ) Malignancy Pregnancy Induced Causes Acute Fatty Liver HELLP Syndrome

17. ETIOLOGY Numerous different etiologies leads to ALF, and they can be grouped as Metabolic Causes Alpha-1-Antitrypsin Deficiency Fructose Intolerance Reye Syndrome Tyrosinemia Malignancy Induced Causes Hepatocellular Carcinoma Secondary Tumors with extensive Hepatic Metastasis Infectious Causes Viral Hep A,B,D,E HSV VZV CMV EBV Drug Induced Causes Acetaminophen Abx (Augmentin, Cipro, doxy, ATT, tetracycline, etc Antidepressants Antiepileptic NSAIDS Salicylates

18. Presentation & Diagnosis

19. CLINICAL PRESENTATION History: In patient’s with ALF, majority of the initial symptoms are non-specific and may Include: Fatigue Malaise Jaundice Lethargy Anorexia Nausea and\or vomiting RUQ pain Pruritus Abdominal Distension Symptoms progress and patients who were non-jaundiced may develop jaundice, or patients with slight mental status impairment may progress to comatose state

20. CLINICAL PRESENTATION The most important step in patients with acute liver failure is to identify the cause. Prognosis in acute liver failure is dependent on the etiology. Acute liver failure from certain causes demands immediate and specific treatment. It is also critical to identify those patients who will be candidates for liver transplantation.  

21. CLINICAL PRESENTATION History: The following points are important to ask at presentation: Onset of Jaundice and Encephalopathy Hx of Alcohol or Substance abuse Medication use Family Hx of liver disease (Wilsons disease) Exposure to hepatotoxic substances (Mushrooms, Organic Solvents, etc) Hx of or risk factors for Viral hepatitis (Travel, transfusions, sexual hx , etc) Evidence of Complications on presentation (Seizures, Renal Failure, Bleeding, Infection

22. CLINICAL PRESENTATION Physical Examination: Patients should be examined for the following: Jaundice is a common finding but may be absent early in the course of acetaminophen poisoning or herpes simplex virus (HSV) infection Kayser -Fleisher rings (Wilsons Disease) Vesicular skin lesions suggestive of HSV (present in 30 to 50 percent of patients with acute liver failure due to HSV) Mental Status and Grading of Hepatic Encephalopathy Stigmata of Chronic Liver Disease (usually Absent) RUQ Tenderness Hepatomegaly Rapid Accumulation of Ascites + Abdominal pain (Budd Chiari Syndrome) Elevated ICP signs

23. CLINICAL PRESENTATION Hepatic Encephalopathy Presence of HE is a defining factor in ALF, however the patient’s mental status and grade of HE must be determined as they play an important role in management and determining patient prognosis Cerebral Edema may develop in ALF patients leading to increased ICP. It is uncommon with HE Grades I and II, but is present in 25-35 % of patients with Grade III HE and >75% patients with Grade IV HE Other accompanying signs include: systemic hypertension, bradycardia, respiratory depression (Cushing's triad), seizures, and abnormal brainstem reflexes (eg, oculocephalic reflex, corneal reflex, jaw reflex, cough response to tracheobronchial suctioning)

24. DIAGNOSIS The typically seen laboratory Abnormalities in ALF Include: Prolonged Prothrombin Time – resulting in INR>1.5 Despite this some patients maybe in Hemostasis without any Hypercoagulability while others may present with severe symptoms Elevated Aminotransferase Levels (Marked Elevation) These aren’t reliable as they decrease during the course of disease which may indicate either spontaneous recovery or worsening liver failure with loss of Hepatocytes. Elevated Bilirubin Levels Low Platelets counts <150,000\ microL

25. DIAGNOSIS Other Laboratory Findings Include: Elevated serum Creatinine and BUN Coomb’s Negative Hemolytic Anemia Hypoglycemia due to impaired glycogen production and gluconeogenesis Hypomagnesemia Acidosis or Alkalosis Elevated Ammonia Levels Elevated LDH Levels Autoimmune Markers (ANA, ASMA, Immunoglobulins)

26. DIAGNOSIS Disease Specific Laboratory Findings: Acetaminophen Toxicity: associated with very high aminotransferase levels >3,500 IU\L , low Bilirubin, and high INR + high acetaminophen-protein adducts levels in serum Ischemic Liver Injury: Aminotransferase levels 25 to 250 times the upper normal limit, and elevated serum LDH Hepatitis B: Aminotransferase up to 1000-2000, ALT higher then AST, and Reactive Viral Markers

27. DIAGNOSIS Disease Specific Laboratory Findings: 4. Wilson Disease: Coombs Negative hemolytic anemia, Aminotransferase <2000, AST to ALT ratio >2, Alk Phos to Bilirubin ratio <4, low uric acid levels, rapidly progressive renal failure 5. Acute Fatty Liver of Pregnancy\HELLP Syndrome: Aminotransferase <1000, elevated bilirubin, low platelets, and\or hemolysis

28. DIAGNOSIS Disease Specific Laboratory Findings: 6. Viral Serologies : Hepatitis A virus immunoglobulin M (IgM), hepatitis B surface antigen ( HBsAg ), and hepatitis B virus anticore IgM serologies help identify acute infection with HAV or HBV. Hepatitis C virus (HCV) antibody test results may remain negative for several weeks or months. Acute HCV infection as a cause of fulminant hepatic failure appears to be exceedingly uncommon. If the HBsAg assay is positive, consider testing for hepatitis D virus (HDV) IgM. This test is particularly advisable if the patient is a known intravenous (IV) drug abuser.

29. DIAGNOSIS Disease Specific Laboratory Findings: 7. Blood Cultures: Most patients with acute liver failure develop infection during or before hospitalization. Patients are at risk of catheter sepsis and complications from all other invasive procedures. Fungal infections are common, most likely as a result of decreased host resistance and antibiotic treatment. Infection may be associated with bacteremia. Early identification and treatment of bacteremia is important because the mortality from fulminant hepatic failure increases significantly with the development of this serious complication.

30. DIAGNOSIS IMAGING ULTRASONOGRAPHY A Doppler ultrasonography scan of the liver establishes the presence of ascites and may determine the patency and flow in the hepatic veins (allowing exclusion of Budd-Chiari syndrome), hepatic artery, and the portal vein. Liver ultrasonography may not be necessary if an obvious explanation exists for the hepatic failure. However, it may assist the clinician in excluding the presence of a hepatocellular carcinoma or intrahepatic metastases

31. DIAGNOSIS IMAGING CT SCAN OF HEAD AND ABDOMEN Computed tomography (CT) scanning of the abdomen may be required for further definition of hepatic anatomy and to help the clinician exclude other intra-abdominal processes, particularly if the patient has developed massive ascites, if the patient is obese, or if transplantation is being planned. CT scanning of the head may help identify cerebral edema, although CT scans do not reliably demonstrate evidence of edema, especially at early stages. Head imaging with CT scanning is also used to exclude other causes of decline in the mental status, such as intracranial mass lesions (especially hematomas) that may mimic edema from fulminant hepatic failure.

32. DIAGNOSIS LIVER BIOPSY A  percutaneous liver biopsy  is contraindicated in the setting of coagulopathy. However, a transjugular biopsy is helpful for diagnosis if autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex hepatitis is suspected. Liver biopsy findings may be nonspecific, but in general, the findings depend on the underlying etiology of the acute liver failure. Liver biopsy specimens in patients with idiosyncratic medicati on-induced hepatitis leading to fulminant hepatic failure generally shows panlobular necrosis. In patients with acetaminophen-induced fulminant hepatic failure, centrilobular necrosis is typical but panlobular injury may also be observed. Viral hepatitis typically produces a panlobular injury and maybe difficult to distinguish from medication-induced hepatitis.

33. Management

34. MANAGEMENT Treatment Components: General Supportive Measures Etiology specific treatments Management of Complications Liver Transplantation All patients are to be admitted to the ICU and Prepared for transfer to a transplant center

35. MANAGEMENT General Measures + Complications : Airway Protection: to provide oxygenation and prevent aspiration in patients as most have altered mentation. Intubation is required for Comatose patients. (Propofol maybe useful in cases of increased intracranial blood flow and pressure) Hemodynamic Stability: Hypotension with SBP<80mmHg occurs in >15% of patients. Dehydration, renal injury, sepsis, cirrhosis, or hepato -renal syndrome can cause further hemodynamic compromise, and patients require fluid resuscitation Some patients may require pressers to keep MAP>75mmHg

36. MANAGEMENT General Measures + Complications : 3. Coagulopathy and Bleeding Risk: patients with ALF develop coagulopathy with mostly no bleeding therefore, unless patient is undergoing invasive procedure, it is not recommended to treat the coagulopathy of ALF. However, since most common bleeding site is from GI Tract, Stress Ulcer prophylaxis with PPIs or H2 blockers are indicated 4. Nutrition: This is a vital component in the treatment of ALF and should be initiated early. It is required to prevent catabolism of body stores of proteins and it may decrease the risk of gastrointestinal bleeding from stress ulceration in critically ill patients a daily intake of 60 grams of protein is reasonable for most patients with acute liver failure .

37. MANAGEMENT General Measures + Complications : 3. Acetaminophen Toxicity: patients are given the antidote N- Acetylcysteine which works by a number of protective mechanisms. Early after an overdose, NAC prevents the formation and accumulation of (NAPQI) It also increases glutathione stores and combines directly with NAPQI and enhances sulfate conjugation. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic and vasodilating effects

38. MANAGEMENT General Measures + Complications : 4. Infection: Patients with ALF are at higher risk for acquiring infections due to many reasons including: These patients are immunocompromised and thus are more likely to develop severe infection and sepsis Due to their altered mentation, they are at higher risk of aspiration Its is recommended that these patients be started on Broad Spectrum Antibiotics Even before confirming focus of infection

39. MANAGEMENT Medications to Avoid In general, sedation should be avoided because patients with acute liver failure have a severely impaired ability to clear sedatives, and the effects of sedation may mask the signs of worsening encephalopathy or cerebral edema. However, in patients with severe agitation that cannot be managed in any other way, short-acting benzodiazepines in low doses may be given. In patients who require sedative medications, benzodiazepines, barbiturates , and  Propofol are preferable to opioids because opioids can decrease the seizure threshold. Hepatotoxic and Nephrotoxic Drugs should also be avoided

40. MANAGEMENT Un-Helpful Treatments A number of interventions have been studied that are unhelpful for acute liver failure and should generally not be used. Such treatments include: ●Glucocorticoids, which increase the risk of sepsis ●Hepatic regeneration therapy using insulin and  glucagon ●Charcoal hemoperfusion ●Prostaglandin E, which appeared to have promise in uncontrolled studies

41. MANAGEMENT LIVER TRANSPLANTATION This is the ONLY effective treatment for acute liver failure in patients who fail to spontaneously recover Patients referred for transplant is determined by the King’s College Criteria

42. COMPLICATIONS Common Complications of ALF Include: Cerebral Edema with HE Hemodynamic Collapse Infections Coagulopathies and Bleeding Renal Failure Metabolic Derangements

43. Prognosis

44. PROGNOSIS The cause of ALF is the most significant predictor of patient outcome Acetaminophen Toxicity, Hepatitis A, Shock Liver, Pregnancy Related ALF – Have a >50% Transplant free survival rate All Other causes have <20% Transplant free survival rate Mortality of ALF depending on the etiology ranges from 50 to 80% of all cases HE Grades I and II have 65-70% Spontaneous recovery rate while Grades III and IV have <20%

45. THANK YOU