ACUTE LIVER FAILURE

Gagan Brar

ACUTE LIVER FAILURE

Rare disorder with high mortality and resource

cost.

Can be associated with rapidly progressive

multiorgan failure and devastating complications

Outcomes have been improved by use of

emergency liver transplantation

DEFINITIONS & TERMINOLOGY

FULMINANT HEPATIC FAILURE

The original term defined as “a severe liver injury, potentially reversible in nature and with onset of hepatic encephalopathy within 8 weeks of the first symptoms in the absence of pre-existing liver disease”.

ACUTE LIVER FAILURE

The terminology developed by O’Grady and

colleagues in 1993

This classification recognises the central

prognostic importance of the development of encephalopathy and

altered consciousness after initial hepatic injury.

ACUTE LIVER FAILURE• Divides the presentation into three groups:

HYPERACUTEACUTESUBACUTE Dependent on the interval between development of jaundice and onset of encephalopathy

DEFINITIONS

•Definition accepted for clinical and research studies is that of a

Multisystem disorder in which severe impairment of liver function, with or without encephalopathy, occurs with hepatocellular necrosis in a patient with no reported underlying chronic liver disease

INCIDENCE

Acute liver failure is rare. Much less common in the developed world than in the developing world

Overall incidence between one and six cases per million people every year.

High rates in locations where infective hepatitis is common

ETIOLOGIES OF ACUTE LIVER FAILURE

AND SPECIFIC THERAPIES

In the Western world, drug-induced liver injury is the most common In the developing world viral infections (hepatitis A, B, and E) are the predominant causes

ACETAMINOPHEN

Most common cause of toxic liver injury.

Consumption of greater than 10 g of the drug.

Lesser amounts in the setting of alcohol use or underlying liver disease, presumably because of activation of the microsomal enzymes that metabolize acetaminophen.

The risk of developing hepatotoxicity is related to the quantity ingested, the time to presentation and treatment with NAC.

Metabolized in hepatocytes by cytochrome enzymes to the toxic metabolite n-acetyl p-benzoquinoneimine (NAPQI) that normally is detoxified by conjugation with glutathione.

Depletion of glutathione leads to accelerated liver injury by reduced detoxification of NAPQI.

loading dose is 150 mg/kg in 5% dextrose over 15 minutes; maintenance dose is 50 mg/kg given over 4 hours followed by 100 mg/kg administered over 16 hours or 6 mg/kg/hr

N-acetylcysteine (NAC) replenish glutathione stores.

The PRESCOTT NOMOGRAM is used in the uk and europe and RUMACK–MATTHEW NOMOGRAM is used in the USA to determine the risk of acetaminophen toxicity.

They can only be applied to a single acute overdose presenting within 16–24 hours.

If in doubt, commence treatment. NAC administration can be life-saving.

Adverse reactions and unpleasant side effects are rare.

DRUG INDUCED LIVER INJURY(DILI)

•More than 1000 drugs and herbal remedies implicated •Most cases are idiosyncratic reactions.•Allergic DILI is characterised by fever, skin reactions, eosinophilia and autoantibody formation•Risk factors include age, female gender, polypharmacy and active co-morbidity.• Genetic polymorphisms have been associated with diclofenac hepatotoxicity.

AMANITA POISONING

• Heat-stable toxin• Gastrointestinal symptoms• Liver injury • Mortality approaches 10%

to 30%.

Treatment with silibinin(20-50 mg/kg/24 hr) or with penicillin G (400,000 U/kg/24 hr) early on in high dosages may ameliorate the hepatic injury

VIRAL HEPATITIS

VIRAL HEPATITISViral infection with viruses such as hepatitis A, B, and E is associated with acute liver injury

No specific therapies for hepatitis A or E

Antiviral agents inhibit the replication of hepatitis B

Acute HBV may be more severe if there is coinfection or superinfection with hepatitis D virus (HDV)

Other viral infections that are associated with ALF

include

Herpes simplex virus

Varicella zoster virus

Cytomegalovirus

Epstein-barr virus (EBV) infection

METABOLIC DISORDERS• These include Acute fatty liver of pregnancy (AFLP ) Wilson’s disease Fructose intoleranceGalactosaemia Reye’s syndrome Tyrosinaemia

WILSON S DISEASE• Inherited, autosomal recessive,

condition. • Defective coding of a copper-

transporting ATPase • Inefficient copper excretion in the bile• Accumulation in the brain, liver and

cornea.• Often suspected when ALF occurs in the

presence of psychiatric symptoms.

WILSON’S DISEASE

Liver failure can be presenting feature usually in patients <20 yrsALF caused by Wilson disease typically is accompanied by a

Nonimmune hemolytic anemiaLow alkaline phosphatase to bilirubin ratio (less than four) ALT to AST ratio of less than 2 Markedly elevated serum copper greater than 200mg/dl 24-hour urine copper often greater than 200mg.

Kayser-fleischer rings are

pathognomonic,

Present only in approximately 30% to 50% of

Ceruloplasmin levels poorly

predictive in the setting of ALF

ACUTE FATTY LIVER OF PREGNANCY (AFLP)Significant maternal mortality. Often complicated by pre-eclampsia.

Defective β-oxidation of long chain fatty acids in the fetus can cause elevated serum levels of circulating fatty acids in the motherMothers heterozygous for long-chain-3 hydroxyacyl CoA dehydrogenase are at risk of hepatotoxicity

• Typically presents in the third trimester • Marked elevation of liver tests • May progress rapidly to jaundice and liver failure.• Delivery of the fetus is necessary for maternal and fetal survival.

VASCULAR•Acute obstruction of hepatic venous outflow or Budd Chiari Syndrome may result in ALF. •Hepatomegaly, new and rapid onset of ascites, and imaging studies showing hepatic venous thrombosis.•Acute decompression of the obstruction with TIPS or surgical PORTOSYSTEMIC SHUNT procedure may prevent further hepatic injury •Transplantation may become necessary.

OTHER VASCULAR CAUSES…..

•SINUSOIDAL OBSTRUCTION SYNDROME that occurs with smaller vessel veno-occlusive disease

•Infiltrative disease associated WITH MALIGNANCY, LYMPHOMA, OTHER TUMORS.

ISCHEMIC HEPATITIS •Shock liver is associated with acute liver injury mainly in the central zone.•History of significant hypotension•Treatment of the underlying condition that led to the hepatic injury is critical for recovery

AUTOIMMUNE HEPATITIS

•May be acute or chronic disease if the earlier injury was unrecognized.•Up to 30% of patients who have acute presentation will not have the typical serum markers for autoimmune hepatitis.•Some patients may respond to High-dose steroid.•Liver biopsy may help to identify these individuals

CLINICAL FEATURES

EVALUATION OF THE PATIENT WITH ACUTE LIVER FAILURE

• Early recognition• Rapid identification of the etiology of the liver failure• Initiation of etiology-specific treatments when appropriate• Proper mobilization of personnel involved in various aspects of patient

care.

FIRST PHASE EVALUATION •DETAILED HISTORY from the patient if possible or from others who may know the patient’s medical history.•Physical examination should assess the patient’s MENTAL STATUS and evaluate liver and spleen size and presence or absence of ascites.

NEUROLOGIC EVALUATION

•Pupil size and reactivity •Reflexes•The presence or absence of HEPATIC ENCEPHALOPATHY•Encephalopathy should be graded using a standard scale such as the glasgow coma scale or WEST HAVEN CRITERIA.•Needs to be monitored frequently in patients who have rapidly accelerating disease.

Complete Blood Cell Count International Normalized Ratio [INR] ElectrolytesLiver Tests • TWICE DAILY ………………………•Specific testing such as blood glucose levels should be obtained more frequently.

Important Points………

•Falling plasma aminotransferase do not necessarily imply that liver function is improving.•In the setting of worsening jaundice, coagulopathy and encephalopathy, it suggests that necrosis is massive, especially if the liver volume is decreasing.• In acute toxic injury and ischaemic hepatitis aminotransferase enzymes may be increased to several thousand IU/l

•In alcohol-related liver disease AST activity is frequently twice that of ALT•An elevated serum concentration of alkaline phosphatase (ALP) is seen most frequently in patients with biliary disease (extra- and intrahepatic) and in those with an infiltrative process involving the liver.

IMAGING•Radiology is an important aspect of the assessment of a patient with liver disease. •Ultrasound is readily available and easy to perform. •Allows assessment of the liver parenchyma (whether homogeneous or heterogenous, high reflectivity associated with fatty infiltration). •The biliary tree may be examined for dilation, and the parenchyma for abnormal areas suggestive of tumour deposits.

•CT and magnetic resonance imaging allow further detailed visualisation of the abdominal anatomy. •These modalities provide further information regarding vascular supply and possible areas of tumour infiltration.•Endoscopic retrograde cholangiography is used in patients with biliary obstruction who require decompression of their biliary system

COMPLICATIONS AND ICU BASED INTERVENTIONS

Management of the patient with ALF involves aggressive supportive care and ongoing assessment of clinical, physiological and laboratory variables.

•Reduced mortality due to advances in critical care medicine and in management strategies.

•Mortality is attributed to three complications in particular:

Cerebral EdemaMultiorgan Dysfunction Syndrome (MODS)

Sepsis

The prognosis is worse in

•Patients who are younger than 10 years or older than 40 years, •Causes other than acetaminophen toxicity or hepatitis a and b virus infection •Long period between the development of symptoms and encephalopathy.•Persistent acidosis, INR >3.5 , increasing serum bilirubin and creatinine concentrations also suggest a worse prognosis in those with non-acetaminophen aetiologies

RESPIRATORY FAILURE: MECHANICALVENTILATION

Ideal timing for endotracheal intubation is not always clear

Should be considered strongly once advanced encephalopathy becomes evident

Mechanical ventilation and judicious sedation may help manage extreme agitation and dangerous surges in ICP

Development of acute respiratory distress syndrome (ARDS) is common

Attention should be paid to pCO2 once a low tidal volume ARDS protocol is instituted

For patients suspected of having brainstem herniation, acute hyperventilation can be used emergently

High levels of PEEP can cause increase in ICP.

HEMODYNAMIC FAILURE: SHOCK MANAGEMENT

Marked by a state of High Cardiac Output and Reduced SVR

Hypotension is commonMimics Septic Shock and differentiating between the two can be challenging.

Concurrent Infectious Workup is mandatoryRelative Adrenal Insufficiency occurs frequently Treatment with Moderate-dose Corticosteroids is reserved for those unresponsive to pressors

Assessment of volume status and adequate resuscitation

Vasopressors can be used adjunctively to maintain a MAP above 50 mm hg, with a goal CPP of 50 to 80.

Surges in MAP also should be avoided as this may lead to cerebral hyperemia

WHICH VASOPRESSOR???Risks and benefits of individual vasopressor agents have not been evaluated carefully in this setting.

Extrapolation of data from TBI suggests that norepinephrine should be preferred.

Associated with consistent and predictable increases in CPP

NEUROLOGIC FAILURE: CEREBRAL EDEMA AND INTRACRANIAL HYPERTENSION

Management of intracranial hypertension (ICH) remains challenging.

Left untreated, mortality can exceed 90%

Up to a third of patients succumb to brainstem herniation while awaiting an organ

RISK FACTORS

•High-grade encephalopathy (grades 3 to 4),•Elevated serum ammonia (greater than 150 to 200mm)•Rapid/hyperacute progression of liver injury to hepatic encephalopathy,• Infection or systemic inflammatory syndrome (SIRS)•Requirement for vasopressor support or renal replacement therapy

NEUROIMAGING•Not reliable in diagnosing early ICHtn•May help exclude intracranial bleeding or stroke.•Invasive intracranial pressure(icp) monitoring gold standard for measuring and monitoring ICHtn.

INTRACRANIAL PRESSURE MONITORING: GENERAL CONSIDERATIONS

• ICP monitoring remains controversial• Randomized controlled trials are lacking• In nonrandomized studies, such devices have not been shown to improve survival.•Despite lack of consensus, many centers place ICP monitors to actively manage cerebral edema in patients who have advanced(stage 3 or 4) encephalopathy

ADVANTAGES•Early edema can be clinically silent•Placement of a device may allow for early detection and intervention•Provides prognostic information regarding neurologic recovery after orthotopic liver transplant (OLT)•Sustained ICP > 40 mmhg (or cerebral perfusion pressure less than 40 mmhg) for > 2 hours is associated with brainstem herniation or poor neurologic recovery post-OLT

DISADVANTAGES•Intracranial bleeding is encountered in 10% to 20% of patients•Most intracranial bleeding is mild and of little clinical significance.•Correction of coagulopathy should be continued for approximately 48 hours after the insertion of probes/catheters•Infections

INTRACRANIAL PRESSURE MONITORING:PRACTICAL CONSIDERATIONS

• Ideal location of placement remains unclear• Intraventricular placement carries the highest risk of bleeding (although with the added therapeutic potential)•Lowest risk with epidural placement•Local expertise and comfort level defines where and how the monitors are placed

INTRACRANIAL HYPERTENSION: GENERAL MANAGEMENT PRINCIPLES

•Quiet room with minimal stimulus•Infrequent endotracheal suctioning•The head of the bed elevated to 30 (to improve CSF drainage),•Neck rotation or flexion should be limited to avoid compromise of jugular venous drainage•Fevers should be controlled by cooling•Rigoring or shivering avoided as these may exacerbate ICP

•ICP should be maintained below 25mm Hg. •The mean arterial pressure (MAP) should be adequate to maintain cerebral perfusion pressure (CPP) between 50–80 mm Hg. •Care should be taken to avoid an overly robust CPP as this may exacerbate cerebral hyperemia

•Meticulous attention needs to be paid to metabolic and acid–base abnormalities including •Hyper- and hypoglycemia •Hyponatremia•Hyperlactatemia and hypercapnia,These have been shown to contribute to higher ICP.

•Mannitol can be used as first-line therapy•Given as repeated boluses•Serial serum osmolality to be maintained below 320 mosm/L•Hypertonic saline can be used with few adverse effects•Goal of achieving sodium of 145 to 155 meq/L.•Limited evidence•Hypertonic saline never has been tested formally as a treatment of established ICHtn in patients with ALF.

•A controlled trial of the prophylactic induction of hypernatremia with hypertonic saline (to a serum sodium 145-155 meq/L) suggested a lower incidence of ICH compared to management under "normonatremic" conditions•Although survival benefit of induced hypernatremia was not demonstrated, this trial presents the most compelling data favoring the use of osmotic agents in ALF• Hypertonic saline as a prophylactic measure is recommended in patients at highest risk of developing cerebral edema

Murphy N, Auzinger G, Bernal W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2002;39:464-470.

Other Adjunctive Measures………

•Barbiturate coma (to reduce brain metabolism, although incremental benefit is unclear if the patient is already in stage 4 encephalopathy with coma)•Indomethacin•Paralytic agents

•Lactulose or Nonabsorbable Oral Antibiotics(rifaxamin); no good data• May help lower ammonia and are of theoretic benefit.• No role for corticosteroids ; cerebral edema is of cytotoxic, as opposed to vasogenic origin in ALF

KEEPING IT COOL:THERAPEUTIC HYPOTHERMIA

•Moderate hypothermia (32 C to33 C) appears to be a formidable tool for managing refractory ICP elevations.•Alters multiple pathways important in the pathogenesis of cerebral edema and ich and leads to:

Reductions in brain energy metabolism(both metabolic and electrophysiologic components)

Possible suppression of subclinical seizure activity

Normalization of cerebral blood flow and autoregulation

Reduced delivery of ammonia to the brain

Amelioration in anaerobic glycolysis and oxidative stress in astrocytes

Decrement in brain extracellular glutamate and normalization of brain osmolarity

May restore vascular responsiveness and added benefit of less vasopressor requirement

Intraoperative surges in ICP may be averted with maintenance of moderate hypothermia in the operating room

ADVERSE EFFECTS ArrhythmiaInfection (Which Increases With Degree And Duration Of Hypothermia)

Bleeding Electrolyte ImbalanceHyperglycemiaAlteration In Drug Metabolism.

• Many of these abnormalities are difficult to distinguish from physiologic changes that commonly accompany ALF itself

MANY UNANSWERED QUESTIONS….•Optimal Target Population, Timing, Degree And Duration Of Treatment, Hypothermia, And Rewarming Techniques

•Rapid rewarming can exacerbate electrolyte abnormalities and lead to hemodynamic instability and worsening CPP.

NEUROLOGIC MANIFESTATIONS: SEIZURES

•Seizures can aggravate cerebral edema and ICH•Can be a manifestation of ICP surges•No recommendation on prophylaxis for seizures •Continuous EEG monitoring may be useful for patients at high risk for seizures.

HEPATIC ENCEPHALOPATHYAcute encephalopathy is usually precipitated by: •Infection •Metabolic disturbances (Electrolyte Abnormalities, Excessive Diuretic Therapy Or Fluid Restriction, Excessive Paracentesis, Uraemia, Alkalosis, Anaemia, Hypoxaemia). •Gastrointestinal disturbances (Haemorrhage, Constipation, Excessive Protein Load).

•Hepatic abnormalities (Acute Liver Necrosis, Disease Progression, Portal Vein Thrombosis, Ischaemia, Hepatoma,, Tips Or Surgical Shunts). •Psychoactive drugs. •Medication non-compliance.

•Putative toxins include ammonia, mercaptans, gamma-aminobutyric acid, endogenous benzodiazepines and serotonin/tryptophan.

•Ammonia has been the most studied and probably is a relevant toxin along with an inflammatory milieu which appears to potentiate the risk of encephalopathy.

MANAGEMENT•Resuscitative measures e.g. Control of airway, support of circulation. • Diagnosis and treatment of the precipitant. • Treat infection and biochemical abnormalities. • Protein intake of 1–1.5 g protein/kg/day depending on level of encephalopathy (can be reduced to 0.5 g/kg/day transiently).

• Lactulose/lactilol. The cathartic effect removes endogenous and exogenous ammonia-generating compounds from the bowel and maintains an acidic environment that retains ammonia within the bowel lumen. • Neomycin may have an additive benefit but is not often used because of the risk of oto-and nephrotoxicity.

•There is no evidence to support the use of benzodiazepine antagonists. •Recent studies suggest benefit with Rifaxamin in preventing encephalopathy in an outpatient setting. •Use of ammonia lowering agents such as L-ornithine and L-arginine have some role in chronic liver disease but had no beneficial effect when studied in the context of ALF.

SEDATION AND ANALGESIA•Agitation (including excessive coughing and straining) and pain can exacerbate ICP elevations•Adequate analgesia and judicious sedation are required.•Short-acting agents are preferred•All sedative drugs are subject to delayed metabolism.•Recovery time from Propofol tends to be shorter than from Benzodiazepines •May allow for more reliable serial neurologic testing

•Despite adverse effects on hemodynamics, Propofol has the added benefit of decreasing CBF and lowering ICP.

•Both Propofol and Benzodiazepines can increase g-aminobutyric acid (GABA) neurotransmission and theoretically exacerbate hepatic encephalopathy

HEMATOLOGIC FAILURE: DEALINGWITH COAGULOPATHY

•Clinically significant spontaneous bleeding uncommon despite severe derangement•Subclinical vitamin K deficiency contributes to coagulopathy in up to 25% of patients

Empiric administration of vitamin K 10 mg intravenously recommended.

•Prophylactic transfusions unnecessary

Not been shown to alter the risk of significant bleeding or future transfusion requirement

Carries a risk of volume overload Obscures the trend of Prothrombin Time

•Patients with clinically significant bleeding or before placement of invasive devices, an attempt at improving coagulopathy should be made.

•No strict guidelines exist.•Rough target to correct the INR to approximately 1.5 •Platelet count to approximately 50,000/mm3 before procedures•Cryoprecipitate is recommended if significant hypofibrinogenemia (less than 100 mg/dl). •When FFP fails to adequately normalize PT/INR, use of RECOMBINANT FACTOR 7A (rf7) can be considered to facilitate placement of ICP monitors.

•FFP or cryoprecipitate should be administered before rf7 (40mg/kg) if fibrinogen levels are less than 100•Procedure generally should be performed within 30 to 60 minutes of infusion of rf7. •Repeat prophylactic doses of rf7 are probably not necessary after successful device placement, unless there is clinical evidence of oozing or bleeding.

RENAL FAILURE MANAGEMENT

•Renal insufficiency may accompany liver failure.•Multifactorial – • Ischemia from hypotension may cause atn,•Hepatorenal syndrome, •Other toxic injuries such as copper induced tubular injury in wilson disease and contrast-induced nephropathy

•Avoid excess fluid administration that can exacerbate cerebral edema , cause pulmonary congestion and accelerate ascites formation.• Important to establish euvolemia

•Renal Replacement Therapy should be started early -Worsening renal function or academia•To help with control of acid–base status and electrolyte balance. •Continuous Veno-venous Hemofiltration With Dialysis is the preferred method •If the patient moves forward to transplantation, Continuous Veno-venous Hemofiltration may be continued intra- and perioperatively as necessary

INFECTIOUS DISEASE CONSIDERATIONS

•Most common cause of death and morbidity •Kuppfer cell function is impaired•Clearance of normal gut bacteria that translocate is less efficient. •Most common site of bacterial infection is the lung, then urinary tract and blood.• Most frequently identified organisms are staphylococcus, streptococcus and enteric gram- negative bacilli. •Fungal infections may be present in up to one third of patients who have ALF

•Catheter-related sepsis is a serious concern •Avoidance of unnecessary intravenous lines and careful attention to proper hygiene and changing of access are important

•No recommendations for prophylactic antibiotics BUT…•Justification for careful surveillance for infection •Low threshold for treatment. •Survival has not been shown to be altered by the use of prophylactic antibiotics.•However, the numbers of patients studied may not have been large enough to definitively preclude benefits of prophylactic treatment

•Empiric use of antibiotics is recommended :•Surveillance cultures are positive•Encephalopathy is rapidly progressive•Hemodynamic instability with refractory hypotension or•Systemic signs of infection such as elevated temperature, tachycardia, and leucocytosis

Leukocytosis may occur merely as a result of the liver injuryDifferential of the CBC should be watched for changes from baseline values

CHOICE OF AN ANTIMICROBIAL AGENT

Need to cover broad spectrum of gram-positive and -negative organisms. In general, third-generation cephalosporin drugs are recommended.Once speciation from any culture is possible, antimicrobial therapy may be narrowed accordingly

•Antifungal therapy in patients who have had prior antibiotic treatment or the lack of a prompt response to institution of antibacterial therapy and for those who have renal failure

NUTRITION FOR THE PATIENT WITH ACUTE LIVER FAILURE

•Patients are prone to hypoglycemia • Injury because of loss of glycogen stores, impairment of gluconeogenesis, and increased circulating insulin•Intravenous glucose solutions recommended if the patient is not being fed. •Marked hyperglycemia should be avoided, because this may impair control of intracranial pressure;•Benefits of tight control must be weighed against the risk of hypoglycemia

• Need for nutritional supplementation as these patients are catabolic.• Oral feeding may need to be discontinued if there is a risk of aspiration. •This clearly holds for patients transitioning from grade 2 to grade 3 hepatic coma.•Enteral supplementation by means of feeding tube is recommended, at a minimum to provide the gut with some trophic feeds to reduce the risk of bacterial translocation

•Caloric goals should be approximately 25 to 30 kcal/kg/d. •Protein intake of approximately 1 g/kg/d does not appear to worsen hyperammonemia. •Excess glutamine supplementation should be avoided given glutamine’s role in the production of ammonia and development of cerebral edema in ALF

LIVER SUPPORT DEVICES

LIVER SUPPORT DEVICES

•May benefit by being used as a bridge to liver transplantation or liver recovery •Utility has been tested only in nonrandomized studies to date

•There are two main types of liver support devices:

•Artificial (cell-free systems) such as those based on plasma filtration and removal of substances by use of dialysis or charcoal or other ion exchange columns

•Bioartificial systems that rely upon the use of liver cells (human or nonhuman) to perform detoxification and secretion of hepatocytes derived factors

•A truly effective device will perform three key functions: detoxification, biosynthesis and regulation

•Only bioartificial systems can do all three functions.

•Artificial systems only detoxify

ARTIFICIAL SUPPORT DEVICES•Remove toxins responsible for hepatic encephalopathy and multiorgan failure secondary to liver failure•Hemodialysis, hemofiltration, hemodiafiltration and hemadsorption•Problem with these techniques is the difficulty of removing toxins bound to large protein molecules•Albumin is the main carrier of toxins in blood, it may be used as an acceptor substance for toxins in liver support devices

Molecular Adsorbents Recirculating System•Toxins diffuse across an albumin-impermeable membrane •Bind to a 20% albumin solution in a secondary circuit.•Two columns(activated charcoal and anion exchange) then adsorb the toxins.

A low-flux dialyzer also removes water-solve substances in the secondary circuit (via either intermittent hemodialysis or continuous renal replacement therapy)

• A meta-analysis of four randomized controlled trials concluded that treatment with MARS provided no survival benefit •These studies and even the meta-analysis were severely underpowered to evaluate mortality•MARS improves other parameters including bilirubin ,encephalopathy ,decreased serum copper levels in Wilson’s disease , pruritus , renal function and hemodynamics•MARS may worsen coagulopathy and bleeding • It is hence more prudent to use MARS as a bridge to transplantation

• Fractionated Plasma Separation And Adsorption (Prometheus)

• Single Pass Albumin Dialysis (SPAD)

Bioartificial Support Devices•Bioartificial liver using human hepatocytes• Immortalized C3A human hepatocytes derived from a hepG2 hepatoblastoma are used in the extracorporeal liver assist device (ELAD)• The patient’s plasma enters bioreactors where it is ultrafiltrated through hollow fibers into spaces packed with these hepatocytes allowing metabolic exchange.• In a randomized controlled trial in 24 patients with ALF, the ELAD improved bilirubin and ammonia levels and encephalopathy but not mortality

Bioartificial Liver Using Porcine Hepatocytes

•Porcine hepatocytes resemble human hepatocytes and,being more readily available, contribute to the bulk of clinical studies on the bioartificial liver.• Porcine systems resemble the ELAD – plasma or ultrafiltrate is perfused through the hepatocytes to allow metabolic exchange•Other similar systems include the modular extracorporeal liver support system (MELS], the Academic MedicalCenter-Bioartificial Liver (AMC-BAL; the TECA-Hybrid Artificial Liver Support System Bioartificial Liver Support], the Radial FlowBioreactor , the Hybrid-Bioartificial Liver , and the Bioartificial Hepatic Support

• No device has been conclusively shown to improve survival by acting as a bridge to Liver transplantation, let alone as a bridge to recovery

LIVER TRANSPLANTATION

•Survival has been transformed by the introduction of emergency transplantation• Now part of routine care in many countries for those patients with acute liver failure who meet criteria indicative of a poor prognosis•Emergency transplantation outcomes are consistently lower than are those of elective surgery•High early post-transplant mortality, mainly as a result of sepsis and multiorgan failure

•The ideal means for identification and selection of patients remains controversial•Different selection criteria for emergency transplantation are used worldwide

•Findings from case series and meta-analysis have confirmed that these criteria have clinically acceptable specificity•Sensitivity might be low and be unable to identify some patients who would die without emergency transplantation.

•Three interacting factors affect the outcome of emergency liver transplantation: age of recipient, severity of pretransplant illness, and the nature of graft used.•The more unwell a patient is, the less probable that transplantation will be done or be successful•Severity varies by reason for liver failure, and is greatest in patients with paracetamol-related disease•Recipient’s age has a strong effect on the outcome of emergency transplantation, with postoperative mortality more than doubled in those over 50 years of age

•The third main factor that determines outcome is the nature and quality of the graft used.• Inferior outcomes in those patients receiving size-reduced, abo-incompatible, or steatotic grafts.•Successful transplantation requires individual matching of recipient and graft •The most ill patients might only respond to the best possible graft

•Auxiliary liver transplantation is theoretically a promising treatment for acute liver failure. • A partial liver graft is placed either heterotopically or orthotopically, and all or part of the native liver is left in place.• With resolution of the insult the native liver could subsequently regenerate, allowing withdrawal of immunosuppression and graft atrophy or removal, and avoiding long-term side-eff ects and costs.

•Technically demanding procedure, findings from initial reports showed high rates of complication and retransplantation.•Outcomes have improved substantially by improvements in surgical technique and from selection of patients

EVIDENCE FOR NAC IN NON ACETAMINOPHEN INDUCED LIVER FAILURE

Retrospective study in children – Improved survival with or without transplantation

Prospective study with historical control: Improved survival

No difference in overall survival at 3 weeks; however, better transplant-free survival, seen only in low grade encephalopathy

OVERALL SURVIVAL

FAVORSCONTROL

FAVORSNACNo effect on survival

FAVORSCONTROL

TRANSPLANT-FREE SURVIVAL

KEY POINTS……..•Rapidly progressive, life-threatening condition which occurs when there is massive liver injury•Characterised by coagulopathy and encephalopathy which occurs within days or weeks•Often complicated by multi-organ failure•Aggressive resuscitation of the circulation ameliorates hepatic parenchymal ischaemic injury and promotes regeneration.•Hypoglycaemia must be actively sought, monitored and treated• The diagnosis of the cause of these patients’ ALF must go hand in hand with basic resuscitative manoeuvres.• The key to a successful outcome rests intimely recognition, resuscitation and referral to a specialist centre for consideration of transplantation.

THANK YOU

Kortsa et al. Retrospective study in children – Improved survival with or without transplantation

Mumtaz et al. Prospective study with historical control: Improved survival

Lee et al. No difference in overall survival at 3 weeks; however, better transplant-free survival, seen only in low grade encephalopathy

Squires et al. Transplant free survival was lower

This is a Forest plot of the meta analysis

The horizontal lines are individual studies

The squares on the middle of the line indicates effect size – the bigger the square, the bigger the effect size. The arms on either side of the square indicates the CI. If the CI cuts the midline, it indicates, null effect. If the CI does not cut the midline, it indicates significance

The diamond at the bottom is the summary effect of the meta-analysis with the sides indicating the CI

So, if you take overall survival, there is no effect, as the diamond cuts the midline

With transplant free survival::

The Kortaz study: square is favouring NAC, with the arms not crossing midline, hence there is a signicant favourable effect on transplant free survival

Squires study shows transplant free survival is better with placebo, square is towards control, arms do not cross midline

Other two studies, cross midline, hence no effect.

Summary effect: diamond favors NAC and does not touch midline. Hence, significant impact of NAC on transplant free survival