Acute liver failure

1. Acute liver failure by Prof. Dr / Ahmed Elgohary Hepatobiliary Unit

2. Definition • Acute liver failure (ALF) is a rapidly progressive, life threatening condition with massive liver injury (either necrotic or apoptotic), occurring in the absence of chronic liver disease. • The condition is characterized by coagulopathy, encephalopathy and jaundice which develops within days to weeks, and is often complicated by multi-organ failure.

4. Clinical presentation

5. Symptoms • ALF typically presents with jaundice, coagulopathy and encephalopathy, and is often preceded by a prodromal illness of nausea and vomiting. • The rate of development of encephalopathy is variable and may not be present when the patient is first seen. Similarly, if liver failure develops quickly e.g. paracetamol (acetaminophen) overdose encephalopathy may precede the development of jaundice and the prodromal illness is absent.

6. Signs • Early clinical features in ALF are often nonspecific. Jaundice ranges from mild to severe, depending on etiology. Anorexia, malaise, fatigue, and abdominal pain may be present. • Encephalopathy can rapidly progress to cerebral oedema and brain stem herniation; a feature not seen in those with chronic liver disease. • Poor prognostic signs include deep coma, a shrinking liver and hypoglycemia. • Kayser Fleischer ring (seen in ALF and chronic liver disease in Wilson's disease) . Acute cerebral oedema . Cardiovasular changes in ALF and chronic liver disease.

8. Chronology • onset is considered hyperacute, acute or subacute. • The chronology may help to localize a precipitating event and will help to determine likely aetiologies. It also carries some prognostic value. In general, the incidence of cerebral oedema is highest in hyperacute ALF, while the prognosis without transplantation is worst in the subacute group. • ALF is commonly complicated by multi organ failure (MOF) which is phenotypically similar to severe septic shock, with hyperdynamic, vasoplegic circulation, microcirculatory dysfunction and capillary leak. lf sepsis occurs, it results from immune dysfunction and is associated with further progression of encephalopathy and MOF.

9. Diagnosis

10. The diagnosis of ALF should be considered in any patient with deranged liver function, coagulopathy (INR>1.5) and altered consciousness. • The clinical history should include the type and duration of symptoms leading to presentation (including cardiorespiratory symptoms). It is important to establish whether there has been any contact with viral hepatitis and/or travel, or there is a family history of liver disease. • It is also essential to obtain a full drug history, including prescribed, over the counter, herbal and recreational drugs. Clinical examination should be thorough. • The clinical stages of encephalopathy are pupillary, upper and lower limb reflexes, and the absence/presence of clonus should be elicited in the sedated and intubated patient.

11. Laboratory findings • Hematology (complete blood count) and PT/INR • Biochemistry: AST, ALT, ALP, GGT, bilirubin, albumin, Na, K, urea, creatinine, Mg, phosphates, glucose, amylase, lipase • Arterial blood gas, lactate • Blood group • Acetaminophen level/Toxicology screen • Hepatitis serology: anti HAV lgM, HBsAg, anti HBC lgM, anti HEV • Autoimmune markers: ANA, ASMA, LKM, SLA, immunoglobin levels • Ceruloplasmin is insensitive in ALF due to Wilson's disease; use serum copper and bilirubin alkaline phosphatase ratio >2 Arterial ammonia • CMV, EBV, HSV (if immunosuppressed), HIV • Note that falling transaminases may indicate that massive necrosis has occurred especially if INR and bilirubin is increasing and liver volume is decreasing

12. Endoscopy findings • There are no specific endoscopic findings that help to establish a diagnosis of ALF. • Portal hypertensive gastropathy and varices are non specific findings which may be present in the patient with subacute liver failure. Larger varices suggest underlying cirrhosis.

13. Radiology findings • Transabdominal ultrasound examination allows evaluation of the liver parenchyma in terms of heterogeneity, reflectivity (fatty infiltration) and tumour. The biliary tree may be examined for duct dilatation and the vasculature examined for patency. Budd Chiari syndrome, ischaemic hepatitis, portal vein thrombosis and even tricuspid regurgitation may be reliably diagnosed. • CT imaging provides the above as well as additional information about the remaining abdominal anatomy, including liver perfusion and lymphadenopathy.

14. Histology findings • Liver biopsy is rarely undertaken in the acute setting unless the etiology of ALF is uncertain. • Biopsy may be useful in patients who are suspected of having autoimmune hepatitis, HSV or malignancy (especially lymphoma) where systemic chemotherapy may be required. These patients are at increased risk of bleeding, and the risk vs benefit of biopsy should be carefully considered. • It is most safely performed via the transjugular route, although there remains a risk of sampling error. • Histological features include centrilobular/panlobular necrosis in paracetamol toxicity, panlobular injury in viral and drug induced liver injury and microvesicular steatosis in fatty liver of pregnancy.

15. Other procedures • 1. Echocardiogram for the diagnosis of hypoxic liver injury, and for the assessment of cardiac function in any ALF patient, particularly for those being considered for transplantation • 2 Bone marrow biopsy may be required to confirm or refute a diagnosis of lymphoma or haemophagocyticlymphohistiocytosis (HLH), which occurs after immunological activation and is characterised by activation of lymphocytes and macrophages • 3. Hepatic venography to diagnose Budd Chiari syndrome • 4. Intracranial pressure monitoring allows rapid detection and treatment of surges in intracranial pressure. However, there is no consensus regarding therapeutic goals and there is a risk of bleeding on insertion • 5. Renal replacement therapy is often required in the context of renal dysfunction and metabolic disarray

16. Differential diagnosis • Acute on chronic liver failure (ACLF) • Alcoholic hepatitis with underlying cirrhosis • Autoimmune hepatitis with cirrhosis • Eclampsia and pre eclampsia • Sepsis with multiorgan failure • Malignancy • Malaria • Heat Shock Injury • Cardiac failure (cardiomyopathy, tamponade, etc) • Acute portal vein thrombosis • Niemann Pick, urea cycle defects, etc

17. Scores

18. Scores / BiLE • Description: The BiLE score was developed based on a retrospective analysis of 102 patients in a single institution who fulfilled diagnostic criteria for acute liver failure. • Equation • Bilirubin (umoI/L)/100 + lactate (mmol/L) + aetiology score. • Aetiology score =+4 for seronegative, BCS, -2 for acetaminophen toxicity and 0 for all other aetiologies. • Interpretation • The authors claim a sensitivity of 79% and a specificity of 84% for predicting death or the need for transplant if the score is above 6.9 (based on multivariate regression analysis). The positive predicative value was 89%, negative predictive value 71%. Patients who survived without transplantation had a mean Bilirubin level of 103umol/L vs 263umo|/L in the death or transplantation group. Similarly, mean lactate level was 2.9 vs 4.7 mmol/L.

19. Clichy criteria • Description The Clichy criteria were developed from a group of 115 patients with acute hepatitis B causing ALF utilizing the two variables, hepatic encephalopathy and clotting factor V levels. • Equation • Presence of hepatic encephalopathy and factor V level: • <20°/o of normal in patients <30 years of age, or • <30% of normal in patients >30 years of age. • Interpretation : A comparison study assessing this group of adult patients with ALF due to hepatitis B yielded a positive predictive value (PPV) of 75% and a negative predictive value (NPV) of 58% for the Clichy criteria.

20. Kings College poor prognostic criteria • Description :The criteria are based on the INR, presence of hepatic encephalopathy (HE), acidosis and serum creatinine. The criteria include the serum lactate level after vigorous fluid resuscitation of the circulation. The criteria have been developed for both acetaminophen and non acetaminophen aetiologies. • Acetaminophen Induced ALF • Strongly consider OLT listing if: • Arterial lactate >3.5 mmol/L after early fluid resuscitation • List for OLT if: pH <7.3 or arterial lactate >3.0 mmol/L after adequate fluid resuscitation • List for OLT if all 3 occur within a 24 hour period: • Presence of grade 3 or 4 hepatic encephalopathy • INR >6.5 • Creatinine >300 umol/L (>3.4 mg/dL)

21. Non Acetaminophen Induced ALF • List for OLT if: • INR >6.5 and encephalopathy present (irrespective of grade) • or • any three of the following (encephalopathy present; irrespective of grade): • Age <10 or >40 years • Jaundice for >7 days before development of encephalopathy • INR >3.5 • serum bilirubin 300 umoI/L (>17 mg/dL) • Unfavorable etiology, such as Wilson Disease, idiosyncratic drug reaction, seronegative hepatitis

22. MELD • The MELD Score (Model for End Stage Liver Disease), was introduced in 1999 to predict 3 month survival of cirrhotic patients after portosystemic shunt. In 2002, the MELD system was implemented by the UNOS to prioritize patients on the waiting list for liver transplantation (transplantation: sickest first). → reduction of waiting list deaths, reduced registrations, improved transplantation rates. Outcome prediction after liver transplantation is unreliable based on the MELD score before transplantation. • Patients with a MELD score exceeding 15 have a significant transplant benefit. • The MELD Score has only been proven to be an accurate predictor of pretransplant mortality (on the waiting list). • Interpretation • Alcoholic Steatohepatitis Different cut off points have been suggested. • MELD score > 21 had a 3 month mortality of 20% in a recent retrospective report of largely untreated patients with alcoholic Steatohepatitis. Its advantages are a good validation, ease of calculation and lack of standardisation issues. In alcoholic Steatohepatitis, there is no clearly validated cut off, and it has not been prospectively studied in a clinical trial (Dunn et al, Hepatology 2005;41:353 8). • Acute Liver Failure • In acute liver failure (ALF), the US ALF Study Group reported that a MELD score >30 in patients with acetaminophen toxicity had a negative predictive value of 82% (so patients with MELD <30 had a high probability of survival). For other aetiologies, a MELD score >30 had a positive predictive value of 81

23. Complications • Cardiovascular • The haemodynamic profile of ALF is similar to that seen in septic shock, with elevated cardiac output and vasoplegia. Hyperlactataemia reflects circulatory dysfunction and the quality of resuscitation. It is an important prognostic marker and has been added to the King's College Criteria. Hyperlactataemia is considered significant when elevated >3 mmol/L despite adequate fluid resuscitation. • Respiratory • lntubation and ventilation is indicated in grade 3/4 encephalopathy for airway protection and the control of intracranial hypertension. ARDS (acute respiratory distress syndrome) occurs secondary to the high concentrations of circulating inflammatory mediators and increased vascular permeability, and the necessary fluid loading for resuscitation of the circulation. Ventilator associated pneumonia is common. • Nutrition • Hypoglycaemia occurs as glycogen stores are diminished and gluconeogenesis fails (tight glycaemic control is controversial). ALF is associated with a negative nitrogen balance and early enteral feeding is recommended, although problems with absorption frequently arise. There is no evidence that early nutritional support worsens encephalopathy or intracranial hypertension. Total parenteral nutrition may be considered (after 5-7 days). Vitamins and trace elements should be supplemented.

24. Immunity • The incidence of clinical bacteraemia is high monocyte and neutrophil deactivation is a leading cause and is associated with worsening hepatic encephalopathy. We recommend the empirical use of broad spectrum antibiotic/antifungal therapy in any patient with high grade encephalopathy. Ventilator care bundles, indwelling catheter surveillance, oral hygiene and gut decontamination increase the median time to bacteraemia. • Renal • The incidence of acute kidney injury is higher in ALF than in other critically unwell populations. It is an important prognostic marker. The mechanisms involved include a functional hypovolaemia and intraglomerular arteriolar vasoconstriction. Continuous renal replacement therapy (CRRT) is frequently indicated. The dose and timing remains the subject of controversy. • Coagulopathy • Platelet number and function and severe hypofibrinogenaemia often correlate better with bleeding risk than Prothrombin time, although the latter acts as an important prognostic marker in ALF. The use of fresh frozen plasma is indicated only for uncontrolled bleeding, and it should not be used for line insertion as it confounds prognostication and may defer the decision to proceed to transplantation. • Other • Relative adrenal insufficiency is common. Steroid use has been shown to diminish vasopressor requirements but not to impact on mortality.

25. Management and therapy

26. General measures • Patient outcomes are largely determined by the severity of the underlying liver insult and the development of organ failure, and episodes of sepsis can impact heavily on mortality. Early recognition and treatment of sepsis and the prevention and support of organ dysfunction is, therefore, key to increasing the potential for hepatic regeneration. • Intubation and ventilation may be indicated for airway protection, neuroprotection with the development of high grade encephalopathy, or respiratory failure. • Cardiovascular resuscitation may be best guided by invasive cardiac output monitoring. Hypoglycaemia should be sought and corrected. Renal replacement therapy is frequently required. Targeted strategies are few. • The below listed therapies have never been subject to RCT, and so efficacy is unproven. Steroid therapy in autoimmune hepatitis may defer the decision to proceed to liver transplantation, and thus ultimately prove harmful. • Hepatitis B: nucleos(t)ide analogues • Herpes simplex virus: acyclovir / foscarnet • Autoimmune hepatitis: immunosupression • Budd Chiari syndrome: anticoagulation / TIPS Amanita phalloides: penicillin G / silibinin • Malignancies: antineoplastics • The components of the management strategy are: • determination of aetiology • assessment of the severity of the disease and the associated prognosis • prevention or treatment of complications • liver transplantation when spontaneous survival is considered unlikely • possible use of liver support devices

27. Specific measures • Biological and non biological extra-corporeal liver support systems. • Management of intracranial hypertension. • Transjugular intrahepatic portosystemic shunt (TIPS) for acute Budd-chiari syndrome. • Transplantation.

28. Specific measures / Management of intracranial hypertension • Indications • Vasogenic oedema, hyperammonaemia and increased cerebral blood flow conspire to cause cerebral oedema and intracranial hypertension. The risk is highest with hyperacute presentations and in patients with raised arterial ammonia. A higher MELD score, younger age, and requirement for vasopressor and renal replacement therapy are additional independent risk factors. • Precautions • There is a bleeding risk with ICP monitor insertion (epidural monitoring is said to be less accurate, but penetration of the dura is said to be associated with higher rates of bleeding) and there is no consensus over therapeutic goals. The role of ICP monitoring is controversial; there is no randomised controlled trial demonstrating benefit.

29. Drugs / Hypertonic Saline (3-30%) • Indications: It should be noted that there are no data to support the treatment of intracranial hypertension, only in its prevention. • The prophylaxis and treatment of cerebral oedema and raised intracranial pressure • Posology • Dependent on solution used and whether CVVH is in progress, and the volume exchange (dose) of CWH. Aim to induce hyperosmolality with serum sodium concentrations of 145-150 mmol/L. • Side effects • Volume expansion may cause peripheral oedema. Hyperchloraemic metabolic acidosis. Platelet aggregation and clotting times may be affected. • Precautions • There is concern over the potential to worsen cerebral oedema if there is extravasation across an inflamed blood brain barrier. Hypernatraemia and brain dehydration are . theoretical concerns with osmotic shifts. Rapid correction of hyponatraemia may lead to central pontine myelinolysis. Rebound brain oedema may occur if hypertonic saline is rapidly withdrawn.

30. Drugs / Mannitol 20% • The treatment of cerebral oedema and the reduction of raised intracranial pressure. • Posology Early studies used 1g/kg, and the ALFSG has recommended a dose of 0.25-0.5 g/kg. Higher doses are recommended for control of raised ICP in the neurosurgical literature. • Mannitol use elicits a classically described biphasic response. There is an early fall in lCP as blood rheology improves. The improved blood flow enhances oxygen delivery and, via flow/metabolism coupling, results in cerebral vasoconstriction. A later decrement in intracranial pressure is observed approximately 30 minutes later as mannitol increases plasma osmolality and draws brain water across the blood brain barrier down its osmotic gradient. Mannitol also acts as an oxygen free radical scavenger. Plasma osmolality should not exceed 320mosmol/kg. Furosemide1mg/kg has a similar effect on ICP to 1g/kg of mannitol • Side effects • angina like chest pains CHF • hypotension • phlebitis • convulsions • chills • dizziness • headache • acidosis fluid/electrolyte imbalances thirst • nausea • vomiting • blurred vision

31. Drugs / N acetylcysteine • Indications • Indicated for the treatment of paracetamol (acetaminophen) overdose, NAC is most effective if started within 8 hours after ingestion. The dose required for toxicity may be lower in patients with risk factors such as alcohol abuse or low body weight (diminished cytochrome P450 activity/reduced glutathione levels), or when paracetamol is co ingested with other drugs, such as codeine which increases gut transit time and enzyme inducing drugs such as phenytoin and carbamazepine. In such cases, the patient should be considered ‘high risk'. In all other cases of unstaggered (acute ingestion) overdose NAC should be started immediately. In a staggered overdose (multiple overdoses taken over a period of time) the paracetamol level cannot be interpreted based on the nomogram and one must assess the risk of hepatoxicity based on close alone. If any doubt regarding timing, dose or risk factors exists treatment should be commenced and continued until it becomes clear that hepatotoxicity is unlikely. Patients that present within 4 hours after ingestion should also be treated with activated charcoal for decontamination. • Posology • 20 hour IV protocol according to Prescott et al.: • Administer an initial loading dose of 150 mg/kg lV over 15 to 60 minutes (60 min is recommended) Next, administer a 4 hour lV infusion at 50 mg/kg per hour • Finally, administer a 16 hour IV infusion at 100 mg/kg per hour • The required dose of NAC should be diluted in 5% dextrose as follows: • Adults and children >12 years: Initially 200ml over 15 mins, then 500ml over 4 hours, then 1L over 16 hours Children <12 years, body weight >20kg: Initially 100ml over 15 mins, then 250ml over 4 hours, then 500ml over 16 hours Children body weight <20kg: Initially 3ml/kg over 15 mins, then 7ml/kg over 4 hours, then 14 ml/kg over 16 hours. • The treatment period may be extended if patients have large ingestions, or elevated serum transaminase activity or increased INR.

32. Algorithms • Referral to specialist centre in a timely fashion is paramount in order to achieve good outcomes. • Encourage early referral, with longitudinal assessment by telephone, where appropriate. Referral should not delay start of NAC administration in cases of acetaminophen poisoning if indicated.

33. Hepatic Encephalopathy

34. Definition • Hepatic encephalopathy (HE) is a disturbance in the central nervous system function attributable to hepatic insufficiency and/or portal systemic shunting. • The neurological manifestations are potentially reversible with the normalization of liver function, treatment of precipitating factors or correction of portal systemic shunting. • In some patients, irreversible sequels (brain atrophy, cognitive dysfunction) may persist

35. Clinical presentation

36. Symptoms • Symptoms are variable and depend on the severity of liver failure, the nature of the precipitating factor and the degree of portal systemic shunting. Patients with HE usually request consultation because relatives observe: • Alterations of consciousness (most relevant manifestation) • Cognitive dysfunction (memory loss, confusion, disorientation) • Disturbance of the motor function (asterixis, tremor or apraxia) • Sleep disturbance (insomnia or hypersomnia) • Decline in their performance of social activities • Increase in the numbers of falls

37. Physical findings and signs • Physical signs are variable, depending on the stage of HE. • Common signs include: • Somnolence • Confusion • Bradykinesia • Asterixis (flapping motions of outstretched, dorsiflexed hands) • Dysarthria • Ataxia • Progressive alterations in muscular reflexes • Coma • Uncommon signs include: • Seizures . • New onset of focal deficits • Nystagmus

38. Chronology • Disturbance in the sleep pattern (insomnia during the night or hypersomnia during the day) is usually present and typically precedes overt neurological manifestations. • More advanced neurologic features include bradykinesia, asterixis, hyperactive deep tendon reflexes, and, less commonly, transient decerebrate posturing. • Some patients may exhibit focal neurologic deficits (e.g. hemiplegia) that resolve after resolution of HE.

39. Diagnosis

40. Diagnosis generalities • For establishing the diagnosis of HE it is necessary to demonstrate encephalopathy that is attributable to liver failure or portal systemic shunting. • Clinical and laboratory data should exclude other causes of mental status changes. The severity of encephalopathy is established according to the degree of neurological impairment and could be quantified by a categorical or a continuous approach. • HE is divided into episodic or persistent based on its clinical course and presentation over time. • Patients with episodic HE do not exhibit clinically detectable manifestations between episodes. Contrastingly, patients with persistent HE never become free of HE. Those with minimal hepatic encephalopathy (MHE) exhibit neuropsychological impairment that remains below the clinical detection level and is detected with several psychometric and electrophysiological methods.

41. Laboratory findings • No specific laboratory tests for the diagnosis of HE. • Patients should be evaluated for exclusion of other non hepatic causes of encephalopathy.

42. Radiology findings • Abdominal imaging should be performed to exclude underlying disorders (hepatocellular carcinoma, large portal systemic shunts). Various imaging techniques can be used; being the most valuable computed tomography (CT), magnetic resonance (MR), and endoscopic ultrasonography. • Neurological Imaging: CT head or MR brain are useful to exclude alternative diagnoses (e.g. stroke, viral encephalitis, Wernicke’s encephalopathy, etc.) • MRI of the brain can detect a series of abnormalities that are characteristically present in the brain of cirrhotic patients who develop HE: • 1. Deposition of paramagnetic substances in the basal ganglia (high T1 intensity in pallidum). • 2. A decrease in the size of the brain, particularly in those with alcoholic cirrhosis. • 3. An increase in brain water (research settings). • 4. Changes in organic osmolytes. • MR spectroscopy of the brain (available in some centers) shows atypical pattern in HE patients: an increase in the glutamine peak and a decrease in the choline-containing and myo-inositol peaks.

43. Other procedures • The diagnostic value of blood ammonia levels to establish liver failure and hepatic encephalopathy has not been established. Nevertheless, it may be useful as a part of the initial work up. There is a high variation in the concentration of blood ammonia in individual patients. Furthermore, several non hepatic conditions can elevate blood ammonia levels and the pre processing of the sample has to be performed very rapid and careful to avoid spurious results. • The recommendation is to limit ammonia determination to estimating the risk of brain edema in patients with acute liver failure, i.e. not in patients with cirrhosis. • Therapeutic decisions should be taken according to the course of encephalopathy, not to evolution of ammonia levels.

44. Differential diagnosis • Evaluation of a patient with cirrhosis and an acute change in mental status should be initiated by excluding toxic, metabolic, and structural encephalopathies. • In parallel, the patient should be assessed to investigate precipitating factors and undergo blood tests and imaging studies to evaluate liver function and portal systemic circulation.

45. Scores

46. Clinical Hepatic Encephalopathy Staging Scale (CHESS) • The Clinical Hepatic Encephalopathy Staging Scale (CHESS), as compared to other clinical scales, was developed without a previous arbitrary definition of the severity of hepatic encephalopathy. The proposing authors assessed the presence or absence of 48 items in a group of 36 patients with episodic hepatic encephalopathy. The items were selected by a group of experts and were finally reduced to 9 after applying principal component analysis. This is currently undergoing independent validation. • Interpretation: The final CHESS is a linear scale that scores HE from 0 (unimpaired) to 9 (deep coma). The CHESS shows good metric characteristics in terms of internal consistency, reproducibility, criterion-related validity, and external responsiveness, but it needs to be validated in other patient samples and other centres. The Hepatic Encephalopathy Scaling Algorithm (HESA) and the CHESS, complemented with the Glasgow Coma Score, are adequate for clinical trials.

48. Confusion Assessment Method (CAM) • In patients with apparently unimpaired mental status or chronic low grade hepatic encephalopathy, assessment of cognition can benefit from the application of neuropsychological tests. However, psychometric tests are not adequate for patients with a decreased level of consciousness; hence, confusion should be excluded before beginning neuropsychological testing. • This is easily done with the four questions provided in the Confusion Assessment Method. • Interpretation: Delirium (acute confusional syndrome) is diagnosed when 1+2+3a or 1+2+3b.

49. Glascow coma scale

50. Psychometric Hepatic Encephalopathy Score (PHES) • The Psychometric Hepatic Encephalopathy Score (PHES) has been specifically developed to measure the effects of MHE, and has been shown to be sensitive to impairment in patients with cirrhosis. • This battery has showed good correlation with functional neuroimaging results in these patients. • The PHES battery is composed of five neuropsychological tests: • Digit Symbol Test (DST), • Number Connection Tests A and B (NCTA, NCT B), • Serial Dotting Test (SDT), • Line Drawing Test (LDT).