Acute liver failure by Prof Dr Ahmed Elgohary

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

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.

Clinical presentation

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.

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.

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.

Diagnosis

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 whethere 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.

Laboratory findings Hematology (complete blood count) and PT/INR Biochemistry: AST, 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 lg. M, HBs. Ag, anti HBC lg. M, 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

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.

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.

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.

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 haemophagocytic lymphohistiocytosis (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

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

Scores

Scores / Bi. LE Description: The Bi. LE 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 (umo. I/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 103 umol/L vs 263 umo|/L in the death or transplantation group. Similarly, mean lactate level was 2. 9 vs 4. 7 mmol/L.

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.

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: p. H <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/d. L)

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 umo. I/L (>17 mg/d. L) Unfavorable etiology, such as Wilson Disease, idiosyncratic drug reaction, seronegative hepatitis

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

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.

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.

Management and therapy

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

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.

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.

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.

Drugs / Mannitol 20% The treatment of cerebral oedema and the reduction of raised intracranial pressure. Posology Early studies used 1 g/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 l. CP 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 320 mosmol/kg. Furosemide 1 mg/kg has a similar effect on ICP to 1 g/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

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 P 450 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 l. V over 15 to 60 minutes (60 min is recommended) Next, administer a 4 hour l. V 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 200 ml over 15 mins, then 500 ml over 4 hours, then 1 L over 16 hours Children <12 years, body weight >20 kg: Initially 100 ml over 15 mins, then 250 ml over 4 hours, then 500 ml over 16 hours Children body weight <20 kg: Initially 3 ml/kg over 15 mins, then 7 ml/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.

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.

Hepatic Encephalopathy

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

Clinical presentation

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

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

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.

Diagnosis

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.

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

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 T 1 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.

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 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.

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.

Scores

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.

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+3 a or 1+2+3 b.

Glascow coma scale

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).

West Haven scale The West Haven scale establishes four stages of episodic hepatic encephalopathy based on alterations in the state of neuromuscular Hepatic encephalopathy, consciousness, intellectual function, and behavior, and on syndromes and therapies. Interpretation The scale includes several manifestations for each stage, but lacks specific definitions. In clinical practice, doctors do not check for the presence of all the manifestations listed; instead, they use the scale in an intuitive way (0 = absence of HE, 1 = mild manifestations, 2 = moderate manifestations, 3 = severe manifestations, 4 = coma). This makes HE grading subjective, a fact that does not invalidate the scale in individual cases, but causes discrepancies between different assessors. This limitation, which is especially relevant in clinical trials, has been overcome in the various adaptations of the West Haven scale.

Management and therapy

General measures Nutritional aspects: patients with cirrhosis who develop HE should receive a nutritional intake that satisfies their needs. Protein restriction has not shown to improve the outcome. The amount of protein necessary for a balanced nitrogenous metabolism has been calculated to be 0. 7 0. 8 g/kg of protein. Protein intake has been recommended to reach 1. 2 g/kg to cover nitrogenous needs of 95% of the population of patients with cirrhosis. Vegetable enriched diets have some superior effects, but they may be explained by the presence of high fiber content. Supplementation with branched chain aminoacids have shown some benefits in some indexes, but its use is currently limited to refractory HE, especially in malnourished patients who do not tolerate high protein diets (>0. 8 g/kg/d). Prevention of motor vehicle accidents: cognitive decline has been associated with impaired driving skills. Avoid activities that need high levels of concentration or precision tasks (eg. heavy machinery): Patients with minimal hepatic encephalopathy (MHE) have attention, response inhibition, and working memory difficulties that are associated with navigation difficulty. Falls are frequent in patients with MHE. Prevention of falls implies counselling: Avoid slippery floors Use adequate footwear Assess the need of eye glasses Recommend a walking stick if necessary Avoid walking alone Encourage physical activity Modify environmental difficulties

Specific measures / Acute episode Indications Assessment for airway protection is mandatory in all inpatients with presumed HE. Patients with a Glasgow coma scale < 8 points should be considered for oral intubation. Nutritional therapy should be initiated in all patients with HE. The enteral route is always preferred (specialized nursing is necessary to avoid respiratory aspiration). Limit the parenteral route to patients with digestive intolerance (vomiting, ileus. . . ). Gut cleansing is indicated in all patients with an acute episode of HE. Enemas of lactulose/lactitol should be part of the initial treatment of hospitalized patients. Supervised transfers of hospitalized patients are indicated for all patients with overt HE to minimize the risk of falls. Measures to avoid self injury should be instituted, including restraining strips if necessary. Continuous monitoring respiratory function (pulse oximetry) is recommended for those in stage III IV that have not been intubated and ventilated.

Drugs / Lactitol Indications Lactitol enema is indicated as initial treatment in patients with overt HE and orally if the patient is able to tolerate the oral route. Lactitol its indicated in the acute episode of HE, treatment of persistent HE and as a first line for prophylaxis for HE recurrence. Posology Oral dose of 10 g every 6 hours to induce 2 -3 soft bowel movement daily. Rectal administration of 200 -300 g of lactitol solution should be mixed with 700 m. L of water or physiologic saline and retained for 30 to 60 minutes. Lactitol enema may be repeated every 4 to 6 hours. If this lactitol enema is inadvertently evacuated too promptly, it may be repeated immediately. Interactions Non absorbable antiacids: may inhibit the desired lactitol induced drop in colonic p. H. Other laxatives: may falsely suggest that adequate lactitol dosage has been achieved.

Side effects Abdominal distention Flatulence Belching Cramps (20% of patients) Diarrhea Hypokalemia Hypernatremia Nausea Vomiting Precautions infants receiving lactitol may develop hyponatremia and dehydration.

Drugs / Lactulose Indications Lactulose enema is indicated initially in patients with overt HE. The drug can be given orally if the patient is able to tolerate the oral route. Lactulose is indicated in acute episodes of HE, persistent HE and for prevention of recurrence. Posology Oral dose of 20 g (15 -30 ml) 2 -4 times dailly to induce 2 -3 soft bowel movement daily. Rectal administration of 200 -300 g of lactulose solution should be mixed with 700 m. L of water or physiologic saline and retained for 30 to 60 minutes. Lactulose enema may be repeated every 4 to 6 hours. If this lactulose enema is inadvertently evacuated too promptly, it may be repeated immediately. Interactions Non absorbable antacids: may inhibit the desired lactulose induced drop in colonic p. H. Other laxatives: may falsely suggest that adequate lactulose dosage has been achieved. Side effects Abdominal distention Flatulence Belching Cramps (20% of patients) Diarrhea Hypokalemia Hypernatremia Nausea Vomiting

Precautions Since lactulose solution contains galactose (less than 1. 6 9/15 m. L) and lactose (less than 1. 2 9/15 m. L) it should be used with caution in diabetics. lnfants receiving Iactulose may develop hyponatremia and dehydration.

Drugs / Ornitine aspartate Indications This is a substrate for ureagenesis and allows the conversion of ammonia to urea and glutamine. Ornitine aspartate has been use in the EU in the treatment of the acute episode of HE as well as in the chronic phase of the disease. However, the data on efficacy is conflicting and not FDA approved for the treatment of HE. Posology Orally 6 -10 g every 8 hours. Intravenously: 20 -30 g /day. Side effects Nausea Abdominal pain Vomiting

Drugs/Rifaximin Indications: Rifaximin is a minimally absorbed oral antibiotic indicated for the secondary prophylaxis of HE (after at least 2 episodes of overt HE). Posology Rifaximin is given orally, at the dose of 550 mg twice daily or 400 mg three times a day, depending on the formulation available. side effects Nausea (14%) Vomiting Flatulence Abdominal pain Constipation Dizziness (13%) Headache (10%) Muscle spasms (9%) Myalgia Anemia (8%) Cough Nasopharyngitls Rhinitis Depression Insomnia Urticaria (rare) Angloedema (rare)

Sodium benzoate Indications: forms hippuric acid when interacting with glycine, Hippurate has renal excretion thereby providing an alternative mechanism for ammonia excretion. It has been indicated in the treatment of the acute episodes and chronic phases of the disease. Posology: orally 5 g twice daily Interactions: Penicillins Probenicid Valproic acid Side effects: Free water retention (high sodium load)

Zinc sulfate/ zinc acetate Indications: is a cofactor for several enzymes of the urea cycle and enhances urea formation. In cases of refractory HE, zinc deficiency should be corrected if present. Posology: orally 600 mg/day Side effects: Abdominal pain Gastritis Precautions: Mild elevation of serum alkaline phosphatase, amylase and lipase

Algorithms

Thank you