Acute Liver Failure - Standard Treatment Guidelines

Acute Liver Failure (ALF) is defined as acute hepatitis (elevation in AST/ALT) accompanied by elevation in INR >1.5 and any degree of mental alteration (encephalopathy) within 12 weeks of onset of symptoms, in the absence of chronic liver disease. Its presentation is rapid, dramatic and frequently leads to death over the course of a few days in the absence of emergency liver transplantation.

Ministry of Health and Family Welfare has come out with the Standard Treatment Guidelines for Acute Liver Failure. Following are its major recommendations for Acute respiratory distress syndrome.

Incidence

The exact incidence of ALF in the Indian subcontinent is not known. However, viral hepatitis leading to acute liver failure is the commonest cause in our country. In western countries, the commonest cause of ALF is paracetamol poisoning and it is a relatively uncommon disease (e.g., it affects about 2500 patients in the United States each year). Since there is a high load of hepatotropic viruses in India, the incidence of ALF may probably be higher.

Prognosis

ALF carries a high mortality rate with 15-20% survival without orthotopic liver transplantation (OLT). In developed countries, liver transplantation has revolutionized the prognosis of this disease and survival rates are in the range of 59 to 79%, with liver transplantation. Moreover, it accounts for about 5-11 % of liver transplants among adults.

Hepatitis A, paracetamol overdose and ischemic insults typically present as hyper acute liver failure, and have a relatively good spontaneous survival rate of 36%, whereas idiosyncratic drug reactions and indeterminate causes present later, with only a 14% survival rate without OLT. The other etiologies with very poor prognosis include acute hepatitis B (and other non-hepatitis A viral infections), autoimmune hepatitis, Wilson’s disease and Budd-Chiari syndrome. Patients presenting in grade III/IV encephalopathy also have a very poor prognosis.

Differential diagnosis

Differential diagnosis includes severe malaria, leptospirosis, rickettsial diseases, enteric fever, and Hanta virus infection.

Clinical features

The initial clinical features of ALF may be non-specific, and may include anorexia, fatigue, abdominal pain, jaundice and fever before progressing to hepatic encephalopathy.

Hepatic encephalopathy is graded from I to IV based on clinical features and neurological signs.

Grades of Hepatic encephalopathy

I	Changes in behaviour with minimal change in level of consciousness
II	Gross disorientation, drowsiness, possibly asterixis, inappropriate behaviour
III	Marked confusion, incoherent speech, sleeping most of the time but arousable to verbal stimuli
IV	Comatose, unresponsive to pain, decorticate or decerebrate posturing

This grading is clinically robust and increasing grades of hepatic encephalopathy have a strong negative correlation with outcome. The evolution to grade III/IV HE is a grave prognostic sign as this group is at risk of intracranial hypertension, and subsequent brain herniation.

Clinical signs suggestive of increasing intracranial pressure include worsening of hepatic encephalopathy, systemic hypertension and bradycardia (Cushing reflex), altered pupillary reflexes and decerebrate rigidity. All of these clinical signs occur late in the clinical course.

Causes

Etiological category	Specific causes
Viral	HAV, HBV±HDV, HRV, HSV Human herpes virus 6, CMV, EBV, VZV, Parvovirus B19, Yellow fever
Drug/toxin induced (dose dependent)	Paracetamol, Amanita phalloides, tetracyclines, Bacillus cereus, carbon tetrachloride
Drug/toxin induced (idiosyncratic)	Halothane, anti-tubercular therapy, co-amoxiclav, macrolides, ofloxacin, phenytoin, valproate, statins, NSAIDs, disulfiram, metformin, dapsone, amiodarone, labetolol, methyl dopa, HAART, etoposide, ecstasy/amphetamines, cocaine, herbal remedies, etc
Vascular	Ischemic hepatitis, Budd Chiari syndrome, right heart failure, veno-occlusive disease
Metabolic	Wilson’s disease, acute fatty liver of pregnancy, HELLP
Miscellaneous	Autoimmune hepatitis, malignant infiltration, sepsis, heat stroke
Others	Cryptogenic

Criteria for hospital admission

All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have immediate measurement of prothrombin time and careful evaluation for subtle alterations in mentation. If the prothrombin time is prolonged by >4-6 seconds or more (INR>1.5) and there is any evidence of altered sensorium, the diagnosis of ALF is established and hospital admission is mandatory.

Criteria for ICU admission

Patient with any one of the following:

• Altered sensorium: Patients in grade I and perhaps, grade II encephalopathy, could be managed in a ward. However, rapidly worsening encephalopathy or grade III/IV encephalopathy warrants ICU admission.


• Respiratory distress, i.e., respiratory rate >30/m.


• Any evidence of gastrointestinal bleeding


• Any hemodynamic instability

Optimal diagnostic criteria, investigations, treatment and referral

A. Non metro/ Secondary hospital

Investigations

2) Prothrombin time(PT)/INR

3) Chemistries: serum sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, glucose

4) Liver function test: AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin

5) Renal function test : serum creatinine, blood urea nitrogen

6) Arterial blood gas (with arterial lactate, if possible)

7) Complete blood count

8) Blood type and screen

9) Viral hepatitis serologies: anti-HAV IgM, HBsAg, anti-HEV.

10) Ultrasound abdomen to look at the echotexture of the liver and rule out chronic liver disease/ Budd-Chiari syndrome.

11) Blood culture

12) Blood smear for malaria, serology for Dengue and Widal test in selected cases (based on clinical suspicion)

Laboratory monitoring

Frequency to repeat tests	Tests
Twice daily	Blood glucose (bedside glucostix adequate)
Daily	PT, serum sodium and potassium Arterial blood gas
Alternate day	Blood count, serum creatinine
Twice weekly	Magnesium, phosphate

Treatment

1) Nutrition: A carbohydrate rich diet with protein restriction (60 g/day) is recommended. If enteral feeds are not tolerated, dextrose infusion should be started. A record of intake and output should be maintained and a positive balance of no more than 500 ml is acceptable.

2) Bowel decontamination with lactulose and antibiotic for gut sterilization (ampicillin / metronidazole / rifaximin)

3) Intravenous ranitidine or proton pump inhibitors.

4) Rehydration is required in many patients as they may be dehydrated at admission due to vomiting and anorexia. Subsequently, maintain euvolemia.

5) Careful and repeated neurological examination for grade of encephalopathy and evidence of cerebral edema is mandatory.

6) Avoid sedation in grades 1 and 2 encephalopathy.

7) All patients in grade 3 or 4 hepatic encephalopathy should be intubated electively for airway protection. In addition, respiratory support and mechanical ventilation should be provided for those with inadequate respiratory effort.

8) Treatment for clinical evidence of cerebral edema includes:

1. Elevation of head end of the bed to 15-30°


2. Head in neutral position


3. Limiting all nonessential physical examination


4. Maintaining normotension (mean arterial pressure atleast 70-80 mm Hg)


5. Hydrotherapy for fever control; judicious use of paracetamol to control fever


6. Prevent hypo and hyperglycemia


7. Parenteral mannitol (for raised ICP) in 0.5-1 gm/kg boluses


8. Look for and correct hypercapnia and hypoxemia

9) Give one dose of vitamin K. Fresh-frozen plasma transfusion is required for bleeding manifestations, as and when required. Platelet transfusion is required for platelet counts <10,000/mm3 or invasive procedures.

10) N acetyl cysteine should be given in patients with acetaminophen induced ALF.

11) The role of antibiotics is not definitive. However, in grades 3 and 4 encephalopathy, prophylactic antibiotics may be advisable. Third generation cephalosporin, e.g., Ceftriaxone, is adequate.

Referral

The following are reasons for referral to a higher centre:

1) Liver transplantation: Planning for transfer to a transplant center should begin in patients with grade I or II encephalopathy because they may worsen rapidly. Early transfer is important as the risks involved with patient transport may increase or even preclude transfer once stage III or IV encephalopathy develops.

2) Renal replacement therapy: Renal replacement therapy forms an integral part of care given to all patients with renal failure. Continuous modes of dialysis such as continuous veno-venous hemofiltration are better as hemodynamic stability is maintained and fluctuations in intracranial pressure are avoided.

3) Transfusion requirement: Patients with significant gastrointestinal bleed should be referred to an institution where blood products can be arranged adequately.

B. Metro/ Super specialty situation

Investigations

All those listed in the previous section. In addition, the following may be added:

1) Toxicology screen including acetaminophen level

2) Serum Ceruloplasmin

3) Serum ammonia ( if possible)

4) Autoimmune markers: Antinuclear antibody, anti smooth muscle antibody, anti liver-kidney microsomal antibodies, Immunoglobulin G level

5) HIV status (liver transplant)

6) Liver biopsy (via the transjugular route) may be done, if expertise with this technique is available.

Laboratory monitoring

Frequency to repeat tests	Tests
Four times a day	Blood glucose (bedside glucostix adequate)
Twice daily	Serum sodium and potassium, Arterial blood gas
Daily	PT/INR, blood count
Alternate day	Serum creatinine, magnesium
Twice weekly	Serum phosphate, Liver function tests

Treatment

Treatment enumerated in the previous section should be instituted. The following are recommended, in addition.

1) Enteral nutrition is preferred and should be started through a nasogastric tube. Total parenteral nutrition may be considered, in case enteral nutrition is not tolerated or there are contraindications. However, the risk of fungal infections increases with parenteral nutrition.

2) Invasive hemodynamic monitoring in the form of intra-arterial blood pressure and central venous pressure monitoring.

3) Maintenance of adequate cerebral perfusion pressure Keeping mean arterial pressure >80mm Hg. - PaCO2 in the range of 30-35 mm Hg.

4) In ventilated patients, sedation should be instituted to avoid coughing and bucking on endotracheal tube. Bolus of lignocaine and sedation should be given prior to suctioning.

5) Pts with renal failure should be started on continuous renal replacement therapy to minimize fluctuations in intracranial pressure during dialysis.

6) Urgent hepatic transplantation is indicated in acute liver failure where prognostic indicators suggest a high likelihood of death.

7) Artificial and bio-artificial liver devices may be used as bridge to liver transplant.

Complications

Infection

If antibiotics are not given prophylactically, surveillance for infection (including chest radiography and periodic cultures of sputum, urine and blood for bacterial and fungal organisms) should be undertaken. In case the patient develops ascites, spontaneous bacterial peritonitis should be ruled out. A low threshold for starting appropriate anti-bacterial or anti-fungal therapy should be maintained.

Bleeding

Replacement therapy for thrombocytopenia and/or prolonged prothrombin time is recommended only in the setting of hemorrhage or prior to invasive procedures. Prophylactic platelet transfusions are needed only for platelet count <10,000/mm3 .

Criteria for referral for liver transplant

Several prognostic indicators suggest a high likelihood of mortality and in these patients, liver transplantation is the only option. Currently available prognostic scoring systems do not adequately predict outcome; neverthless, the King’s college hospital criteria (KCH criteria) have been most commonly used and most frequently tested of the several criteria proposed.

Kings College Hospital Criteria

Etiology of ALF	Criteria predicting death
Acetaminophen overdose	Arterial pH <7.30 OR All of the following: PT > 100 seconds (INR > 6.5) Creatinine level > 3.4 mg/dL Grade III/IV encephalopathy
Non-acetaminophen overdose	PT > 100 seconds (INR > 6.5 ) OR Any three of the following: Non A non B hepatitis/drug/halothane Jaundice to encephalopathy interval > 7 days Age < 10 years or > 40 years PT >50 seconds (INR >3.5) and bilirubin level >17.4 mg/dL

Prevention & Counseling: Hepatitis A & E, which spread mainly by faeco-oral contamination, can be controlled by clean and safe water supply & other hygienic measures. . Universal precautions, viral screening of blood for Hepatitis B & C should be made mandatory. Recycling of syringes should be discouraged and declared unlawful.

Guidelines by The Ministry of Health and Family Welfare :

Dr AK Baronia, Professor & Head, Department of Critical Care Medicine, SGPGI, Lucknow