ACUTE HEPATIC FAILURE

Acute hepatic failure (AHF) is a life-threatening event, characterized by rapidly progressive hepatocellular dysfunction and multisystemic manifestations, e.g. encephalo­pathy, coagulopathy, hemodynamic disturbances and dyselectrolytemia.

While acute liver failure may also develop in cases with pre-existing chronic liver disease, AHF is usually defined as:

• Biochemical evidence of liver dysfunction for lt; 8 weeks duration,

• Coagulopathy with INR gt;1.5 in patients with encepha­lopathy or gt;2.0 in those without encephalopathy, not corrected by vitamin K, and

• No evidence of chronic liver disease.

Depending on the onset and course, liver failure is classified as fulminant (lt;1 week), acute (1-4 weeks), sub­acute (4 weeks to 6 months) and chronic (gt;6 months).

Etiology: AHF in children is usually infective, toxic or metabolic in origin (Table 15.8). Viral hepatitis, autoimmune hepatitis and metabolic disorders, e.g. Wilson disease are predominant causes of AHF in children. However, 30-40% cases are idiopathic.

Cases with pre-existing liver disease may also develop AHF due to superimposed insult lie viral, toxic or drug- induced hepatic injury.

Pathologically, AHF is characterized by massive necrosis of hepatocytes, loss of normal hepatic architecture and occasionally cholestasis, apart from features of primary disease.

Pathogenesis: Sudden and severe impairment in metabolic and excretory liver functions is the hallmark of AHF. Gastrointestinal bleeding, hypoglycemia, hypokalemia, drug therapy, abdominal paracentesis and high protein meal are common precipitating factors for AHF in cases with pre-existing liver disease.

TABLE 15.8: Important causes of AHF in Indian children

• Infective (60-90%)

- Viral hepatitis: HAV, HEV, HBV, others.

- Leptospirosis

- Fulminant bacterial septicemia

• Drug and toxins: (6-8%)

- Drugs: INH, rifampicin, Na valproate, anesthetics

- Poisoning: Paracetamol, heavy metals

• Metabolic

- Reye syndrome

- Wilson disease

- Inborn errors: Galactosemia, tyrosinemia

- Indian childhood cirrhosis

• IschemicZhypoxic

- Circulatory shock

- Vascular obstruction: Budd-Chiari syndrome

• Malignancies (primary/metastatic)

EBV: Epstein-Barr virus, CMV: Cytomegalovirus

Hyperammonemia d ue to impaired detoxification of ammonia into urea is the most important cause of hepatic encephalopathy, characterized by severe cerebral edema and intracranial hypertension.

Clinically important features of AHF include:

• Encephalopathy of variable severity-subtle mental changes, e.g. altered personality and abnormal sleep pattern, are earliest indicators of hepatic ence­phalopathy, which may rapidly progress to coma (Table 15.9). However, presence of encephalopathy is not essential for diagnosis of AHF in children.

• Progressive deep jaundice, though highly suggestive, is also not essential, as many cases succumb before the appearance of jaundice.

• Other signs of hepatic damage include: (i) fetor hepaticus, i.e. ammonical breath odor and intractable vomiting due to hyperammonemia, (ii) bleeding tendency due to deficiencies of vitamin K dependent clotting factors, (iii) dyselectrolytemia with metabolic acidosis, (iv) ascites due to hypoproteinemia, and (v) diarrhea due to fat malabsorption

• Hepatomegaly may or may not be present. Absence of hepatomegaly or rapid reduction in liver size is a bad prognostic indicator in AHF.

• Secondary complications are common, e.g. fulminant infections due to impaired immunity, renal failure (acute tubular necrosis), pulmonary complications (aspiration, pulmonary edema), etc.

Laboratory investigations are needed to identify the cause as well as to monitoring progression of liver damage and include:

• Hematological:

- CBC (leukocytosis, thrombocytopenia)

- Coagulation profile, e.g. prothrombin time

• Biochemical:

- LFT, e.g.

- Serum ammonia (elevated in encephalopathy)

- Serum proteins (reduced with altered A:G ratio)

- Serum electrolytes, e.g. Na⁺, K⁺, HCO₃^-, Ca⁺⁺

- Blood glucose (hypoglycemia)

- Blood gas analysis (metabolic acidosis)

• Microbiological: Cultures, viral serology

• EEG to confirm/monitor encephalopathy

• Specific etiological investigations

Management of AHF is non-specific and aims to provide life support and prevent/treat complications till spontaneous recovery. All patients need intensive care and monitoring. Important measures include:

• Stabilization of hemodynamic status with fluid therapy, volume expanders, e.g. plasma, and vasopressor agents.

• Continuous monitoring for—(a) vital signs, (b) intake/ output, (c) neurological assessment, (d) biochemical parameters, e.g. electrolytes, blood gases, blood sugar, PT/INR, LFT, (e) urine output and renal functions, and (f) sepsis.

• Gut sterilization to reduce ammonia production, produced due to breakdown of food-proteins or blood, by ammonia-producing microbial flora. Important measure to prevent it include:

- PO Rifaximin (20-30 mg/kg/day) or Neomycin to eliminate ammonia-producing organisms

- PO Lactulose (10-50 ml 4 hourly) to produce acidic media and reduces activity of organisms, dose must be adjusted to produce 2-4 loose motions per day.

• Fluidlelectrolyte therapy is guided by intake­output record, central venous pressure monitoring and electrolyte estimation. Generally, N/2 saline in DW 10% with 15 mEq/l of potassium is used to provide 90% of total maintenance fluid requirements. However, volume and composition of IV fluids needs to be modified according to electrolyte status, specially to keep sodium levels between 145-155 mEq/l. Hypoglycemia, hypokalemia and metabolic acidosis are very common and need to be treated promptly.

• Cerebral edema is the major cause of mortality and needs to be treated promptly by IV Mannitol (0.5-1 g/kg/dose) or hypertonic saline, and controlled ventilation to prevent CO₂ retention.

• Coagulopathies must be treated with fresh frozen plasma, platelets and IV vitamin K supplements (5-10 mg/day). Blood transfusion should be avoided, if possible. Cryoprecipitate may be used in low- fibrinogen states (lt;100 mg/dl). Plasmapheresis is useful to eliminate anticoagulant and fibrinolytic products, produced during hepatic injury.

• Esophageal variceal bleeding may require endoscopic sclerotherapy or ligation in emergency, though IV Octreotide (1-10 pg/kg 12 hourly) may be useful, if endoscopy is not possible. Antacids or proton pump inhibitors may also benefit in GIT bleeding.

• Treatment of other complications, e.g. ascites, renal failure (dialysis) and infections. Empirical antibiotic therapy, though controversial, is preferable in all cases, which must be modified after cultures. N-acetyl cysteine-A glutathione precursor (IV infusion 100 mg/kg/d) may or may not be useful even in non-acetaminophen induced AHF, due to anti­inflammatory, antioxidant, inotropic, and vasodilating effects.

• Removal of toxic metabolites by activated charcoal, plasmapheresis or exchange transfusion may be attempted in non-responsive cases.

• Liver transplantation, is the final option in refractory cases, with success rate of 60-80%.

Prognosis: Overall mortality in AHF is very high (70%), but still better in children than in adults. Bad prognostic factors include—(a) rapid onset of encephalopathy within 7 days of icterus, (b) prothrombin time gt;50 seconds, (c) serum bilirubin gt;17.5 mg/dl, (d) stage IV coma, and (e) multi-organ failure.

15.6