Acute liver failure is a dangerous disease that causes liver malfunction. It may heal or require, in cases with a more severe course, a liver transplant

Acute liver failure in childhood, although rare, is a serious disease

It is caused by massive and rapid damage to liver cells (hepatocytes) with associated reduced liver function.

It must be recognised and treated early as it can rapidly progress irreversibly to the point of requiring liver replacement and, in severe cases, leading to death.

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The main causes of acute liver failure can be grouped into the following broad categories:

• Viral infections: major hepatotropic viruses (A, B, B+D, E), non-A, non-G hepatitis, varicella-zoster virus, measles, adenovirus, Epstein-Barr virus, cytomegalovirus, echovirus, yellow fever, lassa, ebola, Marburg, Dengue, Toga virus (rarely), etc;
• Bacterial infections: salmonellosis, tuberculosis, sepsis, malaria, bartonella, leptospirosis;
• Medications: Paracetamol, Halothane, acetylsalicylic acid, solvents, Sodium valproate, Carbamazepine, Lamotrigine, antibiotics (Penicillin, Erythromycin, Tetracyclines, etc.), Isoniazid, Phenytoin, Non-steroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen, Ketoconazole, Amiodarone, Allopurinol;
• Intoxications: Amanita phalloides (mushroom intoxication), herbal medicines, yellow phosphorus, Chlorobenzene, industrial solvents;
• Metabolic diseases: galactosemia, tyrosinemia, hereditary fructose intolerance, neonatal haemochromatosis, Niemann Pick type C disease, Wilson’s disease, mitochondrial diseases, congenital defects of glycosylation;
• Autoimmune diseases: gigantocellular hepatitis with Coombs-positive haemolytic anaemia;
• Haematological diseases: haemochromatosis, marcrophage activation syndrome, familial lymphohistiocytosis, lymphomas;
• Vascular diseases: veno-occlusive disease (VOD), Budd-Chiari syndrome.

In relation to age, in children under 5 years of age toxic, pharmacological, infectious and autoimmune causes are more frequent, whereas in older children autoimmune causes and Wilson’s disease are more frequent.

However, in between 18% and 47% of cases, the cause cannot be identified and is referred to as a picture of ‘unknown origin’.

One of the very frequent causes of acute liver failure in paediatric patients is Paracetamol (N-acetyl-p-aminophenol) toxicity

Symptoms of toxicity appear when the administered dose exceeds 150 mg/kg/day: it may result from a single administration or from several administrations over 24 hours.

Early recognition of the first symptoms of liver failure is crucial: it allows doctors to quickly refer the child to referral centres specialised in paediatric haematology and able to transplant the child’s liver if necessary.

Acute liver failure must be suspected in all children with:

• Jaundice, yellowish discolouration of the skin and eyes;
• Unexplained bleeding (epistaxis, gingivorragia, etc.);
• Appearance of reddish haemorrhagic spots under the skin and mucous membranes (purpura);
• Changes in neurological state with irritability, crying, drowsiness, confusional state (encephalopathy).

Other symptoms may be:

• Malaise;
• Persistent lack of appetite (anorexia);
• Sweetish breath odour (fetor hepaticus);
• Motor dysfunction;
• Abnormal increase in heart rate (tachycardia);
• Abnormal increase in breathing frequency (tachypnea);
• Lower blood pressure (hypotension);
• Sepsis (a general infection of the body);
• Cerebral oedema.

Diagnosis first requires a careful collection of the child’s history and an equally careful examination.

Laboratory tests to confirm the presence and severity of liver failure include determination:

• Of liver enzyme levels;
• Of bilirubin levels;
• Of prothrombin time;
• of albumin levels.

Acute liver failure is usually confirmed if the prothrombin time is prolonged or if consciousness is altered in children with acute liver damage

The tests that are performed during the initial assessment are:

• Blood count;
• Liver function tests;
• Serum electrolytes;
• Renal function tests;
• Urinalysis.

If acute liver failure is confirmed, the following should be performed:

• Haemogas analysis;
• Ammonium levels: high levels are toxic to the central nervous system and suggest encephalopathy;
• Determination of lactate levels, which rise if the liver is unable to dispose of them;
• Blood type;

Determination of levels of factor V, a protein produced by the liver that is necessary for blood clotting.

Instrumental examinations include ultrasound with Doppler study of the liver.

Liver biopsy, which is performed to observe a liver fragment under a microscope, is not performed in the context of liver failure because it is dangerous; the possible indication, depending on the values of the coagulation parameters (INR < 1.5) is usually decided on a case-by-case basis.

Once the diagnosis has been established, it is essential to carry out laboratory tests aimed at identifying the causes

• Child’s history: intake of toxic drugs (e.g. paracetamol), mushrooms, drugs, travel to foreign countries.
• Basic examinations:  aspartate-aminotranferase (AST or GOT – glutamic-oxalacetic transaminase) , alanine-aminotransferase (ALT or GPT – glutamic-pyruvate transaminase), total and fractionated bilirubin, alkaline phosphatase, gamma-glutamyl transferase, albuminemia, prothrombin time, tissue thromboplastin time, international normalised ratio, fibrinogen, D-dimers, blood glucose, azotemia, creatinine, sodium, potassium, chlorine, calcium, phosphate, ammonium, acid-base balance, lactate, haemogasanalysis, lacticodehydrogenase, α-fetoprotein, assay of individual coagulation factors, blood count, blood group, Coombs test, erythrocyte sedimentation rate, C-reactive protein, urine test.
• Screening for infectious diseases:
• Culture tests on blood, urine, faeces, CSF;
• Serological, molecular investigations (blood, urine, CSF, respiratory tract swabs, skin) for hepatitis A, B, C and E viruses, herpes viruses (Herpes simplex virus 1 and 2, human herpes simplex virus 6, 7 and 8, cytomegalovirus, Epstein-Barr virus, Varicella zoster virus), adenovirus, enterovirus, parvovirus B19.

Metabolic screening:

• Tyrosinaemia: urinary succinylacetone assay, plasma minoacidogram, pulse X-ray;
• Galactosemia: urine reducing substances, urine sugar chromatography, galactose-1-phosphate-uridyltransferase enzyme activity in the red blood cell;
• Neonatal haemochromatosis: ferritin, salivary gland biopsy for iron deposits, MRI of the pancreas;
• OCT deficiency: plasma aminoacidogram, urinary orotic acid;
• Wilson’s disease: serum ceruloplasmin, 24-hour cupruria basal and after penicillamine loading, Kaiser-Fleischer ring, cupremia, genetic investigation, intrahepatic copper assay
• Reye’s syndrome, β-oxidation defects.

Autoimmune diseases:

• Mitochondrial hepatopathies: mitochondrial DNA, liver and muscle biopsies for quantitative determination of respiratory chain enzymes, lactic acid on CSF, creatinine phosphokinase, echocardiography with cardiac Doppler examination;
• Erythrocyte sedimentation rate, immunoglobulins G, A, M, anti-nuclear autoantibodies, anti-smooth muscle, anti-hepato-renal microsomes, anti-hepatic soluble antigen, anti-hepatic cytosolic antigen type 1, C3 and C4 levels in blood.
• Toxins: blood levels of Paracetamol, Salicylate, urinary toxicology screening, immunoglobulin E.
•  Other causes: lymphohistiocytosis and macrophage activation syndrome triglycerides, cholesterol, ferritin, peripheral smear, bone marrow examination, perforin, natural killer cell activity.

There is no specific effective therapy for advanced acute liver failure, with the exception of liver transplantation.

The management of the patient with acute liver failure is based on the use of all useful measures to support liver function and prepare the patient for an eventual liver transplant.

In particular:

• Medications (Bioarginine, sodium benzoate, lactulose, antibiotics, etc) that help eliminate toxic substances normally disposed of by the liver and thus avoid or mitigate encephalopathy (intoxication of the brain);
• Vitamin K, fresh plasma and and coagulation factors to replace those normally produced by the liver and avoid blood clotting deficits that can be very dangerous (haemorrhage);
• Possible continuous venovenous haemofiltration (CVVH).

It is very important to properly assess the time required to transfer the patient to a transplant centre of reference, evaluating the speed of disease progression and the risks associated with transport.

Specifically, the therapy for Paracetamol toxicity is the administration of N-acetylcysteine as a continuous intravenous infusion, which must be started within 24 hours of Paracetamol ingestion and continued for at least 72 hours or until liver failure has resolved and coagulation has returned to normal.

Despite many attempts, it is still not possible to predict the prognosis of a child with acute liver failure.

The prognosis varies depending on the cause.

The best prognosis, with spontaneous functional recovery of liver cells, is in children with infections or paracetamol intoxication (50-70%).

The worst prognosis is when early encephalopathy occurs; in these cases spontaneous recovery occurs in only 10% of sick children.

The prognosis also varies according to age and is generally worse under 3 years of age.

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Source:

Bambino Gesù