Introduction

Acute liver failure (ALF) in children is a rare and severe disease, which can be associated with a high a mortality in the absence of liver transplantation. In 1999, a multidisciplinary team composed of 24 researchers from the USA, Canada and Europe introduced the PALF criteria for children with ALF. According to them, ALF in children is a syndrome characterized by uncorrectable hepatic coagulopathy after parenteral administration of vitamin K, respectively an INR (International Normalized Ratio) of 1.5-1.9 in the presence of hepatic encephalopathy or INR>2 in the absence of hepatic encephalopathy without having a chronic liver disease⁽¹⁾. The etiology of ALF is different from that in adults and depends on age.

I. Infections

In Europe, the viral infections are currently the leading cause of ALF in children. Depending on the liver cell tropism of the infectious virus (specific or nonspecific), the viral agents that can cause ALF in children are classified into hepatotropic and nonhepatotropic agents^(1,2).

I.1. Hepatotropic viruses

The viral etiology of ALF varies geographically, he­pa­titis A virus (HAV) being one of the most common etio­lo­gi­cal agents in Asia and South America, while in Africa, Europe or Asia, the infection with hepatitis B vi­rus (HBV) is a significant public health issue. Table 1 pre­sents the main hepatotropic viruses that can cause ALF in children^(1,2).

Hepatitis A virus (HAV)

HAV is an RNA virus that belongs to the Hepatoviruses genus, family Picornaviridae. It is transmitted by the fecal-oral route and is the most common cause of hepatitis in developing countries (20-25%). The prevalence of HAV infection is increased in Asia, Southern Europe and South America, representing a major public health problem. The most common infection is mild or self-limiting, but sometimes HAV can cause severe hepatitis or ALF and other complications. The incidence of ALF cases secondary to HAV infection in children varies between 0.1% and 0.4%^(6,7).

Hepatitis B virus (HBV)

HBV infection is a public health problem worldwide, highly prevalent in Europe, Asia, Africa and Latin Ame­ri­ca (5-20%). According to the World Health Organization (WHO), about a quarter of the world’s population (about 2-3 billion) has gone through HBV infection, and over 3% (250-300 million) are chronically infected with HBV. In endemic areas, the transmission of the infection is mainly perinatal (2-5%) or intrapartum (95%), while in developed countries, sexual transmission, tattooing or injecting drugs are the main ways of HBV infection. HBV infection can evolve with ALF at any age, with an incidence of 0.1-0.5% and a mortality of up to 80%. The highest risk of developing ALF is posed by children born to mothers with high viremia. They may develop ALF in the first 3-10 weeks of life, with an extremely high mortality rate, or progress to chronic infection in 90% of cases. The evolution of the infection to fulminant forms or chronicity depends on the HBV genotype and the host’s immune status. This is one of the main reasons the neonates and infants present severe forms of HBV infection^(8-11).

Hepatitis C virus (HCV)

HCV infection rarely causes ALF in children, the pre­va­lence of HCV infection in children and adolescents in Europe being below 0.2%, except for endemic areas where it can reach up to 5%. Most of the time, the transmission is maternal-fetal (60% of infected children), the risk being amplified if mothers are HIV coinfected or if they have high viremia during pregnancy. Among older children, those who receive regular blood transfusions, perform extracorporeal treatment methods, or adolescents who inject drugs are at an increased risk of infection^(12,13).

Hepatitis D virus (HDV)

HDV is more common in areas where HBV is ende­mic, with a low socioeconomic level (Mediterranean basin, Eastern Europe, Asia or Africa). The virus can cause coinfection (the infection occurs concomitantly with HBV) or superinfection (a patient already infected with HBV becomes infected with HDV). Coinfection is more frequently associated with severe forms of the disease, sometimes fulminant (70-80%), while superinfection progresses mainly to chronicity (90% of cases)^(13,14).

Hepatitis E virus (HEV)

HEV infection is a rare cause of ALF in children, although in adults it is one of the leading causes of severe liver injuries in developing countries (20-40% of cases). It is endemic mainly in tropical countries, where it causes approximately 70,000 deaths/year. HEV belongs to the family Hepeviridae, genus Hepevirus, and is transmitted by the fecal-oral route, especially by contaminated water or secondary to the consumption of contaminated meat. Not least, the virus can be transmitted through the administration of blood products from infected donors. Most of the time, the infection is self-limiting (2-10 weeks), rarely progressing to ALF or to chronicity if the infection occurs in immunosuppressed patients (HIV, preexisting liver disease). The neonates have the highest risk of developing ALF, especially if mothers become infected in the last trimester of pregnancy^(13,15-19).

Hepatitis F virus (HFV) and hepatitis G virus (HGV)

HFV or HGV infection is sporadic in children. Still, it may progress to fulminant forms of infection, especially in patients with a liver transplant or preexisting liver disease^(20-22).

I.2. Nonhepatotropic viruses

ALF can be secondary to viral infections that are not specific to the liver cell alone. The main viral agents involved are presented in Table 2.

Herpes simplex virus (HSV-1,2)

Although rare (less than 1% of ALF cases), liver damage in HSV infection can be extremely severe, with a mortality of over 85% in the absence of treatment. The only source of infection is humans; the transmission is made through close contact with infected people. In neonates, HSV is usually transmitted during delivery through an infected maternal genital tract (85%). Less often, intrauterine (5%) or postpartum transmission (10%) may account. The incidence of neonatal HSV infection varies from 1:3,000 to 1:20,000. In older children, disseminated HSV infection associated with ALF occurs with predilection in immunosuppressed hosts or with preexisting chronic liver disease (chronic hepatitis B)^(23-26).

Varicella zoster virus

Varicella hepatitis predominantly affects immunosuppressed hosts, such as transplant recipients, cancer and AIDS patients, but it can also be seen in immunocompetent children^(23-26).

Cytomegalovirus (CMV)

Cytomegalovirus is part of the Herpesviridae family and is also called Herpesvirus-5. It is the leading cause of congenital infection in humans, with an incidence of 0.5-2.2%. CMV infection can cause severe forms of hepatitis with ALF, especially in neonates or in children with immunosuppression (HIV/AIDS, patients receiving prolonged corticosteroids, organ transplants). In congenital CMV infection, the transmission is transplacental, intrapartum or postnatal through breast milk. In 90% of the cases, there are no clinical signs of infection in the first days after birth. In older children and teenagers, the transmission is horizontal, through direct contact with drops of infected saliva, exposure to contaminated biological products or organ transplants. Most often, CMV infection causes anicteric forms of acute hepatitis, with moderate increases in serum transaminases but with high levels of bilirubin and cholestasis enzymes, sometimes progressing to severe forms of ALF^(27-30).

Epstein-Barr virus (VEB)

Epstein-Barr virus is a DNA virus included in the Herpesvirus family, being extremely widespread in the world (90-95% of the adult population is seropositive). ALF may be a complication of infectious mononucleosis in children (1/3000 cases) or it may be the only manifestation of EBV infection, occurring with predilection in immunosuppressed patients (HIV/AIDS, prolonged corticosteroid therapy, organ transplantation, malnutrition). Most often, there are forms of anicteric hepatitis that can associate high fever, pseudomembranous tonsillitis, splenomegaly, adenomegaly or thrombocytopenia^(31-32).

ALF secondary to infection by other viruses, such as parvovirus, adenovirus and enterovirus, is very rare, with only a few cases described in the literature and these mainly in adults^(33-39).

1.3. Bacterial, parasitic and fungal infections

Despite numerous advances in medicine and the emergence of new classes of antibiotics, the bacterial infections with systemic resonance continue to cause a high morbidity and mortality among children, in some countries being the leading cause of death in infants and young children. The liver plays the role of a large lymphatic organ in systemic bacterial infection. Hepatic impairment occurs in 20-45% of cases with systemic bacterial infection, with an incidence of ALF of 8.5%. The liver lesions are secondary to the direct action of the pathogen, toxins and mediators released. Gram-negative bacilli (BGN) are the leading infectious agents involved in sepsis-associated liver dysfunction. The hepatic injury usually occurs in the early stages of infection, therefore the association of ALF can be considered a prognostic factor in the evolution of systemic infection^(40-42).

Leptospirosis, considered the most common zoonosis in humans, is caused by spirochetes from the genus Leptospira interrogans. It represents a rare cause of ALF in children, but it can determine severe forms of infection. Humans become infected through contact with mucous membranes, conjunctiva or skin lesions with contaminated soil or water from infected animals (most commonly rats). The systemic form of infection is Weil’s disease and associates ALF with cholestasis, acute renal injury, myalgia, myocarditis, pulmonary hemorrhage or adult-type respiratory distress (ARDS)^(43,44).

Extremely rare, Toxoplasma gondii, a protozoan pa­ra­site, can cause ALF in immunosuppressed or transplanted children. In these cases, the infection is associated with severe systemic phenomena: fever, generalized lymphadenopathy or multiple organ failure (MSOF). It is transmitted by the fecal-oral route, the reservoir being the cats that contaminate the soil with cysts. Also, it can be transmitted from the infected pregnant woman to the fetus, primarily if she acquires the infection in the last trimester of pregnancy⁽⁴⁵⁾.

II. Toxic causes of ALF

Toxicity is one of the most common causes of ALF in children, with a prevalence of 20-25%. The most common toxics which cause ALF are mushrooms (Amanita phalloides) and drugs (acetaminophen, sodium valproate, tuberculostatic medication)^(46-48).

Mushrooms

Mushroom poisoning represents an important cause of ALF worldwide in children and adults. In Europe, approximately 50-100 deaths/year are reported due to mushroom ingestion⁽⁴⁶⁾. Amanita phalloides intoxication is the most common cause of severe mushroom poisoning worldwide, being responsible for 90% of deaths due to mushroom consumption^(47,49). The clinical picture of ALF in mushroom poisoning appears late, 2-4 days after ingestion, and includes jaundice, hepatic encephalopathy and severe hemorrhages^(49-51).

Drugs

Drugs ingestion represents another important cause of toxic ALF in children. Drugs can cause hepatotoxicity by two mechanisms: intrinsic or dose-dependent toxicity (acetaminophen, halothane) and idiosyncratic reactions (antibiotics, nonsteroidal anti-inflammatory drugs, isoniazid). Depending on the mechanism of action, drugs determine the destruction of the hepatocyte membrane or bile ducts, activating T lymphocytes and tissue necrosis factor (TNF-alpha), altering the mitochondrial function or inducing apoptosis in the hepatocyte. Intrinsic drug hepatotoxicity is dose-dependent, independent of the genetic load of the body, and the symptoms of toxicity appear after a short period (hours, days) after ingestion. Idiosyncratic hepatotoxicity occurs in people with genetic predisposition, is dose-independent and involves immune-mediated phenomena. In this case, the manifestations of hepatotoxicity occur at a distance (weeks) from drug exposure, often associated with elements of autoimmunity, rash, fever, arthralgia or eosinophilia^(52-55).

III. Immune causes

Autoimmune hepatitis (AIH)

AIH is a rare condition in children with a genetic predisposition (HLA-DR3/DR4). It is an inflammatory disease of the liver that is characterized by an increased serum IgG level (most often), the presence of specific antibodies (antinuclear antibodies – ANA, anti-smooth muscle antibodies – SMA, anti-liver kidney microsomal – LKM1), and inflammatory infiltrate in the portal space at the histopathological examination. Although a chronic disease, in over 50% of cases the onset of the disease can be acute, and in 10-11% even with ALF. The clinical picture, the family history of autoimmunity (positive in 40% of cases), the personal history of another autoimmunity (20% of cases), the treatment response and the long-term prognosis are most often similar in both types of AIH. However, the acute onset is more common in type 2 AIH, with significant coagulopathy and encephalopathy. Most often, children with AIH presenting with ALF and hepatic encephalopathy do not respond to any form of immunosuppression therapy and need urgent liver transplantation^(56,57).

Neonatal hemochromatosis

Neonatal hemochromatosis, also called GALD (gesta­tio­nal alloimmune liver disease), is the consequence of an alloimmune gestational pathology, which consists of the deposition of extrahepatic iron in the presence of antibodies directed against fetal liver cells. The process begins around the gestational age of 12 weeks and is immune-mediated (IgG from the mother). The hepatic impairment begins intrauterinely and continues postnatally with ALF. The neonates will show signs of intrauterine distress, growth retardation, premature birth, oligohydramnios, prenatal signs of cirrhosis or ascites. In the first hours/days after birth, the manifestations of ALF will occur with jaundice, severe coagulopathy (INR>4), hypoalbuminemia, edema, hyperammonemia, hypoglycemia or with manifestations of neonatal sepsis^(58-61).

IV. Metabolic causes

IV.1. Inborn errors of metabolism (IEM)

Galactosemia

It is a genetic disease with autosomal recessive transmission caused by mutations in the gene that encodes the enzymes involved in galactose metabolism. Depending on the deficient enzyme, there are three types of the disease, the most severe and the most common being the classic form (galactose-1-phosphate uridylyl-transferase [GALT] deficiency), with an incidence of 1:20,000-50,000 neonates. GALT enzyme deficiency leads to the accumulation of toxic metabolites (galactose, galactitol or galactose-1-phosphate) in almost all cells of the body, causing severe damage. In the neonates or infants, the clinical manifestations appear early, with severe ALF, acute renal injury, nonimmune hemolytic anemia, convulsions (due to severe episodes of hypoglycemia) and coma. The toxic metabolites affect the phagocytic function of neutrophils, causing severe systemic infections, often with Escherichia coli. The most severe is hepatic impairment, often with ALF. The other clinical manifestations are secondary to the accumulation of galactose-1-phosphate in the tissues, where it causes cataracts “in oil stain”, acute tubular necrosis with secondary Fanconi syndrome, or neuropsychiatric disorders. Type 2 (due to galactokinase deficiency) and type 3 (due to uridine diphosphate galactose-4 epimerase deficiency) are less common and cause milder forms of the disease^(62-66).

Hereditary fructose intolerance

It is a rare autosomal recessive condition (1:20,000-30,000 neonates), caused by mutations in the ALDOB gene that reduce aldolase B activity (one of the three enzymes involved in fructose metabolism). The ingestion of fructose leads to the impossibility of its metabolism, with the accumulation of fructose-1-phosphate and the appearance of ALF phenomena, renal impairment, neurological toxicity or hypoglycemia⁽⁶⁷⁾.

Tyrosinemia

It is a genetic disease with an autosomal recessive trans­mis­sion, caused by the reduction or absence of the ac­ti­vi­ty of fumaryl acetoacetate (tyrosinemia type I) or other enzymes involved in the metabolism of tyrosine (type II and III disease). It is a rare condition, with an incidence of 1:100,000 neonates in type I; the other forms are even rarer. Tyrosine is a metabolite of phenylalanine and results from the metabolism of food proteins. The symptomatology is very severe and most often appears in the first weeks of life, secondary to the accumulation of succinylacetone in the liver and kidneys.  Severe ALF, hepatosplenomegaly, ascites, coma, acute renal injury or coagulopathy are the manifestations of the disease that obscure the prognosis of these patients^(68,69).

In recent years, many other inborn errors of metabolism have been involved in the etiology of ALF, such as mitochondrial respiratory disorders, fatty acid oxidation defects or urea cycle disorders⁽⁷⁰⁾.

IV.2. Wilson disease (WD)

Wilson disease is an autosomal recessive genetic condition in which the ATP7B gene on chromosome 13 is affected. The disease was first described in 1912, by Kinnear Wilson, as combining hepatolenticular degeneration and neuropsychic manifestations. The ATP7B gene synthesizes the ATP7B protein found in the hepatocyte, renal tubular cells, erythrocyte and neuronal cells. In hepatocytes, ATP7B plays a role in transmembrane and intrahepatocyte transport of copper and favors its incorporation into apoceruloplasmin in the Golgi apparatus to form ceruloplasmin. Mutations in the ATP7B gene cause the deposition of excess copper in cells and tissues. WD generally occurs in older children and adolescents, with a prevalence of 1:30,000-50,000 cases in Europe. The clinical manifestations are varied: hepatic manifestations, more common in children (jaundice, hepatic steatosis, hepatitis, ALF, cirrhosis, ascites), neurological manifestations, psychiatric manifestations, or ocular changes (Kayser-Fleischer ring). In adolescents, the onset may be as ALF associated with hemolytic anemia and sometimes with acute renal injury, manifestations known as fulminant WD. Most of the time, the prognosis is poor in these forms of the disease, the only therapeutic option being the emergency liver transplant^(71-75).

V. Vascular causes

Although it is a very rare cause, ischemia secondary to severe hypotension, cardiac arrest or low flow syndrome can cause ALF in children. Also, sinusoidal obstruction syndrome (veno-occlusive disease), Budd-Chiari syndrome or hepatic stasis from acute heart failure represent extremely rare causes of severe liver injuries in children, being found especially among adults^(1-4).

VI. Malignancies

ALF as a presentation of hemophagocytic lymphohistiocytosis (HLH) or leukemia is rare and often results from the multiorgan failure during the progression of these disorders or secondary to chemotherapy. HLH is classified as either primary (or familial HLH) or secon­dary (or acquired HLH) and represents a spectrum of inherited and acquired conditions secondary to an uncontrolled immune response. The diagnosis of HLH includes high fever, hepatosplenomegaly, high alkaline phosphatase, lactate dehydrogenase and abnormalities on peripheral blood film^(1-4).

Etiology of ALF in children around the world

The infectious and metabolic disorders represent the leading causes in neonates and infants, while in children and teenagers, in addition to viral causes, toxic, autoimmune hepatitis or Wilson’s disease are incriminated (Table 3). Despite the numerous investigations that can be done, more than 45% of ALF cases in children remain of unknown etiology^(2,77-81) – Table 3.

The management requires a multidisciplinary approach and is directed at establishing the etiology and monitoring, anticipating and managing the multisystem complications in children with ALF. Overall, the short-term outcomes are better in children than in adults, but are dependent upon the degree of encephalopathy and diagnosis.

Conclusions

In recent years, liver transplantation has increased the chance of survival in children with ALF. However, the risk of death of these patients remains high. The knowledge of ALF etiology plays a critical role in the management of such cases, as sometimes the child could benefit from specific therapies in emergency (specific diets in metabolic disorders, copper chelator in WD, administration of antidotes, liver dialysis, hemoperfusion or plasma separation in severe toxic hepatitis), thus reducing the need for transplant intervention.  

 

Conflicts of interests: The authors declare no con­flict of interests.

insuficienţă hepatică acutăcopiietiologietoxiceboală metabolicăinfecţieboală hepatică autoimună