Liver disorders

Published on 21/03/2015 by admin

Filed under Pediatrics

Last modified 22/04/2025

Print this page

This article have been viewed 2682 times

Liver disorders

Features of liver disorders in children are:

• Prolonged (persistent) neonatal jaundice is the most common presentation of liver disease in the neonatal period.

• The earlier in life biliary atresia is diagnosed and treated surgically, the better the prognosis.

• Transmission of hepatitis B surface antigen-positive mothers is prevented by immunising their babies.

• Chronic liver disease (Fig. 20.1), cirrhosis and portal hypertension are uncommon and should be managed by, or in conjunction with tertiary or national centres.

Figure 20.1 Clinical features of liver disease. In addition, these children may have growth failure and developmental delay.

• Liver transplantation is an effective therapy for acute or chronic liver failure, with a >80% 5-year survival rate; it is only performed at national centres.

Neonatal liver disease

Many newborn infants become clinically jaundiced. About 5–10% are still jaundiced at >2 weeks of age (3 weeks if preterm), when it is called ‘prolonged (or persistent) neonatal jaundice’. This is usually an unconjugated hyperbilirubinaemia, which resolves spontaneously (Box 20.1). Prolonged neonatal jaundice caused by liver disease is characterised by a raised conjugated bilirubin (>20 µmol/L) and is usually accompanied by:

There is an urgency to diagnose liver disease as early as possible in the neonatal period, because early diagnosis and management improves prognosis.

In prolonged (persistent) neonatal jaundice, check if it is conjugated hyperbilirubinaemia, as this is due to liver disease.

Bile duct obstruction

Biliary atresia (see Case History 20.1)

This occurs in 1 in 14 000 live births. It is a progressive disease, in which there is destruction or absence of the extrahepatic biliary tree and intrahepatic biliary ducts. This leads to chronic liver failure and death unless surgical intervention is performed. Babies with biliary atresia have a normal birthweight but fail to thrive as the disease progresses. They are usually mildly jaundiced and, following passage of meconium, their stools are pale and their urine dark. Although stool colour may fluctuate, pale stools is an important abnormality and warrants investigation, even in the absence of clinical jaundice. Hepatomegaly is often present and splenomegaly will develop secondary to portal hypertension.

Standard liver function tests are of little value in the differential diagnosis. A fasting abdominal ultrasound may demonstrate a contracted or absent gallbladder, though it may be normal. A radioisotope scan with TIBIDA (iminodiacetic acid derivatives) shows good uptake by the liver, but no excretion into the bowel. Liver biopsy demonstrates features of extrahepatic biliary obstruction, although features may overlap with those of neonatal hepatitis, especially if carried out at an early stage of the disease. The diagnosis is confirmed at laparotomy by operative cholangiography which fails to outline a normal biliary tree.

Treatment consists of surgical bypass of the fibrotic ducts, hepatoportoenterostomy (Kasai procedure), in which a loop of jejunum is anastomosed to the cut surface of the porta hepatis, facilitating drainage of bile from any remaining patent ductules. If surgery is performed before the age of 60 days, 80% of children achieve bile drainage. The success rate diminishes with increasing age – hence the need for early diagnosis and treatment. Postoperative complications include cholangitis and malabsorption of fats and fat-soluble vitamins. Even when bile drainage is successful, there is frequently progression to cirrhosis and portal hypertension. If the operation is unsuccessful, liver transplantation has to be considered. Biliary atresia is the single most common indication for liver transplantation in the paediatric age group.

Choledochal cysts

These are cystic dilatations of the extrahepatic biliary system. About 25% present in infancy with cholestasis. In the older age group, choledochal cysts present with abdominal pain, a palpable mass and jaundice or cholangitis. The diagnosis is established by ultrasound or radionuclide scanning. Treatment is by surgical excision of the cyst with the formation of a Roux-en-Y anastomosis to the biliary duct. Future complications include cholangitis and a 2% risk of malignancy, which may develop in any part of the biliary tree.

Neonatal hepatitis syndrome

In neonatal hepatitis syndrome, there is prolonged neonatal jaundice and hepatic inflammation. Its causes are listed in Box 20.1, but often no specific cause is identified. In contrast to biliary atresia, these infants may have intrauterine growth restriction and hepatosplenomegaly at birth. Liver biopsy (Fig. 20.6) is often non-specific, demonstrating a giant cell hepatitis.

Figure 20.6 Liver biopsy in neonatal hepatitis showing inflammatory infiltrate throughout the liver, and giant cell and rosette formation of liver cells.

α₁-Antitrypsin deficiency

Deficiency of the protease α₁-antitrypsin is associated with liver disease in infancy and childhood and emphysema in adults. It is inherited as an autosomal recessive disorder with an incidence of 1 in 2000–4000 in the UK. There are many phenotypes of the protease inhibitor (Pi) which are coded on chromosome 14. Liver disease is primarily associated with the phenotype PiZZ.

Case History

20.1 Biliary atresia

A term infant was given oral vitamin K shortly after birth. He was breast-fed. He became mildly jaundiced on the third day of life. At 5 weeks of age, he presented with poor feeding and vomiting and a history of bruising on his forehead and shoulders. His urine had become dark and stools intermittently pale. He was pale, jaundiced, had several bruises and hepatomegaly. Investigations showed:

• Hb 8.8 g/L

• Platelets 465 × 10⁹/L

• Prothrombin time – 28 s (normal range 10–13 s)

• Serum bilirubin 178 micromol/L – 140 micromol/L conjugated.

The investigation of conjugated hyperbilirubinaemia is shown in Figure 20.2. The TIBIDA radionuclide scan showed no excretion at 24 h (Fig. 20.3) and a liver biopsy suggested biliary atresia (Fig. 20.4). A hepatoportoenterostomy was performed at 6 weeks of age (Fig. 20.5).

Figure 20.2 Evaluation of neonatal conjugated hyperbilirubinaemia.

Figure 20.3 Radioisotope scan TIBIDA of liver showing good hepatic uptake of isotope and no excretion into bowel. This scan suggests extrahepatic biliary obstruction or atresia or severe intrahepatic cholestasis.

Figure 20.4 Liver biopsy of biliary atresia showing bands of fibrous tissue with bile duct proliferation.

Figure 20.5 Shortly after successful bile drainage by hepatoportoenterostomy (Kasai procedure) for biliary atresia.

In persistent neonatal jaundice, early diagnosis of biliary atresia improves the prognosis.

In persistent jaundice, always look to see if the stools are pale – suggests bile duct obstruction.

The majority of children who present with α₁-antitrysin deficiency will either have prolonged neonatal jaundice or, less commonly, bleeding due to vitamin K deficiency (haemorrhagic disease of the newborn). Hepatomegaly is present. Splenomegaly develops with cirrhosis and portal hypertension. The diagnosis is confirmed by estimating the level of α₁-antitrypsin in the plasma and identifying the phenotype. Approximately 50% of children have a good prognosis, but the remainder will develop liver disease and may require transplantation. Pulmonary disease is not significant in childhood, but is likely to develop in adult life. Advice to avoid smoking (both active and passive) should be given. The disorder can be diagnosed antenatally.

Intrahepatic biliary hypoplasia

Syndromic causes

Alagille syndrome is a rare autosomal dominant condition with widely varying penetrance. Infants may have characteristic triangular facies, skeletal abnormalities, congenital heart disease (classically peripheral pulmonary stenosis), renal tubular disorders, defects in the eye and intrahepatic biliary hypoplasia with severe pruritus and failure to thrive. Prognosis is variable, with 50% of children surviving into adult life without liver transplantation. Intrahepatic biliary hypoplasia also occurs in Down syndrome; there is also a non-syndromic biliary hypoplasia.

Viral hepatitis

The clinical features of viral hepatitis include nausea, vomiting, abdominal pain, lethargy and jaundice; however, 30–50% of children do not develop jaundice. A large tender liver is common and 30% will have splenomegaly. The liver transaminases are usually markedly elevated. Coagulation is usually normal.

Hepatitis A

Hepatitis A virus (HAV) is an RNA virus which is spread by faecal–oral transmission. The incidence of hepatitis A in childhood has fallen as socioeconomic conditions have improved. Many adults are not immune. Vaccination is required for travellers to endemic areas.

The disease may be asymptomatic, but the majority of children have a mild illness and recover both clinically and biochemically within 2–4 weeks. Some may develop prolonged cholestatic hepatitis (which is self-limiting), or fulminant hepatitis. Chronic liver disease does not occur.

The diagnosis can be confirmed by detecting IgM antibody to the virus.

There is no treatment and no evidence that bed rest or change of diet is effective. Close contacts should be given prophylaxis with human normal immunoglobulin (HNIG) or vaccinated within 2 weeks of the onset of the illness.

Hepatitis B

Hepatitis B virus (HBV) is a DNA virus which is an important cause of acute and chronic liver disease worldwide, with high prevalence and carrier rates in the Far East, sub-Saharan Africa and parts of North and South America (Fig. 20.7). HBV is transmitted by:

• Perinatal transmission from carrier mothers

• Transfusion of infected blood or blood products

• Needlestick injuries with infected blood

• Renal dialysis

• Horizontal spread within families.

Among adults it can also be transmitted sexually.

Infants who contract HBV perinatally are asymptomatic, but at least 90% become chronic carriers. Older children who contract HBV may be asymptomatic or have classical features of acute hepatitis. The majority will resolve spontaneously, but 1–2% develop fulminant hepatic failure, while 5–10% become chronic carriers. The diagnosis is made by detecting HBV antigens and antibodies. IgM antibodies to the core antigen (anti-HBc) are positive in acute infection. Positivity to hepatitis B surface antigen (HBsAg) denotes ongoing infectivity. There is no treatment for acute HBV infection.

Chronic hepatitis B

Infants infected with HBV by vertical transmission from their mothers usually become asymptomatic carriers. Approximately 30–50% of carrier children will develop chronic HBV liver disease, which may progress to cirrhosis in 10%. There is a long-term risk of hepatocellular carcinoma. Current treatment regimens for chronic HBV have poor efficacy. Interferon treatment for chronic hepatitis B is successful in 50% of children infected horizontally and 30% of children infected perinatally. Oral antiviral therapy such as lamivudine is effective in 23% but is limited by the development of resistance. Newer drugs such as adefovir or long-acting (peg) interferon may be more effective.

Prevention

Prevention of HBV infection is important. All pregnant women should have antenatal screening for HBsAg. Babies of all HBsAg-positive mothers should receive a course of hepatitis B vaccination (given routinely in many countries), with hepatitis B immunoglobulin also being given if the mother is also hepatitis B e antigen (HBeAg)-positive. Antibody response to the vaccination course should be checked in high-risk infants as 5% require further vaccination. Other members of the family should also be vaccinated. There is evidence that effective neonatal vaccination reduces the incidence of HBV-related cancer.

Summary

Hepatitis B virus (HBV)

• Perinatal transmission from carrier mothers should be prevented by maternal screening and giving the infant a course of hepatitis B vaccine with hepatitis B immunoglobulin if indicated

• Infection may result in chronic HBV liver disease, which may progress to cirrhosis and hepatocellular carcinoma.

Hepatitis C

Hepatitis C virus (HCV) is an RNA virus that was responsible for 90% of post-transfusion hepatitis until the screening of donor blood was introduced in 1991. In the UK, about 1 in 2000 donors have HCV antibodies. The prevalence is high among intravenous drug users. Children previously at risk were those who received unscreened blood or blood products, in particular those with haemoglobinopathies or haemophilia. Vertical transmission occurs in 6% from infected mothers but is twice as common if there is co-infection with HIV, and is now the commonest cause of HCV transmission in children. It seldom causes an acute infection, but the majority become chronic carriers, with a 20–25% lifetime risk of progression to cirrhosis or hepatocellular carcinoma. Treatment is with a combination of pegylated interferon and ribavirin. Success of treatment is dependent on virus genotype. In children with genotypes 2/3, it is effective in up to 90% of cases. Treatment is not undertaken before 4 years of age, as it may resolve spontaneously following vertically acquired infections.

Hepatitis D virus

Hepatitis D virus (HDV) is a defective RNA virus that depends on hepatitis B virus for replication. It occurs as a co-infection with hepatitis B virus or as a superinfection causing an acute exacerbation of chronic hepatitis B virus infection. Cirrhosis develops in 50–70% of those who develop chronic HDV infection.

Hepatitis E virus

This is an RNA virus that is enterally transmitted, usually by contaminated water. Epidemics occur in some developing countries.

Non-A to G hepatitis

Clinical presentation is similar to hepatitis A. When a viral aetiology of hepatitis is suspected but not identified, it is known as non-A to G hepatitis.

Epstein–Barr virus

Children with Epstein–Barr virus (EBV) infection are usually asymptomatic. Some 40% have hepatitis that may become fulminant. Less than 5% are jaundiced.

Acute liver failure (fulminant hepatitis)

Acute liver failure in children is the development of massive hepatic necrosis with subsequent loss of liver function, with or without hepatic encephalopathy. The disease is uncommon, but has a high mortality. Most of the cases in childhood are attributed to paracetamol overdosage, non-A to G viral hepatitis and metabolic conditions (Table 20.1). The child may present within hours or weeks with jaundice, encephalopathy, coagulopathy, hypoglycaemia and electrolyte disturbance. Early signs of encephalopathy include alternate periods of irritability and confusion with drowsiness. Older children may be aggressive and unusually difficult. Complications include cerebral oedema, haemorrhage from gastritis or coagulopathy, sepsis and pancreatitis.

Table 20.1

Causes of acute liver failure in children

Infection	Viral hepatitis A, B, C, non-A to G
Poisons/drugs	Paracetamol, isoniazid, halothane, Amanita phalloides (poisonous mushroom)
Metabolic	Wilson disease, tyrosinaemia
Autoimmune hepatitis
Reye syndrome

Diagnosis

Bilirubin may be normal in the early stages, particularly with metabolic disease. Transaminases are greatly elevated (10–100 times normal), alkaline phosphatase is increased, coagulation is very abnormal and plasma ammonia is elevated. It is essential to monitor the acid–base balance, blood glucose and coagulation times. An EEG will show acute hepatic encephalopathy and a CT scan may demonstrate cerebral oedema.

Management

This includes:

• Maintaining the blood glucose (>4 mmol/L) with intravenous dextrose

• Preventing sepsis with broad-spectrum antibiotics and antifungals

• Preventing haemorrhage, particularly from the gastrointestinal tract with intravenous vitamin K, fresh frozen plasma or cryoprecipitate and H₂-blocking drugs or proton pump inhibitors (PPIs)

• Treating cerebral oedema by fluid restriction and mannitol diuresis

• Urgent transfer to a specialist liver unit.

Features suggestive of a poor prognosis are a shrinking liver, rising bilirubin with falling transaminases, a worsening coagulopathy or progression to coma. Without liver transplantation, 70% of children who progress to coma will die.

Reye syndrome and Reye-like syndrome

Reye syndrome is an acute non-inflammatory encephalopathy with microvesicular fatty infiltration of the liver. Although the aetiology is unknown, there is a close association with aspirin therapy. Since stopping giving aspirin to children aged under 12 years, Reye syndrome has virtually disappeared. With the introduction of tandem mass spectroscopy in the neonatal screening programme, the commonest beta oxidation defect, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, is diagnosed early in many regions of the UK. Many of these patients would have presented with a Reye-like syndrome later in life.

The causes of chronic liver disease are given in Box 20.2. The clinical presentation varies from an apparent acute hepatitis to the insidious development of hepatosplenomegaly, cirrhosis and portal hypertension with lethargy and malnutrition. The commonest causes of chronic hepatitis are hepatitis viruses (B or C) and autoimmune hepatitis, but Wilson disease should always be excluded. Histology may demonstrate varying degrees of hepatitis, with an inflammatory infiltrate in the portal tracts that spreads into the liver lobules.

Autoimmune hepatitis

The mean age of presentation is 7–10 years. It is more common in girls. It may present as an acute hepatitis, as fulminant hepatic failure or chronic liver disease with autoimmune features such as skin rash, lupus erythematosus, arthritis, haemolytic anaemia or nephritis. Diagnosis is based on elevated total protein, hypergammaglobulinaemia (IgG >20 g/L); positive autoantibodies, a low serum complement (C4); and typical histology. Autoimmune hepatitis may occur in isolation or in association with inflammatory bowel disease, coeliac disease or other autoimmune diseases. Some 90% of children will respond to prednisolone and azathioprine.

Cystic fibrosis

Liver disease is the second commonest cause of death after respiratory disease in cystic fibrosis. The most common liver abnormality is hepatic steatosis (fatty liver). It may be associated with protein energy malnutrition or micronutrient deficiencies. Steatosis does not generally progress and treatment involves ensuring optimal nutritional support. More significant liver disease arises from thick tenacious bile with abnormal bile acid concentration leading to progressive biliary fibrosis. Cirrhosis and portal hypertension develop in 20% of children by mid-adolescence. Early liver disease is difficult to detect by biochemistry, ultrasound or radioisotope scanning. Liver histology includes fatty liver, focal biliary fibrosis or focal nodular cirrhosis. Therapy includes standard supportive and nutritional therapy and treatment with ursodeoxycholic acid. Liver transplantation may be considered for those with end-stage liver disease, either alone or in combination with a heart–lung transplant.

Wilson disease

Wilson disease is an autosomal recessive disorder with an incidence of 1 in 200 000. Many mutations have now been identified (on chromosome 13). The basic genetic defect is a combination of reduced synthesis of caeruloplasmin (the copper-binding protein) and defective excretion of copper in the bile, which leads to an accumulation of copper in the liver, brain, kidney and cornea. Wilson disease rarely presents in children under the age of 3 years. In those presenting in childhood, a hepatic presentation is more likely. They may present with almost any form of liver disease, including acute hepatitis, fulminant hepatitis, cirrhosis and portal hypertension. Neuropsychiatric features are more common in those presenting from the second decade onwards and include deterioration in school performance, mood and behaviour change, and extrapyramidal signs such as incoordination, tremor and dysarthria. Renal tubular dysfunction, with vitamin D-resistant rickets, and haemolytic anaemia also occur. Copper accumulation in the cornea (Kayser–Fleischer rings) (Fig. 20.8) is not seen before 7 years of age.

Diagnosis can be problematic. A low serum caeruloplasmin and copper is characteristic, but not universal. Urinary copper excretion is increased and this further increases after administering the chelating agent penicillamine. However, the diagnosis is confirmed by the finding of elevated hepatic copper on liver biopsy or identification of the gene mutation.

Treatment is with penicillamine or trientine. Both promote urinary copper excretion, reducing hepatic and central nervous system copper. Zinc is given to reduce copper absorption. Pyridoxine is given to prevent peripheral neuropathy. Neurological improvement may take up to 12 months of therapy. About 30% of children with Wilson disease will die from hepatic complications if untreated. Liver transplantation is considered for children with acute liver failure or severe end-stage liver disease.

Fibropolycystic liver disease

This is a range of inherited conditions affecting the development of the intrahepatic biliary tree. Presentation is with liver and renal disease. The liver disease may include cystic disease of the liver or biliary tree or congenital hepatic fibrosis.

Congenital hepatic fibrosis (CHF) presents in children over 2 years old with hepatosplenomegaly, abdominal distension and portal hypertension. It differs from cirrhosis in that liver function tests are normal in the early stage. Liver histology shows large bands of hepatic fibrosis containing abnormal bile ductules. The consequent portal hypertension causes bleeding from varices. Cystic renal disease may coexist and may cause hypertension or renal dysfunction.

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the single most common cause of chronic liver disease in the developed world. It is a spectrum of disease, ranging from simple fatty deposition (steatosis) through to inflammation (steatohepatitis), fibrosis, cirrhosis and end-stage liver failure. The prognosis in childhood is uncertain; very few develop cirrhosis in childhood in contrast to 8–17% of adults. Most affected children are obese. They are usually asymptomatic, although some complain of vague right upper quadrant abdominal pain or lethargy. The diagnosis is often suspected following the incidental finding of an echogenic liver on ultrasound or mildly elevated transaminases carried out for some other reason. Liver biopsy demonstrates marked steatosis with or without inflammation or fibrosis. The pathogenesis is not fully understood but may be linked to insulin resistance. Treatment is targeted at weight loss, which may lead to liver function tests returning to normal.

Cirrhosis and portal hypertension

Cirrhosis is the end result of many forms of liver disease. It is defined pathologically as extensive fibrosis with regenerative nodules. It may be secondary to hepatocellular disease or to chronic bile duct obstruction (biliary cirrhosis). The main pathophysiological effects of cirrhosis are diminished hepatic function and portal hypertension with splenomegaly, varices and ascites (see Fig. 20.1). Hepatocellular carcinoma may develop.

Children with compensated cirrhosis may be asymptomatic if liver function is adequate. They will not be jaundiced and may have normal liver function tests. As the cirrhosis increases, however, the results of deteriorating liver function and portal hypertension become obvious (Fig. 20.9). Physical signs include palmar and plantar erythema and spider naevi, malnutrition and hypotonia. Dilated abdominal veins and splenomegaly suggest portal hypertension, although the liver may be impalpable.

Figure 20.9 Cirrhosis and portal hypertension. (i) Malnutrition with loss of fat and muscle bulk; (ii) distended abdomen from hepatosplenomegaly and ascites; (iii) scrotal swelling from ascites; and (iv) no jaundice, despite advanced liver disease.

Investigations include:

• Screening for the known causes of chronic liver disease (see Box 20.2)

• Upper gastrointestinal endoscopy to detect the presence of oesophageal varices and/or erosive gastritis

• Abdominal ultrasound – may show a shrunken liver and splenomegaly with gastric and oesophageal varices

• Liver biopsy – may be difficult because of increased fibrosis but may indicate the aetiology (e.g. typical changes in congenital hepatic fibrosis, copper storage).

As cirrhosis decompensates, biochemical tests may demonstrate an elevation of aminotransferases and alkaline phosphatase. The plasma albumin falls and the prothrombin time becomes increasingly prolonged.

Oesophageal varices

These are an inevitable consequence of portal hypertension and may develop rapidly in children. They are best diagnosed by upper gastrointestinal endoscopy, as a barium swallow may miss small varices. Acute bleeding is treated conservatively with blood transfusions and H₂-blockers (e.g. ranitidine) or omeprazole. If bleeding persists, octreotide infusion, vasopressin analogues, sclerotherapy or band ligation may be effective. Portacaval shunts may preclude liver transplantation, but radiological placement of a stent between the hepatic and portal veins can be used as a temporary measure if transplantation is being considered.

Ascites

Ascites is a major problem (Fig. 20.10). The pathophysiology of ascites is uncertain, but contributory factors include hypoalbuminaemia, sodium retention, renal impairment and fluid redistribution. It is treated by sodium and fluid restriction and diuretics. Additional therapy for refractory ascites includes albumin infusions or paracentesis.