Liver Disorders

What is prolonged neonatal jaundice, how do you distinguish conjugated from unconjugated, and why does this distinction matter clinically?

Prolonged neonatal jaundice is defined as jaundice persisting beyond 14 days in a term infant or beyond 3 weeks in a preterm infant.

The key clinical distinction is between unconjugated jaundice (which resolves spontaneously and is benign) and conjugated jaundice (bilirubin >25 µmol/L), which always indicates underlying liver disease and requires urgent investigation.

In prolonged jaundice, pale stools suggest bile duct obstruction or severe liver disease.

Early diagnosis and management significantly improve prognosis.

Causes of conjugated jaundice include
Bile duct obstruction (biliary atresia, choledochal cysts),
neonatal hepatitis syndrome (congenital infection, α1-antitrypsin deficiency, galactosaemia, tyrosinaemia), and
intrahepatic biliary hypoplasia (Alagille syndrome).

What is biliary atresia, what are its clinical features, investigations, and how is it managed?

Biliary atresia involves progressive fibrosis and obliteration of the extrahepatic and intrahepatic biliary tree.
Without treatment, death occurs within 2 years.

Clinical features include
mild jaundice with increasingly pale stools,
normal birthweight followed by faltering growth,
hepatomegaly initially, and later splenomegaly from portal hypertension.

Investigations show raised conjugated bilirubin, elevated GGT, abnormal LFTs, and a fasting ultrasound may show an absent or contracted gallbladder.

Diagnosis is
confirmed by cholangiogram (ERCP or operative) that fails to outline a normal biliary tree;
liver biopsy shows neonatal hepatitis with features of extrahepatic biliary obstruction.

Treatment is the
Kasai hepatoportoenterostomy (a loop of jejunum anastomosed to the porta hepatis), which clears jaundice in 60% if done before 60 days of age.
Even if successful, most children progress to cholangitis and cirrhosis.

Biliary atresia is the single most common indication for liver transplantation in the paediatric age group.

What are choledochal cysts, how do they present, how are they diagnosed, and what are the treatment and complications?

Choledochal cysts are cystic dilatations of the extrahepatic biliary system.

They may be detected on antenatal ultrasound, present with neonatal jaundice, or in older children with abdominal pain, a palpable abdominal mass, jaundice, or cholangitis.

Diagnosis is established by ultrasound or magnetic resonance cholangiopancreatography (MRCP).

Treatment is surgical excision of the cyst with formation of a Roux-en-Y anastomosis to the biliary duct.

Future complications include recurrent cholangitis and a 2% risk of malignancy, which can arise in any part of the biliary tree.

What are Alagille syndrome and Progressive Familial Intrahepatic Cholestasis (PFIC), including their genetics, features, and management?

Alagille syndrome is a rare autosomal dominant condition with widely varying penetrance.

Clinical features include a
characteristic triangular facies (pointed chin, wide-spaced eyes, prominent forehead),
butterfly vertebrae,
congenital heart disease (classically peripheral pulmonary stenosis),
renal tubular disorders, and eye defects.
Infants are profoundly cholestatic with severe pruritus and faltering growth.

Diagnosis is confirmed by identifying gene mutations.
Most survive into adult life; mortality is mainly from cardiac disease.

Treatment is nutritional support and fat-soluble vitamins;
a small number need liver transplantation.

Progressive Familial Intrahepatic Cholestasis (PFIC) is a group of autosomal recessive disorders affecting bile salt transport genes.

Features include jaundice, intense pruritus, faltering growth, rickets, and sometimes diarrhoea, hearing loss, and gallstones in older children.

Diagnosis is by identifying mutations in bile salt transport genes.

Treatment includes fat-soluble vitamins and ileal bile acid transporter (IBAT) inhibitors to reduce pruritus; most eventually require liver transplantation.

What is α1-antitrypsin deficiency, how does it cause liver disease, and what is its management?

α1-Antitrypsin deficiency is an autosomal recessive disorder caused by the PiZZ phenotype, coded on chromosome 14.

Abnormal folding of α1-antitrypsin leads to protein accumulation in hepatocytes, causing liver disease.

Lack of circulating protein causes emphysema in adults, especially with cigarette smoke exposure.

In children, it most commonly presents with prolonged neonatal jaundice or, less commonly, bleeding due to vitamin K deficiency. Hepatomegaly is present.

Diagnosis is confirmed by measuring plasma α1-antitrypsin level and identifying the protein phenotype.
Approximately 50% have a good prognosis; the rest develop cirrhosis, portal hypertension, and may require transplantation.

Patients should avoid active and passive smoking. The disorder can be diagnosed antenatally.

What is galactosaemia, how does it present, how is it diagnosed, and what is the treatment?

Galactosaemia is a very rare autosomal recessive disorder caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase.

Infants develop poor feeding, vomiting, jaundice, and hepatomegaly when fed milk (which contains galactose).

If untreated, it causes liver failure, cataracts, and developmental delay.
A rapidly fatal course with shock, haemorrhage, and DIC due to Gram-negative sepsis can occur.

Diagnosis is made by detecting galactose (a reducing substance) in the urine and measuring galactose-1-phosphate uridyl transferase in red blood cells — note that a recent blood transfusion may mask the diagnosis.

Treatment with a galactose-free diet prevents progression of liver disease, although ovarian failure and learning difficulties may occur later.

What is Acute Liver Failure (Fulminant Hepatitis) in children, including causes, clinical features, investigations, and management?

Acute liver failure is the development of massive hepatic necrosis with loss of liver function, with or without hepatic encephalopathy. It is uncommon but has high mortality.

In children <2 years:
the most common causes are infection (especially herpes simplex), metabolic disease, seronegative hepatitis, gestational alloimmune liver disease, and mitochondrial disease.

In children >2 years:
drug-induced (paracetamol overdose), seronegative hepatitis, Wilson disease, and autoimmune hepatitis.

Clinical features include jaundice, encephalopathy (early: irritability alternating with drowsiness; later: aggression), coagulopathy, hypoglycaemia, and electrolyte disturbance.

Complications include cerebral oedema, haemorrhage, sepsis, and pancreatitis.

Investigations:
bilirubin may be normal early;
transaminases elevated 10–100x normal;
raised alkaline phosphatase;
very abnormal coagulation; elevated plasma ammonia;
EEG for encephalopathy; CT for cerebral oedema.

Management:
maintain blood glucose >4 mmol/L with IV dextrose;
broad-spectrum antibiotics and antifungals;
IV vitamin K and H2 blockers/PPIs to prevent haemorrhage;
fluid restriction and mannitol for cerebral oedema.

What are the causes and approach to chronic liver disease in older children, and how does autoimmune hepatitis present and respond to treatment?

Causes of chronic liver disease in older children include post-viral hepatitis B and C, autoimmune hepatitis and sclerosing cholangitis, drug-induced liver disease (NSAIDs), cystic fibrosis, Wilson disease, fibropolycystic liver disease, non-alcoholic fatty liver disease, and α1-antitrypsin deficiency. Wilson disease should always be excluded.

Autoimmune hepatitis peaks at age 7–10 years and is more common in girls.
It may present as acute hepatitis, fulminant hepatic failure, or chronic liver disease with systemic autoimmune features (skin rash, arthritis, haemolytic anaemia, nephritis).

Diagnosis is based on elevated total protein, hypergammaglobulinaemia (IgG >20 g/L),
positive autoantibodies,
low serum complement (C4), and characteristic histology.

It may be associated with IBD, coeliac disease, or other autoimmune diseases.
90% of children respond to prednisolone and azathioprine. Associated sclerosing cholangitis is treated with ursodeoxycholic acid.

What is Wilson disease, including its pathophysiology, clinical features at different ages, investigations, and treatment?

Wilson disease is an autosomal recessive disorder caused by mutations in the ATP7B gene.

The defect involves reduced synthesis of caeruloplasmin (the copper-binding protein) and defective biliary copper excretion, leading to copper accumulation in the liver, brain, kidney, and cornea. It rarely presents before age 3.

In childhood, hepatic presentation dominates: acute hepatitis, fulminant hepatitis, cirrhosis, and portal hypertension.
Neuropsychiatric features appear more commonly from the second decade: deteriorating school performance, mood/behaviour changes, extrapyramidal signs (tremor, incoordination, dysarthria).
Other features include renal tubular dysfunction with vitamin D-resistant rickets and haemolytic anaemia.
Kayser–Fleischer rings (copper deposits in the cornea) are pathognomonic but not seen before age 7.

Investigations:
low serum caeruloplasmin and copper (not universal); increased urinary copper excretion (further increased after penicillamine challenge);
diagnosis confirmed by elevated hepatic copper on liver biopsy or identification of ATP7B mutation.

Treatment:
penicillamine or trientine to promote urinary copper excretion;
zinc to reduce copper absorption;
pyridoxine to prevent peripheral neuropathy.

Zinc alone is used in asymptomatic children identified by family screening.

Neurological improvement takes up to 12 months. Without treatment, 30% die from hepatic complications.

What are the indications, criteria, and outcomes for liver transplantation in children, and what are the common post-transplant complications and immunosuppression regimens?

Liver transplantation is an effective therapy for both acute and chronic liver failure.
The most common indication in the paediatric age group is biliary atresia where the Kasai procedure has failed.
Other indications include:
acute liver failure unresponsive to medical management (especially if the child progresses to coma, where 70% will die without transplant),
metabolic liver diseases (Wilson disease, α1-antitrypsin deficiency, galactosaemia),
autoimmune hepatitis refractory to therapy,
cystic fibrosis-related end-stage liver disease (sometimes combined with heart-lung transplant), and
fibropolycystic disease with severe cholangitis or renal failure.

Poor prognostic features necessitating urgent listing:
shrinking liver size, rising bilirubin with falling transaminases, worsening coagulopathy, and progression to coma.

Post-transplant, children require long-term immunosuppression (typically tacrolimus ± prednisolone) to prevent rejection.

Complications include acute and chronic rejection, infections (bacterial, viral — especially CMV and EBV — and fungal), biliary complications, and lymphoproliferative disease associated with EBV.