Cholestasis should be diagnosed quickly in infancy as various diseases require immediate therapy. Numerous aetiologies make diagnosis difficult. The American Academy of Pediatrics has elaborated practical guidelines for the management of hyperbilirubinaemia in newborn infants, mainly concentrating on indirect hyperbilirubinemia¹. The guidelines emphasise the importance of measuring direct bilirubin in sick infants and in those who are jaundiced at or beyond 3 weeks. If the direct or conjugated bilirubin level is elevated, additional assessment for the causes of cholestasis is recommended. For instance, hypothyroidism, galactosaemia, and tyrosinaemia should be taken into account. Infectious diseases may also cause cholestasis, thus urinary tract infections as well as cytomegalovirus (CMV) and toxoplasmosis should be excluded. The role of CMV as the causative factor of cholestasis is still under debate, as congenital CMV infections may present with liver damage and cholestasis. It is very important to assess stool colour to make a timely diagnosis of biliary atresia (BA). BA is a relatively uncommon disease characterized by a biliary obstruction of unknown origin that presents in the neonatal period². However, it is the most important surgically correctable cause of cholestatic jaundice in this age group and is the most common indication for liver transplantation in children. Untreated, BA leads to cirrhosis and death within the first years of life. Surgical treatment usually involves an initial attempt to restore bile flow: the Kasai portoenterostomy³ which is performed as soon after diagnosis as possible. Prognosis of the disease seems to be better in infants operated on before 90 days of age⁴. Other causes of cholestasis with pale stools are: Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), alpha-1-antitrypsin deficiency (α1-ATD), and cystic fibrosis. Neonatal haemochromatosis, Zellweger syndrome, Niemann-Pick disease type C, and glycogen storage disease type IV should also be considered in the differential diagnosis of infantile cholestasis (Tables 9.1, 9.2).

Jaundice is uncommon in children. However, indirect hyperbilirubinaemia can be the presentation of a benign, inherited condition, Gilbert syndrome, which affects about 6% of the adult population. Mutations in hepatic enzyme isoform (1A1) belonging to the urine diphosphoglucuronate glucuronosyltransferase (UGT) family of enzymes are responsible for this condition⁵. Gilbert syndrome can be confirmed by molecular diagnosis but it should be suspected in an otherwise asymptomatic child whose other liver tests are normal and there are no signs of haemolysis.

Several liver diseases may present with jaundice such as infection with hepatitis B, hepatitis A, and hepatitis C virus, autoimmune hepatitis, Wilson disease, and α1-ATD. Cholecystitis is a rare condition in children and acute clinical symptoms with jaundice and fever are very unusual. Choledocholithiasis is also infrequent in childhood.

Familial cholestatic diseases (Alagille syndrome, PFIC) and postoperative biliary atresia may present with episodes of increased hyperbilirubinaemia or symptoms of liver insufficiency. That is why it is important to follow these patients carefully and the primary care physicians have to be aware of possible exacerbation of symptoms. Cholangitis episodes in postoperative biliary atresia require rapid diagnosis and treatment. Septic and hypoxic damage to the liver can cause cholestasis, and septicaemia seems to be a common reason for referral of a jaundiced child to liver clinics.

Alagille syndrome can present with very early cholestasis of infancy but it may also be asymptomatic for a very long time. Liver damage may progress quickly in some patients with portal hypertension, recurrent cholangitis, and malnutrition⁶. Diagnosis of Alagille syndrome is aided by the presence of syndromic features, including bile duct paucity on liver histology, chronic cholestasis, cardiac murmur, vertebral abnormalities, peculiar facies, eye findings, renal disease, and xantomas⁷. Usually differential diagnosis is performed in early infancy when biliary atresia must be excluded.

Typical facial features are a prominent forehead, pointed chin, deep set eyes, moderate hypertelorism, and a saddle or straight nose with a bulbous tip (9.1), but these features are not very typical in early infancy. The parents may also have the typical appearance (9.2) which may indicate the need to diagnose this disease. Pulmonary artery stenosis is a typical finding which may also cause a serious heart disease (9.3, 9.4). Embryotoxon posterior observed in a slit lamp is one of the most common features of the Alagille syndrome. Butterfly vertebrae observed in late infancy are also a characteristic feature (9.5). Liver biopsy is helpful to establish the diagnosis (9.6). Liver disease may slowly progress to liver insufficiency and liver transplantation may be needed. However, in most of the patients liver disease remains stable for a long time.

PFIC is an inherited disorder where bile acid excretion is impaired (Table 9.3). This diagnosis should always be suspected in patients with high serum bile acid concentration, low/normal or elevated gamma glutamyl transpeptidase (GGT), and pruritus.

Pruritus is usually the predominant symptom and skin excoriations due to itching may be observed (9.7). Short stature is a typical feature in later age (9.8). Liver histology may reveal giant cell transformation, ductular proliferation, and fibrosis (9.9). The disease may progress to end-stage liver disease. Some experience from centres in the USA and Poland points to a successful therapy with partial external biliary diversion (9.10) when performed early in the course of the disease⁸. PFIC also seems to be a risk factor for hepatocellular carcinoma⁹. In general, diagnosis of PFIC is not very urgent but doctors should be aware of the potential health effects.

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by intermittent episodes of cholestasis without progression to cirrhosis. The onset of the disease usually occurs before the second decade of life. The attacks of cholestasis vary in severity and duration (from 1 to 18 months) and may be preceded by a preicteric phase with malaise, anorexia, and pruritus. Biochemically it is characterized by increased concentrations of bilirubin, serum bile acid, and alkaline phosphatase; GGT remains low. There are no pathological changes in the liver on biopsy besides some hepatocellular cholestasis. In between episodes patients are totally asymptomatic both clinically and biochemically. Treatment is symptomatic.

BA presents with cholestasis in early infancy (1-2 months of age) in an otherwise healthy child, thus diagnosis may be delayed. The most common clinical features are: jaundice with conjugated bilirubin beyond 2 weeks of life (9.11), white stools and dark urine as well as hepatomegaly, which may not always be evident. Usually a complete work-up of cholestatic diseases is performed to confirm the diagnosis and to exclude other liver diseases with early presentation. The gall bladder may not be visible on ultrasound in many patients with biliary atresia, dynamic scintigraphy (HIDA) does not show any bile passage to the gut (9.12), and liver histology may present ductal plate malformation with bile duct proliferation and fibrosis (9.13), which is regarded as a typical feature that confirms the diagnosis. It is recommended that infants with direct hyperbilirubinaemia exceeding 2 mg/dl (34 μmol/l) over 2 weeks of age be referred to liver centres for further work-up to avoid wasting valuable time in making the diagnosis. BA may progress quickly to cirrhosis with ascites (9.14) and oesophageal varices as a consequence of portal hypertension.