Figure 12.1 Neonatal hepatitis. Hepatocytes show extensive giant cell transformation with multinucleation against the background of lobular cholestasis.
Alagille syndrome is histologically characterised by progressive intrahepatic bile duct loss, which usually starts during infancy (Figure 12.2). The degree to which bile duct loss progresses is variable among children; hence, seemingly preserved bile ducts in liver biopsy do not entirely exclude early Alagille syndrome. Along with the progression of bile duct paucity, lobular cholestasis becomes obvious. Bile ductular reaction with biliary-type interface activity is usually an early sign of biliary disease in other cholangiopathies, whereas Alagille syndrome lacks a severe bile ductular reaction, particularly at the early stage [5]. Copper-associated protein deposition is identifiable in periportal hepatocytes on orcein-stained sections, representing chronic cholestasis. Immunostaining for cytokeratin 7 or 19 is helpful to identify the loss of bile ducts. Periportal hepatocytes aberrantly express cytokeratin 7, another feature of chronic cholestasis. Some cases are associated with extensive fibrosis, rarely progressing to biliary-type cirrhosis.
Figure 12.2 Alagille syndrome. The bile duct is absent in this small portal tract. Bile ductular reaction is not identified.
12.4 CONGENITAL HEPATIC FIBROSIS AND CAROLI’S DISEASE
12.4.1 Congenital hepatic fibrosis
Congenital hepatic fibrosis (CHF) is a disorder typically affecting children and young adults [6]. Common clinical symptoms are portal hypertension, recurrent cholangitis and jaundice. Some patients may be misdiagnosed with ‘idiopathic liver cirrhosis’ based on portal hypertension and imaging findings of distorted liver architecture, but liver biopsy gives a diagnostic clue. Medullary tubular ectasia is the most common kidney disease seen in those with CHF.
The liver in cases of CHF is usually enlarged in size with a smooth hepatic capsule. Slicing reveals fibrotic parenchyma with satellite-shaped stromal foci (Figure 12.3a). Periportal connective tissue may become prominent. Histologically, the parenchyma is divided by broad fibrous septa variable in thickness. Unlike rounded regenerative nodules seen in cirrhosis, parenchymal islands in CHF are somewhat geographic in shape. Fibrous septa contain numerous randomly distributed small bile ducts. Ductal plate malformation-like architecture is also sometimes present. The number of portal vein branches is decreased, which is seemingly the cause of portal hypertension. Bile casts within duct lumens are findings highly suggestive of this condition (Figure 12.3b). Some cases show intense periductal inflammation with predominantly neutrophilic infiltration, giving an overall impression of advanced biliary diseases. This could be a diagnostic pitfall, particularly for small biopsy samples.
Figure 12.3 CHF. (a) Gross picture. The liver parenchyma has patchy fibrotic foci. (b) Histology. The fibrous septum has several bile ducts and ductules, some of which contain bile casts.
12.4.2 Caroli’s disease (see Chapter 7)
Caroli’s disease* frequently develops in conjunction with CHF [6] and is characterised by multiple, discrete cystic dilatations within the intrahepatic bile duct. It may affect the whole liver, but lobular or segmental forms have been reported. As the cystic change is mainly present in the perihilar area, biopsy specimens except for liver explants only rarely confirm the cystic structure. Hence, the diagnosis is based mainly on imaging. A characteristic histological finding is fibrovascular connective tissue bridging the dilated bile duct, the bile duct being associated with an intense chronic and active inflammatory infiltrate, ulcerative changes and regeneration of the lining epithelium. Dysplasia is rarely identified in the epithelium, suggesting multistep carcinogenesis [7].
12.4.3 Neonatal haemochromatosis
This is a rare condition characterised by liver failure during the first few days of life and abundant iron deposition in the liver and extrahepatic organs. Previously, neonatal haemochromatosis was suspected to be a genetic disease given that a mother who had an infant affected with this condition is at high risk in subsequent pregnancies. However, a recent study suggested gestational alloimmune reaction to be the cause of this condition [8,9]. Gestational alloimmune diseases are caused by the activation of fetal complement following the placental passage of reactive maternal immunoglobulin G (IgG). In a pathological study, the remaining hepatocytes in the liver with neonatal haemochromatosis appeared intensely positive for the terminal complement cascade neoantigen [9]. This hypothesis is also supported by a subsequent study, where high-dose intravenous immunoglobulin designed to suppress gestational alloimmunity significantly reduced the frequency of neonatal haemochromatosis in high-risk pregnancies [10].
Figure 12.4 Neonatal haemochromatosis. (a) The liver parenchyma exhibits small nodular transformation with many neoductules surrounding regenerative nodules. (b) Perls staining demonstrates diffuse haemosiderin deposition.
Livers affected by neonatal haemochromatosis are small in size and covered by a finely nodular capsule. Histology shows widespread fibrosis surrounding small regenerative nodules, giving a cirrhotic appearance (Figure 12.4a). Another characteristic finding is extensive bile ductular reaction at the edge of regenerative nodules. The parenchyma is highly cholestatic. Enlarged hepatocytes are arranged in an irregular trabecular pattern. Perls iron staining demonstrates extensive haemosiderin deposition in hepatocytes and bile ducts (Figure 12.4b). Similar haemosiderin deposition is identifiable at extrahepatic sites, including the gastrointestinal tract, pancreas and myocardium. There is diagnostic value in detecting iron deposition in another organ. A practical example of this is the lip biopsy, with iron deposition in the minor salivary glands of an infant with acute liver failure supporting the diagnosis of neonatal haemochromatosis [11].
12.5.1 Autoimmune hepatitis
Autoimmune hepatitis (AIH) in children can manifest as a spectrum of liver diseases, including acute liver failure, acute exacerbation of chronic hepatitis and mild persistent chronic hepatitis [12]. Most have serological autoimmune abnormalities, including hyper-γ-globulinaemia, elevated levels of IgG and positivity for autoantibodies such as anti-nuclear (ANA), anti-smooth muscle (SMA), and anti-liver/kidney microsomal (LKM) antibodies.
AIH is classified into three types based on the autoanti-body profile:
AIH is histologically characterised by a dense portal infiltrate consisting of predominantly lymphocytes and plasma cells, although the latter predominates in places (plasmacytosis). Intense interface activity is another feature. A characteristic finding in the parenchyma is perivenular cell loss associated with perivenular lymphoplasmacytic infiltration (central perivenulitis). In severe cases, bridging confluent necrosis or panlobular necrosis can be present. Hepatocytes are enlarged and arranged in a resetting architecture, particularly in the periportal area. Another unique hepatocellular change is emperipolesis, where inflammatory cells are incorporated in the cytoplasm of hepatocytes.
• Type 1 – most common and characterised by the presence of ANA or SMA
• Type 2 – typically associated with LKM antibodies; more commonly affects children
• Type 3 – linked to autoantibodies against soluble liver antigen/liver pancreas antigen (SLA/LP), but remains a controversial entity because of its overlap with Type 1
12.5.2 Sclerosing cholangitis (see Chapter 11)
In children, sclerosing cholangitis can be caused by various aetiologies, including immunodeficiency, cystic fibrosis and Langerhans* cell histiocytosis. Sclerosing cholangitis of unknown cause is called primary sclerosing cholangitis
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