Hepatic fibrosis in children and adults

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Abbreviations

ARPKD

autosomal recessive polycystic kidney disease

BA

biliary atresia

NASH

nonalcoholic steatohepatitis

TPA

total parenteral nutrition

Liver fibrosis is the accumulation of excess matrix—scar tissue—in the liver as part of a wound‐healing response. Although this new matrix is predominantly fibrillar collagen, there is also increased deposition of unusual matrix proteins (e.g., chondroitin sulfate–rich proteoglycans) and increased posttranslational modification of collagen (e.g., formation of lysyl oxidase–mediated crosslinks). The progression of fibrosis results in markedly abnormal liver architecture, including capillarized sinusoids and fibrous bridges.

In patients of all ages, fibrosis results from chronic rather than acute damage to the liver. This can be caused by a genetic or persistent environmental insult or, in some cases, by biliary injury with duct obstruction. During the process of healing liver damage, hepatic stellate cells (sinusoidal pericytes) and possibly portal fibroblasts differentiate into α‐smooth muscle actin–positive myofibroblasts, which are responsible for matrix deposition and potentially architectural changes.

There are significant differences between pediatric‐ and adult‐onset liver fibrosis. Although poorly understood and studied, these can be roughly categorized in terms of specific etiology, susceptibility to injury, and response to injury (Table 1).

Table 1.

Differences Between Pediatric and Adult Liver Fibrosis

Specific etiology

Genetic defect

Environmental exposure

Susceptibility to injury

Anatomical immaturity

Functional immaturity

Response to injury

Immunity/Inflammation

Myofibroblasts/Matrix deposition

Stem cells

Etiology

Some forms of liver fibrosis begin primarily or exclusively in children (Table 2). Biliary atresia (BA), total parenteral nutrition (TPA)–associated liver fibrosis, neonatal giant cell hepatitis, and certain progressive familial intrahepatic cholestasis syndromes are unique to neonates and young children, whereas liver fibrosis caused by autosomal recessive polycystic kidney disease (ARPKD) and other ciliopathies and Alagille syndrome develops most commonly in older children. Liver fibrosis from hepatitis C infection, primary sclerosing cholangitis, alpha‐1‐antitrypsin deficiency, Wilson's disease, and nonalcoholic steatohepatitis (NASH) can present in both children and adults, although pediatric‐onset liver fibrosis from these diseases tends to occur in older children, rather than in neonates. Many of the causes of liver fibrosis that affect children are genetic, reflecting the prenatal onset of the insult. Causes of adult‐onset liver fibrosis include primary biliary cholangitis, alcohol abuse, hemochromatosis, and hepatitis B infection, with the age of onset in many cases reflecting the timing of environmental exposures.

Table 2.

Common and Unique Etiologies

Pediatric Onset

Biliary atresia

Alagille syndrome

Progressive familial cholestasis

Bile acid synthetic disorders

Ciliopathies (ARPKD and others)

TPN associated

Neonatal giant cell hepatitis

Adult/Late childhood

Primary biliary cholangitis

Hepatitis B

Alcohol

Wilson's disease

Cystic fibrosis associated

Both

Primary sclerosing cholangitis

NASH

Autoimmune hepatitis

Hepatitis C

Alpha‐1‐antitrypsin deficiency

Hemochromatosis

Susceptibility to Injury

The livers of children and adults differ both anatomically and functionally, which could affect susceptibility to injury (Table 3). Neonates in particular have narrow bile ducts and an incompletely developed intrahepatic biliary tree; bile flow is slow and the bile acid profile is immature, all of which could impact the likelihood of duct obstruction and the degree of damage after injury. Other potentially important features of the pediatric compared with the adult bile duct include the immaturity of the mucosa and submucosa. Functionally, neonatal hepatocytes are immature and may fail to detoxify injurious agents or may demonstrate incompletely developed hepatocyte‐protective mechanisms. BA is an example of a disease resulting from an environmental insult where susceptibility is age specific: although the causative agent and susceptibility factors are not understood, the disease occurs exclusively in neonates and not in older children. Some studies suggest that the insult occurs before birth, yet mothers are unaffected.1

Table 3.

Susceptibility to Injury

Bile duct size and state of development

Difference in bile acids and bile flow

Submucosal maturity

Mucosal protective layer

Hepatocyte function:

Detoxification

Protective mechanisms

Response to Injury

Variations in the response to injury are perhaps the most interesting cause of differences in liver fibrosis between the pediatric and the adult populations (Table 4). Particularly notable is the speed of fibrosis progression, which can be remarkably rapid in children. In newborns with BA, for example, the liver may become cirrhotic within several months. Other potential components of the fibrotic response that may differ according to age include inflammation and the immune response, the ability to regenerate or regress fibrosis, the type of matrix, features of stellate cells and other myofibroblast precursors, and the role of the ductular reaction and stem cells. Inflammation and immunity have been particularly well studied, and there are clear differences in cellular and humoral immunity between children and adults. In neonates, for example, there is decreased dendritic cell number and function, with enhanced proinflammatory Th17 T cell responses, decreased regulatory T cell frequency and function, and differences in Th1/Th2 ratios.2

Table 4.

Response to Injury

Inflammation

Immune function

Regenerative ability

Ongoing regression

Matrix protein deposition: stellate cell responsiveness, types of matrix

Ductular reaction/stem cells

Little is known about the features of hepatic stellate cells and other fibrogenic cell precursors in children and adults. One study suggested that there were more stellate cells and that they underwent myofibroblastic activation faster in neonatal compared with adult rat liver fibrosis.3 The actual matrix of the fibrotic liver appears generally similar independent of age, although there is less type III collagen and more collagen crosslinking in aged versus younger adults4; it is therefore possible that matrix amount, type, and distribution vary in adult compared with pediatric populations.

The ductular reaction, which is linked to fibrosis and may participate in the inflammatory response in some diseases,5, 6 is prominent in the injured neonatal liver. Similarly, liver‐resident stem cells in the canal of Hering and peribiliary region are particularly active in the fetal and neonatal liver.7 Together, these findings raise the possibility that stem cells are relevant to the rapid speed of neonatal fibrosis.

BA is marked by a pronounced ductular reaction and prominent inflammatory and autoimmune responses; the response to injury in BA is distinct even compared with adult biliary diseases (including primary biliary cholangitis). Similarly, in NASH, which afflicts adults and older children, the response to injury varies with age. Steatosis is more severe in children, and fibrosis and inflammation are distributed differently, found initially primarily in zone 1 (portal) in children and in zone 3 (lobular) in adults.8 In contrast, the fibrocystic liver diseases, of which ARPKD with congenital hepatic fibrosis is the most common example, produce similar liver responses (massive cholangiocyte proliferation and bile duct dilation with surrounding fibrosis), regardless of the age of disease onset.

Summary

Just as children are not little adults, pediatric liver fibrosis is not adult fibrosis on a small scale. Although there is some overlap between causes of adult‐ and pediatric‐onset liver diseases, they are for the most part different. Similarly, the susceptibility to injury, best illustrated by BA, can vary markedly by age, in part because of size differences and cell maturity, but also because of factors not yet understood. Finally, the response to injury, including the behavior of fibrogenic and progenitor cells in stimulating matrix deposition, may in many diseases be unique in children. Understanding these differences may be critical to the application of radiological and biomarker diagnostics to pediatric liver disease.