Infantile cirrhosis is a very serious, often fatal, liver disease, largely limited to India or to descendants of Indians residing in the region of southern Asia. It occurs most frequently in children between 1 and 3 years of age and affects both sexes with about equal frequency; familial instances are not uncommon.
The clinical picture is characterized by irritability, gastrointestinal upsets, jaundice, anemia and retarded development. In a number of cases there is a history of fever in some stages of the disease. Children with advanced cases develop hepatosplenomegaly, a sharp and hard anterior edge of the liver, and evidence of effects of progressive portal hypertension.
The basic pathogenetic process leading to this liver disease is characterized histopathologically by evidence of profound injury to individual liver cells, resulting in severe degenerative changes and dissociation of the cytoplasmic contents; marked swelling; partial hyalinization of the cytoplasm (Mallory bodies); "bird's eye" nuclei, indicating difficulty in protein synthesis; and satellitosis about Mallory bodies—probably an attempt to remove the necrobiotic liver cells.
In certain cases there is massive progressive degeneration and necrosis of liver cells, causing hepatic insufficiency without formation of regenerative pseudolobules and without development of portal hypertension. This course is interpreted as the result of a severe, diffuse injury of hepatic cells, which are unable to regenerate. This condition can perhaps be compared with the experimental massive acute necrosis due to thiamin deficiency in animals and with the diffuse hepatic necrosis seen in "florid cirrhosis" in human beings.
In the majority of cases, however, there is development of a portal type of cirrhosis with formation of unilobular, regenerative islets, followed by rising portal hypertension with its usual consequences; not infrequently the regenerated elements are again destroyed by the persisting injurious process.
Evidence of a causal relationship between viral hepatitis and infantile cirrhosis cannot be considered established; neither epidemiologic features nor histopathologic findings are thought to be compatible with the effects of viral hepatitis. The familial occurrence appears to be related to environmental factors rather than to a common source of infection from a silent carrier or to heredity. The nonspecific inflammatory infiltrates (satellites) accompanying this process are interpreted as a scavenger reaction secondary to the injury, degeneration, and necrosis of liver cells.
Regeneration of liver cells can take place only if there are viable hepatic elements. The resulting cirrhosis of the liver is characterized by regenerated pseudolobules developing from such surviving liver cells, embedded in and surrounded by the collapsed pre-existent parenchymal stromal elements, including the surviving tissues from the portal canals. The role of the supporting tissue is considered to be entirely passive and incidental to the primary process of cell destruction.
The necrobiotic changes of individual liver cells, with formation of Mallory bodies, the progressive destruction of the hepatic parenchyma, and the development of a portal type of cirrhosis are quite indicative of a nutritional cause, despite the absence of fatty metamorphosis. The histologic changes are unlike those described in persistent viral hepatitis or in the developing stages of posthepatitic (coarse, nodular) cirrhosis. The obliterative vascular changes of advanced infantile cirrhosis are interpreted as secondary phenomena accompanying the complete reorganization of the liver parenchyma.
Electron microscopic studies of liver tissue from cases of histologically established infantile cirrhosis demonstrate profound disorganization of ultramicroscopic structures of liver cells, with reduction in number, distortion and partial obliteration of mitochondria, secretory granules and microsomes; deformity and distention of the channels of the intracytoplasmic reticulum; and alteration of nuclei and nuclear components. The "alcoholic hyalin" of the Mallory body appears to be the result of condensation and fusion of damaged, distorted and obliterated mitochondria.
335. Toward a Cellular Therapy for Metabolic Liver Disease: Gene Targeting of the Ornithine Transcarbamylase (Otc) Locus in Bipotential Murine Oval Liver Cells (BMOL) Using Adeno-Associated Virus
