Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics.
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C/EBP, a heat-stable DNA-binding protein, play a very important role in establishing and maintaining the differentiation state of liver cells as a transcription factor enriched in the liver. In order to identify its distribution, localization and function, immunocytochemical examination (ABC method) was done by using anti-C/EBP polypeptide antibodies 1103#, 425# in 20 normal human adult liver tissues, 5 neonatal liver tissues, 6 hepatitis tissues, 25 liver cirrhosis tissues, 80 hepatocellular carcinoma tissues (40 cases with associated surrounding non-tumor hepatic tissues) and 26 cholangiocarcinoma tissues (15 cases with associated surrounding non-tumor tissues). The results showed that C/EBP expression was restricted to terminally differentiated liver cells, and was very low or undetectable in poorly differentiated liver cells, such as liver tumor cells. Its expression also correlated with the grading of hepatocellular carcinoma. Besides, positive C/EBP stain could be found in all regenerating bile ductules. The C/EBP has a diffuse distribution which could be detected both in nuclei and in cytoplasm, but more abundant in cytoplasm. The results are in accordance with the concept that C/EBP plays an important role in establishing and maintaining the differentiation state of liver cells.
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In animals, the combination of oxidative liver damage and inhibited hepatocyte proliferation increases the numbers of hepatic progenitors (oval cells). We studied different murine models of fatty liver disease and patients with nonalcoholic fatty liver disease or alcoholic liver disease to determine whether oval cells increase in fatty livers and to clarify the mechanisms for this response. To varying degrees, all mouse models exhibit excessive hepatic mitochondrial production of H(2)O(2), a known inducer of cell-cycle inhibitors. In mice with the greatest H(2)O(2) production, mature hepatocyte proliferation is inhibited most, and the greatest number of oval cells accumulates. These cells differentiate into intermediate hepatocyte-like cells after a regenerative challenge. Hepatic oval cells are also increased significantly in patients with nonalcoholic fatty liver disease and alcoholic liver disease. In humans, fibrosis stage and oval cell numbers, as well as the number of intermediate hepatocyte-like cells, are strongly correlated. However, cirrhosis is not required for oval cell accumulation in either species. Rather, as in mice, progenitor cell activation in human fatty liver diseases is associated with inhibited replication of mature hepatocytes. The activation of progenitor cells during fatty liver disease may increase the risk for hepatocellular cancer, similar to that observed in the Solt-Farber model of hepatocarcinogenesis in rats.
Acute liver failure (ALF) carries high morbidity and mortality (>80%) even in the best centres. Orthotopic liver transplantation (OLTx) is the only viable approach to the treatment of ALF. This has significantly improved the survival in these patients. The major limitations of OLTx are non availability of the donor liver, requirement of a major surgical procedure, high cost and longterm immunosuppression. Isolated hepatocyte transplantation is emerging as an appealing method for the treatment of ALF because of its technical simplicity and easy availability of cells. Transplantation of allogenic/xenogenic hepatocytes transplantation in experimentally induced ALF has shown an increased survival rate. Clinical studies in acute, chronic liver failure and metabolic disorders have also been undertaken in a few centres and have shown encouraging results. To maintain the continuous supply of cells, xenogenic source of hepatocytes (porcine, rabbit, canine) have offered a hope. A major concern regarding the use of xenogenic donors is the risk of transmission of zoonosis and immunogenicity. Recently, Porcine endogenous retrovirus (PERV) has been shown to infect human tissue in vitro. The problem of immunogenicity of xenogenic hepatocytes can be overcome to some extent by immunoisolation, encapsulation technique, which may also provide protection to the hepatocytes during cryopreservation. The knowledge of adult hepatic stem from tissue offered a new hope for the treatment of various chronic and metabolic diseases. Further, the transdifferentiation potentiality of haematopoietic stem cells to hepatic lineage has strengthened cell therapy.
In the past 10 years we have examined 20 children with inflammatory liver disease associated with high serum titers of anti-liver-kidney microsome antibody (anti-LKM). The first hepatic symptoms were progressive fatigue and jaundice, the fortuitous finding of hepatomegaly or splenomegaly with raised transaminase activity, or an acute hepatitis-like illness. At the time of diagnosis, hepatomegaly was present in 18 children, splenomegaly in 16, jaundice in nine, and ascites in two. Serum alanine transferase activities were elevated in all but two, who had already received steroids. Serum total gammaglobulin values were greater than 2.0 gm/dl in 16 children, prothrombin activity less than or equal to 60% in six, and serum titer of anti-LKM between 1:100 and 1:100,000. All children but one had cirrhosis, and histologic signs of aggressivity were present in 14. In 11 children one or more extrahepatic diseases were present, including type 1 diabetes, vitiligo, glomerulonephritis, autoimmune hemolytic anemia, hypoglycemia with hyperinsulinism, autoimmune thyroiditis, chronic mucocutaneous candidiasis with hypoparathyroidism, and multiple cutaneous and visceral telangiectasias. Treatment with prednisone and azathioprine improved the liver condition in 16 of the 18 patients given treatment. In eight of them discontinuation of treatment resulted in rapid relapse; 14 are still receiving treatment and have stable hepatic function with follow-up from 8 months to 6 1/2 years. Only two are free of treatment. Four children died, two in spite of immunosuppressive therapy, one during a relapse, and one of extrahepatic disease. These results indicate that this autoimmune inflammatory liver disease may have onset early in life, with several clinical patterns; is frequently associated with certain types of extrahepatic manifestations of autoimmune origin; and is a potentially fatal disease for which immunosuppressive treatment must be started early.
Auxiliary heterotopic liver transplantation is theoretically attractive because it leaves the recipient's liver in place. The surgical trauma of hepatectomy is avoided, and failure of the graft does not necessarily lead to the death of the patient or a second, emergency transplantation. Another advantage is that matching the body sizes of the donor and the recipient is not mandatory, which increases the number of possible donors. However, previous clinical results of auxiliary liver transplantation have been poor. We performed auxiliary partial liver transplantation in six consecutive patients with end-stage chronic liver disease who were not accepted for orthotopic liver transplantation because they had massive ascites, deficient clotting function, cachexia, or poor pulmonary reserve. The donor liver was transplanted to the right subhepatic region after removal of segments II and III, and it was provided with portal and arterial blood. There were no major changes in hemodynamic measurements during surgery. The mean hospital stay after transplantation was 22.7 days (range, 14 to 29). After a mean follow-up period of 14 months (range, 5 to 23), all patients were alive, with good graft function as demonstrated by scintigraphy, Doppler ultrasonography, and synthesis of clotting factors. From these observations we conclude that auxiliary partial liver transplantation is an attractive alternative to orthotopic liver transplantation in high-risk patients. Its role in other patients who need liver transplants remains to be defined.