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The Bridge – November 2001
Journal of Hepatology 35 (2001) 549 www.elsevier.com/locate/jhep
The Bridge – November 2001 Cholesterol gallstone disease in diabetes mellitus type 2 (see pages 550–557) Dubrac and colleagues observe that insulin injections increase the prevalence of gallstones in hamsters fed a lithogenic diet. This is achieved by an upregulation of cholesterol synthesis (induction of HMG-CoA-reductase), a decrease in the key enzyme of the neutral bile acid pathway (cholesterol 7a-hydroxylase) and a decrease in the secretion of antinucleating factors, in particular apolipoprotein A1, into bile. This observation could provide a rationale for the association of cholesterol gallstone disease with diabetes type 2. Mediation of catabolic effects of cytokines (see pages 558– 567) The catabolic state in critically ill patients is mediated by a variety of cytokines, foremost among them tumor necrosis factor a and different interleukins. In models of catabolism, insulin-like growth factors (IGF) are down-regulated; it is conceivable that this could be responsible for the catabolic state. Lelbach and colleagues demonstrate that interleukin 6 was most potent in downregulating IGF production in hepatocytes. The deficiency is further aggravated by concomitant overproduction of IGF binding proteins in both hepatocytes and Kupffer cells; these bind IGF and prevent its interaction with its receptors. Low-grade cerebral edema – detection by 1H magnetic resonance spectroscopy (see pages 598–604, 661–662) Co´rdoba and colleagues demonstrate convincingly that chronic portosystemic encephalopathy is associated with low grade cerebral edema. They were able to measure free water in the brain with a novel magnetic resonance imaging technique: the magnetization transfer ratio (MTR) which is determined by the transfer of signal between protons of free water and those associated with macromolecules. An increase in free water will lead to a decrease in the MTR; and this is exactly what they found in cirrhotic patients with abnormal brain function as determined by psychometric testing but devoid of overt hepatic encephalopathy. MTR was correlated with psychometric test impairment and an increase in osmolytes (glutamine as determined by MR spectroscopy) due to altered ammonia metabolism. These alterations disappeared after liver transplantation. Non-invasive determination of splanchnic and total blood volume (see pages 605–612) Splanchnic pooling of blood is an important aspect of the hyperdynamic circulation syndrome in portal hypertension. It is wellvalidated in experimental animals but difficult to quantitate in patients. Kiszka-Kanowitz et al. validate a seemingly quite simple (or so I am told by our professor of nuclear medicine) nuclear medicine technique based on injection of radiolabeled albumin and quantitating the pooling in different regions of interest. This simple method may become a very useful tool in furthering our
Ju¨rg Reichen [email protected] understanding of the pathophysiology of portal hypertension and perhaps to assess the effects of pharmacological interventions. 8-Hydroxydeoxyguanosine in chronic liver disease (see pages 613–618) Kitada and coworkers demonstrate the nuclear expression of 8-hydroxydeoxyguanosine (HDG) in different liver diseases by immunohistochemistry. They find increased expression in viral, alcohol-toxic and autoimmune liver disease mostly in hepatocytes in the areas of inflammatory infiltration; of particular interest was its almost universal expression in cholangiocytes in patients with primary biliary cirrhosis. HDG formation is an expression of oxidative DNA damage; thus, it is not surprising to find it in areas of inflammation. Is the expression of HDG then just another marker for inflammation? The authors believe not but tie it in with hepatocarcinogenesis since HDG is prone to induce G ! C to T ! A transversion when DNA replicates. Although the importance of HDG in the etiology of hepatocellular cancer remains to be proven, this observation nicely ties chronic inflammation to carcinogenesis. Heat shock preconditioning and tumor necrosis factor a in reperfusion injury (see pages 619–627, 663–665) Reperfusion injury – as seen in major liver surgery during the Pringle manoeuver – can be prevented in experimental animals by exposure to a stress such as heat (preconditioning). The exact mechanism whereby preconditioning protects organs is unknown but might be related to the induction of heat shock proteins preventing NF-kB induced cell death. Yonezawa et al. confirm that preconditioning is protective (ALT release and histology); they also demonstrate that this protection is associated with decreased expression of TNF-a in the liver. This led to decreased levels of cytokine-induced leukocyte chemoattractant and explained the decreased neutrophil invasion and cell damage. They suggest that heat shock preconditioning could be used to render patients with chronic liver disease more tolerant to the Pringle manoeuvre – why this may be premature is explained in the accompanying editorial by Mato and colleagues. Mitochondrial toxicity of amiodarone (see pages 628–636) Amiodarone is a potent antidysrhythmic agent; its use is hampered by many side effects including thyroid disease, pulmonary fibrosis and hepatocellular damage resembling alcoholic hepatitis. It is well established that the latter is due to mitochondrial toxicity. Spaniol et al. ascribe this toxicity to the benzofurane ring while iodination is not important in mitochondrial toxicity. They also demonstrate that the main mode of action is the uncoupling of mitochondrial respiration. However, there is also inhibition of b-oxidation of fatty acids, which could explain the peculiar histological picture of amiodarone toxicity. Their findings also provide the mechanism of hepatotoxicity of other drugs with a benzofurane ring.
0168-8278/01/$ - see front matter q 2001 Published by Elsevier Science B.V. on behalf of the European Association for the Study of the Liver. PII: S 0168-827 8(01)00239-2
The Bridge – November 2001 Cholesterol gallstone disease in diabetes mellitus type 2 (see pages 550–557) Dubrac and colleagues observe that insulin injections increase the prevalence of gallstones in hamsters fed a lithogenic diet. This is achieved by an upregulation of cholesterol synthesis (induction of HMG-CoA-reductase), a decrease in the key enzyme of the neutral bile acid pathway (cholesterol 7a-hydroxylase) and a decrease in the secretion of antinucleating factors, in particular apolipoprotein A1, into bile. This observation could provide a rationale for the association of cholesterol gallstone disease with diabetes type 2. Mediation of catabolic effects of cytokines (see pages 558– 567) The catabolic state in critically ill patients is mediated by a variety of cytokines, foremost among them tumor necrosis factor a and different interleukins. In models of catabolism, insulin-like growth factors (IGF) are down-regulated; it is conceivable that this could be responsible for the catabolic state. Lelbach and colleagues demonstrate that interleukin 6 was most potent in downregulating IGF production in hepatocytes. The deficiency is further aggravated by concomitant overproduction of IGF binding proteins in both hepatocytes and Kupffer cells; these bind IGF and prevent its interaction with its receptors. Low-grade cerebral edema – detection by 1H magnetic resonance spectroscopy (see pages 598–604, 661–662) Co´rdoba and colleagues demonstrate convincingly that chronic portosystemic encephalopathy is associated with low grade cerebral edema. They were able to measure free water in the brain with a novel magnetic resonance imaging technique: the magnetization transfer ratio (MTR) which is determined by the transfer of signal between protons of free water and those associated with macromolecules. An increase in free water will lead to a decrease in the MTR; and this is exactly what they found in cirrhotic patients with abnormal brain function as determined by psychometric testing but devoid of overt hepatic encephalopathy. MTR was correlated with psychometric test impairment and an increase in osmolytes (glutamine as determined by MR spectroscopy) due to altered ammonia metabolism. These alterations disappeared after liver transplantation. Non-invasive determination of splanchnic and total blood volume (see pages 605–612) Splanchnic pooling of blood is an important aspect of the hyperdynamic circulation syndrome in portal hypertension. It is wellvalidated in experimental animals but difficult to quantitate in patients. Kiszka-Kanowitz et al. validate a seemingly quite simple (or so I am told by our professor of nuclear medicine) nuclear medicine technique based on injection of radiolabeled albumin and quantitating the pooling in different regions of interest. This simple method may become a very useful tool in furthering our
Ju¨rg Reichen [email protected] understanding of the pathophysiology of portal hypertension and perhaps to assess the effects of pharmacological interventions. 8-Hydroxydeoxyguanosine in chronic liver disease (see pages 613–618) Kitada and coworkers demonstrate the nuclear expression of 8-hydroxydeoxyguanosine (HDG) in different liver diseases by immunohistochemistry. They find increased expression in viral, alcohol-toxic and autoimmune liver disease mostly in hepatocytes in the areas of inflammatory infiltration; of particular interest was its almost universal expression in cholangiocytes in patients with primary biliary cirrhosis. HDG formation is an expression of oxidative DNA damage; thus, it is not surprising to find it in areas of inflammation. Is the expression of HDG then just another marker for inflammation? The authors believe not but tie it in with hepatocarcinogenesis since HDG is prone to induce G ! C to T ! A transversion when DNA replicates. Although the importance of HDG in the etiology of hepatocellular cancer remains to be proven, this observation nicely ties chronic inflammation to carcinogenesis. Heat shock preconditioning and tumor necrosis factor a in reperfusion injury (see pages 619–627, 663–665) Reperfusion injury – as seen in major liver surgery during the Pringle manoeuver – can be prevented in experimental animals by exposure to a stress such as heat (preconditioning). The exact mechanism whereby preconditioning protects organs is unknown but might be related to the induction of heat shock proteins preventing NF-kB induced cell death. Yonezawa et al. confirm that preconditioning is protective (ALT release and histology); they also demonstrate that this protection is associated with decreased expression of TNF-a in the liver. This led to decreased levels of cytokine-induced leukocyte chemoattractant and explained the decreased neutrophil invasion and cell damage. They suggest that heat shock preconditioning could be used to render patients with chronic liver disease more tolerant to the Pringle manoeuvre – why this may be premature is explained in the accompanying editorial by Mato and colleagues. Mitochondrial toxicity of amiodarone (see pages 628–636) Amiodarone is a potent antidysrhythmic agent; its use is hampered by many side effects including thyroid disease, pulmonary fibrosis and hepatocellular damage resembling alcoholic hepatitis. It is well established that the latter is due to mitochondrial toxicity. Spaniol et al. ascribe this toxicity to the benzofurane ring while iodination is not important in mitochondrial toxicity. They also demonstrate that the main mode of action is the uncoupling of mitochondrial respiration. However, there is also inhibition of b-oxidation of fatty acids, which could explain the peculiar histological picture of amiodarone toxicity. Their findings also provide the mechanism of hepatotoxicity of other drugs with a benzofurane ring.
0168-8278/01/$ - see front matter q 2001 Published by Elsevier Science B.V. on behalf of the European Association for the Study of the Liver. PII: S 0168-827 8(01)00239-2