Liver Cirrhosis: From Pathophysiology to Disease Management. Falk Symposium 162

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This volume is based on the Proceedings of the International Symposium held in Dresden, Germany, in October 2007 under the auspices of the prestigious Falk Foundation. The setting held special meaning for its presenters in that the reconstruction of the city after the massive destruction of the World War II inspired a spirit of renewal and energy among the participants from Europe and the United States, who represent many of the leading authorities in hepatology today.

The hardback book, organized into 6 sections, presents current concepts on the pathophysiology of cirrhosis, and then segues into practical management of cirrhosis and its major complications. It contains an enormous amount of information packed into each section in review format, with extensive references. The chapters could have been more consistently edited, keeping to a single format such as conclusion, rather than ending with “Future Perspectives” or “Take Home Message.” The diagrams, although complex, are clear. The index is comprehensive.

The opening chapter sets the expectations that a better understanding of apoptosis of stellate cells and leukocytes, which may be involved in both promotion and resolution of fibrosis, may open the door to preventive therapies. The subsequent chapters develop the theme that subtle interactions between the immune systems within gut and liver may also hold the key to anti-inflammatory therapy, and that paradoxically, the immune responses of virus specific T cells, although effective in clearing viral load in hepatitis C virus–infected patients, may also exert a damaging effect on the liver. Understanding of the influence of genetic susceptibility to fibrosis and metabolic factors influencing progression of liver disease, such as type of dietary fat on development of nonalcoholic steatosis, is still in its early stages. Elimination of triggers, whether viral load or fat, offers promise. Investigation at the molecular level of the role of the overworked stellate cell, the multitasking facilitator of so many hepatic functions, has led to an understanding that these astonishing cells are also the provocateurs of an irreversible process leading to fibrosis, once differentiated into myofibroblasts. Interferon-γ, a key counterregulator cytokine, reduces the impact of transforming growth factor, which is a major stimulator of fibrogenesis and transformation of stellate cells. Interleukin-10 is also being investigated as an inhibitor of collagen production. At present, there is no evidence that a single magic bullet that can target the fibrotic response. Despite a deeper understanding of the many complex mechanisms of liver fibrogenesis so concisely elucidated here, the answers remain elusive, with the last chapter of this remarkable mystery still unwritten.

A review of the impact of altered portal hemodynamics, including enzymatic regulation of nitric oxide, the role of vasoconstrictor proteins, and the emerging understanding of angiogenesis in portal hypertension, introduces the link to therapy through inhibition of vascular endothelial growth factor to reduce the formation of new blood vessels. The search for noninvasive markers of liver fibrosis is far from over, with competition between various patented serological markers and measures of liver “stiffness.” The role of endoscopy is discussed, as well as acute therapeutic options, including use of prophylactic antibiotics, and TIPs for uncontrolled variceal hemorrhage. Although β-blocker therapy is a mainstay in the treatment of established portal hypertension to delay variceal growth, other agents aimed at increasing nitric oxide release are mentioned as possible therapies. A 2009 randomized, controlled trial published in Gastroenterology by several of the contributing authors has now demonstrated that simvastatin decreases the hepatic venous pressure gradient and improves liver perfusion. The treatment of ascites, spontaneous bacterial peritonitis, encephalopathy, and hepatopulmonary syndromes each receive a chapter. Some of the discussion on portal hypertension is redundant. The chapter on orthotopic liver transplantation discusses the benefits and limitations of the US organ allocation model (Model for End-Stage Liver Disease), with a short segment on the still poignant issues affecting survival and quality of life of patients whose scores are too low, even though they may be severely disabled, to ever undergo transplantation.

Bottom Line: This is a fascinating publication, stressing possible therapeutic strategies based on intensive research at the molecular and physiologic level. Does this book represent a memento of a dynamic symposium, with significance only for the presenters, or is this volume of practical value to practitioners of medicine in other specialties or early phases of training? It is not a timeless definitive text, but rather a provocative challenge, of interest to hepatologists, or would-be hepatologists, focusing on the importance of understanding, and contributing to the understanding, of the pathogenesis of fibrogenesis in order to manage more effectively its clinical manifestations.