Tissue Inhibitors of Metalloproteinases: Role in Liver Fibrosis and Alcoholic Liver Disease

In liver fibrosis, activated hepatic stellate cells (HSC) play a major role in the deposition of excess extracellular matrix, including fibrillar collagens type I and type III. In addition to matrix protein synthesis, HSC regulate matrix degradation in the liver. This is mediated via a combination of synthesis of matrix (pro)metalloproteinases, which activate these zymogens via specific mechanisms and by inhibiting the active matrix-degrading enzymes via expression of tissue inhibitors of metalloproteinases (TIMPs). There are currently four members of the TIMP family described and of these, both TIMP-1 and TIMP-2 are synthesised by HSC. These observations have led to the suggestion that inhibition of matrix degradation mediated by a change in HSC-expression of TIMPs relative to metalloproteinases, such as interstitial collagenase, may contribute to progression of liver fibrosis. This hypothesis is supported by studies of human liver disease in which TIMP-1 expression is upregulated 5-fold in cirrhotic compared with normal liver. TIMP-1 and TIMP-2 expression is also upregulated in animal models of progressive fibrosis, whereas expression of collagenase is unchanged. In a model which is characterized by natural resolution of liver fibrosis, degradation of the deposited fibrillar liver matrix is accompanied by rapid down-regulation of TIMP-1 expression. In alcoholic liver disease, the role of TIMPs has not been studied exhaustively, but the evidence currently available supports a role for inhibition of matrix degradation by TIMPs in this progressive fibrotic liver disease.     

Clinical Laboratory Tests as an Aid in Distinguishing Cirrhotic From Noncirrhotic Liver Disease in Alcoholic Patients

Alcoholism-associated liver disease is a potentially preventable hepatic injury. By use of 25 routinely ordered clinical laboratory tests, alcoholic cirrhosis was distinguishable from noncirrhotic alcoholic liver disease in 53 male inpatients with biopsy-verified liver disease (31 diagnosed with alcoholic cirrhosis and 22 diagnosed with fatty liver and/or alcoholic hepatitis). Linear discriminant analysis correctly classified 77% of subjects with cirrhotic liver disease and 68% of subjects with noncirrhotic liver disease (overall accuracy of 74%). Quadratic discriminant analysis correctly classified 94% of subjects with cirrhotic liver disease and 68% of subjects with noncirrhotic liver disease (81% overall accuracy). These pattern recognition techniques may allow earlier clinical intervention in alcoholic patients with liver disease.     

Chronic (Noncirrhotic) Diffuse Liver Disease

Conclusions Chronic liver disease which is characterized histopathologically by portal fibrosis, portal round-cell infiltration, and/or fatty metamorphosis, in the absence of the perilobular fibrosis of cirrhosis, is usually a subclinical process, detected by the chance discovery of hepatomegaly. This hepatomegaly was a constant feature of the 67 patients reported upon, but it is highly probable that many other cases have been overlooked during the period of study because there was no liver enlargement. Mild splenomegaly and spider angiomas are not rare in chronic noncirrhotic liver disease.Esophageal varices are moderately common in patients with these forms of liver disease, but the precise incidence cannot be given because, as in cirrhosis, varices wax and wane and may disappear from time to time. In most instances they are only of mild or moderate size, and this makes radiologic detection impossible in most cases.Hemorrhage from esophageal varices is not nearly the threat that it is in cirrhosis, yet the risk exists and the ensuing hemorrhage may be severe.The esophageal varices which are encountered in cirrhosis may have their inception during the precirrhotic stages of chronic liver disease, before the beginning of lobular regeneration.     

Advances in Alcoholic Liver Disease

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. In studies from the Veterans Administration, patients with cirrhosis and superimposed alcoholic hepatitis had greater than 60% mortality over a 4-year period, with most of those deaths occurring in the first month. Thus, the prognosis for this disease is more ominous than for many common types of cancer (eg, breast, prostate, and colon). Moreover, ALD imposes a significant economic burden from lost wages, health care costs, and lost productivity. Unfortunately, there is still no Food and Drug Administration–approved or widely accepted drug therapy for any stage of ALD. Thus, a pressing need exists for a more detailed understanding of mechanisms of liver injury. This article reviews recent advances in mechanisms and therapy related to five major areas of direct relevance to ALD: oxidative stress; gut-liver axis and cytokine signaling; malnutrition; fibrin/clotting; and stellate cell activation/fibrosis. We also review why therapies related to these mechanisms have performed well in experimental animals and in vitro systems, but have not necessarily translated into effective therapy for humans with ALD.     

Cyanamide-Associated Alcoholic Liver Disease: A Sequential Histological Evaluation

This is the first study that we are aware of that followed the his-topathological progression of the liver disease that was caused by the combination of both chronic alcohol use and cyanamide, an an-tidipsotropic agent. Two sequential liver biopsy specimens were obtained on 29 alcoholics who relapsed with varying histories of cyan-amide treatment. Cyanamide induced ground-glass inclusions (GGIs) in the hepatocytes. Two groups were identified, depending on whether GGIs proliferated or regressed, which was, in turn, found contingent on the duration of cyanamide treatment and the drug-free period. Group 1 included 14 cases in which GGIs either emerged only in the second biopsy specimen or else were increased in the second specimen as compared in the initial specimen. Group 2 composed of 15 cases in which GGIs were either not observed in either specimen or decreased in the second specimen as compared in the initial specimen. Acidophilic bodies were sequentially increased in five cases (36%) of group 1 and in none of group 2. The severity of portal inflammation worsened in 10 cases (71%) of group 1 but in 2 cases (13%) of group 2, although the changes in fibrotic process did not differ between two groups. These differences could not be explained on the basis of the daily ethanol consumption and the length of relapses of the two groups. Thus, when cyanamide-treated alcoholics relapsed, the combined effect of cyanamide and alcohol produced the development of acidophilic bodies and portal inflammation along with the emergence of GGIs.     

Sclerotherapy in Noncirrhotic Portal Fibrosis

Endoscopic sclerotherapy has emerged as aneffective and safe mode of treatment for long-termmanagement of esophageal varices due to cirrhosis ofliver and extrahepatic portal venous obstruction. There are few studies that have evaluated the role ofsclerotherapy in the management of esophageal varices inpatients with noncirrhotic portal fibrosis (NCPF). Wereport our results of long-term sclerotherapy in patients with NCPF. Seventy-two consecutivepatients (men 29, women 43; age 32.9 ± 11.8years) with recurrent variceal bleeding due to NCPF wereentered into the sclerotherapy program. Forty-eightpatients received intravariceal absolute alcohol and 24patients received intravariceal sodium tetradecylsulfate (STD). Variceal obliteration was achieved in 65(90.3%) patients with a mean of 5.7 ± 3.0 (range1-14) sessions. These patients were followed-up fora mean of 21.4 ± 20.4 (range 1-96) months.Thirteen (17.3%) patients had episodes of uppergastrointestinal bleeding during sclerotherapy. Rebleedafter obliteration was seen in 6 (9.2%) patients. Sclerotherapywas associated with a significant reduction in bleedingrate (bleeds per month per patient) during sclerotherapyand after obliteration of varices as compared to presclerotherapy period (P < 0.000001 forboth). Recurrence of esophageal varices afterobliteration was seen in 9 (13.9%) patients withreobliteration of varices in five patients in whomsclerotherapy was attempted. Complications includingesophageal ulcer and stricture formation were seen in 18(25%) and 4 (5.6%) patients respectively; strictureswere restricted to patients who received absolutealcohol. Two (2.77%) patients died of massive uppergastrointestinal bleed during follow-up. We concludethat sclerotherapy is an effective and safe modality inthe prevention of variceal bleeds in patients with NCPF.     

酒精性肝病的诊断

酒精性肝病的致病因素是单一的，即长期大量的酒精摄入，但其病理过程却十分复杂。长期大量酒精摄入可以造成肝脏的几种不同病变，轻者只有脂肪变性，重者形成酒精性肝炎和肝纤维化，再发展则导致不可逆转的肝硬化。这些病变主要是以组织学的改变为依据命名，但临床上这些病变多为混合存在。