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PubMed2006

Coagulation abnormalities in patients who have liver disease.

The liver plays a central role in the maintenance of normal hemostatic function. Because liver disease alters pathways of coagulation and anticoagulation, patients who have advanced disease can experience severe bleeding or thrombotic complications. Complications of advanced liver disease may also contribute to bleeding or thrombosis. This article reviews and discusses the management of the most common coagulation problems encountered in patients who have end-stage liver disease, which are thrombocytopenia and impaired humoral coagulation as measured by prolongation of the prothrombin time and international normalized ratio.

Blood Coagulation Disorders↗
PubMed2006

Celiac disease and risk of liver disease: a general population-based study.

BACKGROUND & AIMS: Celiac disease (CD) is an important cause of hypertransaminasemia. CD might also be associated with severe forms of liver disease. We investigated the risk of liver disease in 13,818 patients with CD (1964-2003) and 66,584 age- and sex-matched reference individuals from a general population cohort. METHODS: We used Cox regression to estimate hazard ratios (HRs) for later liver disease and conditional logistic regression to estimate the risk of CD in individuals with liver disease before study entry. RESULTS: CD was associated with an increased risk of acute hepatitis (HR, 5.21; 95% confidence interval [CI], 1.88-14.40; P = .001), chronic hepatitis (HR, 5.84; 95% CI, 2.89-11.79; P < .001), primary sclerosing cholangitis (HR, 4.46; 95% CI, 2.50-7.98; P < .001), fatty liver (HR, 6.06; 95% CI, 1.35-27.16; P = .018), liver failure (HR, 3.30; 95% CI, 2.22-4.88; P < .001), liver cirrhosis or liver fibrosis (HR, 2.23; 95% CI, 1.34-3.72; P < .001), and primary biliary cirrhosis (HR, 10.16; 95% CI, 2.61-39.49; P < .001). There was no increased risk of liver transplantation (HR, 1.07; 95% CI, 0.12-9.62; P = .954). Adjustment for socioeconomic index or diabetes mellitus had no notable effect on the risk estimates. Prior liver disease was associated with a statistically significant 4-fold to 6-fold increased risk of later CD. CONCLUSION: This study suggests that individuals with CD are at increased risk of both prior and subsequent liver disease.

Adolescent↗
PubMed2003

Assessment of prognosis in alcoholic liver disease: can serum hyaluronate replace liver biopsy?

1. Only 15-20% of chronic alcohol misusers ever develop cirrhosis. 2. Currently it is not possible to predict clinically who will develop progressive fibrotic alcoholic liver disease. 3. Liver biopsy is currently the gold standard diagnostic test in alcoholic liver disease, but it has associated morbidity and mortality. 4. Serum hyaluronic acid is a simple non-invasive test that may be able to give an estimate of the severity of fibrosis in alcoholic liver disease. The full clinical assessment of alcoholic liver disease includes liver biopsy, since accurate clinical prediction of the severity of liver damage is extremely difficult in all except very advanced cases. Unfortunately, liver biopsy has an associated complication rate and is contraindicated in, or unacceptable to, some patients. A reliable non-invasive test of the severity of fibrotic disease would be clinically useful at initial clinical assessment in some patients with alcoholic liver disease. Such a test would be more useful in subsequent monitoring of disease progression, and in particular may diminish the need for follow-up liver biopsy. Serum hyaluronic acid has been put forward as such a non-invasive test. Based on current evidence, serum hyaluronic acid may well be a useful adjunctive test in the assessment of certain categories of alcoholic liver disease patients, but at present it is unlikely to displace liver biopsy as the investigation of choice in alcoholic liver disease.

Biomarkers↗
PubMed1994

Cellular expression of tumour necrosis factor-alpha and interferon-gamma in the liver biopsies of children with chronic liver disease.

The liver biopsies of patients with autoimmune liver diseases have a dense portal tract mononuclear cell infiltrate. To investigate whether these cells produce tumour necrosis factor-alpha and interferon-gamma, cytokines which could be involved in the autoimmune attack through a direct cytopathic effect and/or through induction/enhancement of major histocompatibility complex antigen expression, we immunohistochemically stained cryostat liver sections from 21 children with autoimmune liver disease and from 15 children with metabolic liver disorders and histological evidence of portal tract inflammation as controls. Tumour necrosis factor-alpha and interferon-gamma producing cells were detected simultaneously within the inflammatory cell infiltrate in the liver biopsies of 18 patients with autoimmune liver disease, but only one patient with a metabolic disorder was positive for tumour necrosis factor-alpha. There was a significant correlation between frequency of tumour necrosis factor-alpha and interferon-gamma producing cells, intensity of inflammatory cell infiltrate (p < 0.03 and p < 0.05, respectively) and transaminase levels (p < 0.008 and p < 0.03, respectively). These results suggest that tumour necrosis factor-alpha and interferon-gamma play a pathogenic role in autoimmune liver cell damage.

Adolescent↗
PubMed1991

Hepatic activity and mRNA expression of aspartate aminotransferase isoenzymes in alcoholic and nonalcoholic liver disease.

In liver and serum, AST activity is dependent on two isoenzymes, which are mitochondrial and cytosolic in nature. In an attempt to explain the well-known increase of serum mitochondrial AST-to-total AST ratio in chronic alcoholism (which is due to a specific increase of the mitochondrial isoenzyme), we analyzed: (a) liver and serum AST, ALT and glutamate dehydrogenase activities in 23 active drinkers with minimal liver changes, 11 alcoholic patients with cirrhosis who had stopped drinking, 18 nonalcoholic patients with viral chronic hepatitis and 11 subjects with normal livers; and (b) the expression of messenger RNAs for AST isoenzymes in the corresponding liver samples. Enzymatic activities were decreased in the liver irrespective of the origin of the liver disease. In patients with viral chronic hepatitis (or in those with alcoholic cirrhosis when abstinent), variations in liver proteins and messenger RNAs paralleled significant decreases in mitochondrial AST, ALT and glutamate dehydrogenase and a nonsignificant decrease of cytosolic AST. In alcoholic patients with minimal liver changes, the significant decrease of hepatic cytosolic AST, ALT and glutamate dehydrogenase activities contrasted with a close-to-normal liver mitochondrial AST activity; the increased amounts of mitochondrial AST messenger RNA give evidence for a pretranslational mechanism of regulation, indicating a possible increase in the total production of mitochondrial AST in the liver. The decrease of hepatic cytosolic AST activity was statistically significant only in alcoholic patients without cirrhosis who had a normal cytosolic AST mRNA level, thus suggesting a contributory role of translational or posttranslational regulation. In conclusion, regulation of AST isozymes during liver disease is complex, including differential, pretranslational and translational or posttranslational mechanisms.

Aspartate Aminotransferases↗
PubMed1987

Thyroid hormones and alcoholic liver disease.

Alcoholic liver disease shares with other nonthyroidal illnesses patterns of serum thyroid hormones that usually do not reflect true thyroid function. Although ethanol can affect the thyroid gland and also may directly interfere with thyroid hormone metabolism, most patients with alcoholic liver disease are euthyroid. However, some have mild hypothalamic pituitary axis dysfunction. In persons who chronically and continuously drink alcohol, there are demonstrable biochemical abnormalities similar to the effects of thyroid hormone on the liver. However, a primary pathogenetic role in alcoholic hepatitis has not been proven for this thyroid hormone mimicry. There is good clinical evidence, however, that serum thyroid hormones can serve as prognostic indicators of the course of liver disease.

Alcoholism↗
PubMedDate not supplied

Thoracic manifestations associated with advanced liver disease.

Advanced liver disease and portal hypertension may produce various intrathoracic complications that involve the pleural space, lung parenchyma, and pulmonary circulation. Dyspnea and arterial hypoxemia are the common clinical symptoms and signs in patients with such complications. In these patients, intrathoracic complications most often develop during the course of hepatic disease, but a few patients may be seen first with respiratory symptoms or radiographic abnormalities. Therefore, radiologists should be made aware of these disorders that occur in patients with chronic liver disease. In this article, the authors describe and illustrate the clinical and imaging spectrum of thoracic abnormalities associated with advanced liver disease and portal hypertension.

Adult↗
PubMed2003

Metabolic bone disease in patients with liver disease.

The coexistence of liver disease and osteopenic bone disease has been recognized for many years and is now the subject of increasing attention. Osteoporosis has been characterized well in patients with cholestatic liver disease, but new research suggests that osteopenia and osteoporosis may also be prevalent in patients with other chronic liver diseases. Although the precise mechanism of bone loss remains unclear, advances in treatment and prevention are bringing heightened awareness to this common problem.

Bone Diseases, Metabolic↗
PubMedDate not supplied

Association of nonalcoholic fatty liver disease with insulin resistance: is OGTT indicated in nonalcoholic fatty liver disease?

Nonalcoholic fatty liver disease (NAFLD) is frequently associated with type 2 diabetes mellitus, obesity, and dyslipidemia. We tested the hypothesis that there may be an association between NAFLD and insulin resistance (IR); and its correlation with glucose tolerance status of subjects who aren't known patients with diabetes. One hundred and seventy-six consecutive patients with elevated serum aminotransferase levels and bright liver were evaluated. Sixty-two patients were excluded from the study. Age, gender, height, weight, body mass index, waist circumferences, and family history of diabetes were recorded. Fasting plasma glucose, insulin, lipid profile were measured. A standard oral glucose tolerance test (OGTT) was performed and the index of IR was calculated according to the HOMA method. Patients with a normal glucose tolerance formed group 1 (64 patients) and patients with impaired or diabetic glucose tolerance group 2 (50 patients). Age, female sex, family history of type 2 diabetes, fasting insulin, fasting plasma glucose and HOMA-R index were statistically significantly different between the groups. Although the subjects in the study are not known patients with diabetes, the prevalence of impaired or diabetic glucose tolerance was prominent. In conclusion, performing OGTT in cases with nonalcoholic fatty liver disease may be useful for early screening of diabetes mellitus.

Adult↗
PubMedDate not supplied

High density lipoprotein subpopulations in chronic liver disease.

Severe liver disease may be associated with a reduction in plasma concentration of high density lipoprotein and an impairment of plasma cholesterol esterification. These changes were confirmed in two patients with severe acute on chronic alcoholic liver disease. In five additional patients with biopsy-proven clinically compensated cirrhosis, there was minimal reduction in concentration of plasma cholesteryl esters; there was, however a reduction of the plasma high density lipoprotein concentration to only 48 to 66% of normal. The particle size distribution of high density lipoprotein in these five patients was determined by gradient gel electrophoresis. The high density lipoprotein2 subfraction was preserved. The high density lipoprotein3 subfraction, however, was markedly changed with a reduction in the normal particles of radius 4.3 m and an accentuation of smaller particles of radius 3.9 m; in two patients, these smaller particles were the major high density lipoprotein subpopulation. Further investigations of this finding of a distinctive distribution of high density lipoprotein subpopulations in patient with chronic liver disease may provide new insights into high density lipoprotein metabolism.

Adult↗
PubMed1998

Liver transplantation for adult polycystic liver disease.

Polycystic liver disease, commonly associated with polycystic kidney disease, can result in massive hepatomegaly and debilitating symptoms. Surgical intervention for symptomatic polycystic liver disease has been associated with significant morbidity and inconsistent long-term palliation; it is more appropriate in patients with a single dominant cyst or cysts which is/are confined to one lobe. At our institution, nine patients have undergone orthotopic liver transplantation for symptomatic hepatic cysts with excellent long-term results and minimal morbidity and mortality. Surgical candidates were selected based on severe limitations in daily activities and on sequelae of hepatic cystic involvement. Other factors considered were the extent and pattern of hepatic cystic disease, the degree of hepatic and renal dysfunction, and prior surgical intervention. Three patients (33%) required combined liver and kidney transplantation because of renal cystic involvement with renal insufficiency. The one-year survival rate was 89% with excellent symptomatic relief and improved quality of life in all the surviving patients. One death occurred in a significantly malnourished 62-year-old female. Complications included one case each of hepatic artery thrombosis requiring retransplantation, biliary leak necessitating biliary reconstruction, and postoperative bleeding requiring re-exploration. The mean hospital stay was 23 days and the mean intraoperative blood transfusion requirement was 18 units. Our experience demonstrates that appropriately selected patients with extensive hepatic involvement with adult polycystic liver disease can have an excellent outcome with transplantation, with morbidity comparable with other surgical options.

Adult↗
PubMed2004

Gene therapy of liver diseases.

Many liver diseases lack satisfactory treatment and alternative therapeutic options are urgently needed. Gene therapy is a new mode of treatment for both inherited and acquired diseases, based on the transfer of genetic material to the tissues. Genes are incorporated into appropriate vectors in order to facilitate their entrance and function inside the target cells. Gene therapy vectors can be constructed on the basis of viral or non-viral molecular structures. Viral vectors are frequently used, due to their higher transduction efficiency. Both the type of vector and the expression cassette determine the duration, specificity and inducibility of gene expression. A considerable number of preclinical studies indicate that a great variety of liver diseases, including inherited metabolic defects, chronic viral hepatitis, liver cirrhosis and primary and metastatic liver cancer, are amenable to gene therapy. Gene transfer to the liver can also be used to convert this organ into a factory of secreted proteins needed to treat conditions that do not affect the liver itself. Clinical trials of gene therapy for the treatment of inherited diseases and liver cancer have been initiated but human gene therapy is still in its infancy. Recent progress in vector technology and imaging techniques, allowing in vivo assessment of gene expression, will facilitate the development of clinical applications of gene therapy.

Animals↗
PubMed2004

Hepatic transmethylation reactions in micropigs with alcoholic liver disease.

Alcoholic liver disease is associated with abnormal hepatic methionine metabolism, including increased levels of homocysteine and S-adenosylhomocysteine (SAH) and reduced levels of S-adenosylmethionine (SAM) and glutathione (GSH). The concept that abnormal methionine metabolism is involved in the pathogenesis of alcoholic liver disease was strengthened by our previous findings in a micropig model where combining dietary folate deficiency with chronic ethanol feeding produced maximal changes in these metabolites together with early onset of microscopic steatohepatitis and an eightfold increase in plasma aspartate aminotransferase. The goal of the present study was to determine potential mechanisms for abnormal levels of these methionine metabolites by analyzing the transcripts and activities of transmethylation enzymes in the livers of the same micropigs. Ethanol feeding or folate deficiency, separately or in combination, decreased transcript levels of methylenetetrahydrofolate reductase (MTHFR), methionine adenosyltransferase (MAT1A), glycine-N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase (SAHH). Ethanol feeding alone reduced the activities of methionine synthase (MS) and MATIII and increased the activity of GNMT. Each diet, separately or in combination, decreased the activities of MTHFR and SAHH. In conclusion, the observed abnormal levels of methionine metabolites in this animal model of accelerated alcoholic liver injury can be ascribed to specific effects of ethanol with or without folate deficiency on the expressions and activities of hepatic enzymes that regulate transmethylation reactions. These novel effects on transmethylation reactions may be implicated in the pathogenesis of alcoholic liver disease.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1994

Unsuspected coeliac disease in chronic 'cryptogenic' liver disease.

BACKGROUND: Earlier reports have suggested that a relationship exists between chronic liver disease and coeliac disease (CD). Gliadin antibodies (GA) have been used to screen for CD. METHODS: Using a micro-enzyme-linked immunosorbent procedure, we analysed sera from 327 consecutive patients with chronic liver disease for GA (IgA and IgG) and evaluated their clinical significance. RESULTS: GA were detected in 19 patients (6%), a prevalence six times greater than that found in healthy blood donors. In 9 of the 19 patients the liver disease had been classified as cryptogenic. The occurrence of GA was independent of the degree of hepatocellular impairment. A diagnosis of CD was confirmed in 5 of the 10 patients who underwent small-bowel biopsy. CONCLUSIONS: Our findings suggest the prevalence of CD in patients with chronic liver disease to be at least 1.5%--that is, 15 times higher than in the general population. They also suggest that the possible presence of CD should be considered in cases of chronic 'cryptogenic' liver disease.

Adult↗
PubMed1986

Cell-mediated immunity in liver disease.

Four liver diseases in which cell-mediated immunity seems to be of major importance but in which the exact pathogenic event has been not fully clarified have been briefly discussed. More precise delineation of the phenotypes of mononuclear cells and the advent of in vitro techniques for the study of lymphocyte function and cytotoxicity have led to better understanding of the importance of cell-mediated immunity in some liver diseases. It seems that the liver itself may be variously affected by different immunologic reactions, not only in various diseases but also in different locations in the same disease.

Antigens↗
PubMed1999

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.

Humans↗
PubMed1999

Treatment options for osteoporosis in chronic liver disease patients requiring liver transplantation.

As patient life expectancy rises after liver transplantation, osteoporosis becomes a significant contributor to morbidity and mortality. Patients who undergo liver transplant have an increased risk of bone fractures secondary to osteoporosis, relative to the general population. Risk factors (pre- and posttransplant) include treatment with steroids, alcohol abuse, smoking, poor nutritional status, immobility, reduced muscle mass, menopause, and hypogonadism. The role of cholestatic liver disease is well recognized, but as of yet, the underlying etiology is unknown. The role of immunosuppressants is also evident, but their exact contribution remains to be established. Currently, there are no established therapies for osteoporosis secondary to liver transplantation. Most of the therapeutic options have been extrapolated from usual treatment options for osteoporosis in the general population. It is reasonable to attempt to lower steroid dosages, especially with the availability of new and more potent immunosuppressants such as mycophenolate mofetil and tacrolimus. Potentially, high-risk patients could be identified early with BMD screening. Preventive measures could be instituted and patients could be monitored more closely for objective signs of osteoporosis, such as decline in BMD and early fractures. Calcium and vitamin D supplementation may be helpful in those with deficiencies or poor nutritional intake, as well as in women older than 25 years. The role of bisphosphonates and hormone replacement therapy remains equivocal as studies in transplant patients are currently lacking. Risk versus benefit must be weighed on an individual basis. Lifestyle measures should be instituted in all patients if possible.

Bone Density↗
PubMed2003

Prolongation of QTc interval: relationship with etiology and severity of liver disease, mortality and liver transplantation.

BACKGROUND: A prolonged QTc interval has been reported in patients with liver disease. The objectives of our study were to determine whether a prolonged QTc interval was an independent predictor of mortality in patients with cirrhosis and to examine the effect of liver transplantation (LT) on QTc interval. PATIENTS AND METHODS: We retrospectively studied two cohorts of patients - QTc interval was measured in 409 patients (pre-transplant group), and in 162 patients (transplant group) before and 6 months after LT. QT interval (mean) corrected (QTc) for ventricular rate was read from a 12-lead EKG. Patients with known cardiovascular disease or other risk factors that are known to cause a prolonged QTc interval were excluded. RESULTS: Pre-transplant group. One hundred and sixty-two patients (40%) had a prolonged QTc interval (>440 ms). By binary logistic regression, age (P=0.005), alcoholic cirrhosis (P=0.007) and Child-Pugh scores (P=0.007) were independent predictors of prolonged QTc interval. Sixty-six patients died during a mean follow-up of 8.9 years. Although the Kaplan-Meier survival curve showed a lower survival in patients with a prolonged QTc interval (P=0.03 by log rank test), when survival was adjusted for the Child-Pugh score by Cox regression survival analysis, there were no survival differences in patients with and without prolonged QTc interval. Cox regression analysis showed that the Child-Pugh score (hazard ratio 1.5, CI 1.3-1.6, s<0.001) was the only independent predictor of survival. Transplant group. In this cohort, 91 patients (56%) had prolonged QTc (>440 ms) before LT. Mean QTc improved significantly after LT (429 +/- 29 ms vs. 450 +/- 39 ms P<0.002). Of the 91 patients with prolonged QTc, 50 (55%) normalized, three (3.3%) remained unchanged, 12 (13.3%) showed further prolongation, and 26 (28%) showed improvement but remained above normal limits. An additional nine patients who had normal QTc before LT developed prolonged QTc (>440 ms) after LT. CONCLUSION: A prolonged QTc interval was common in patients with cirrhosis, but its presence had no independent effect on mortality. Prolonged QTc returns to normal values in about half of the patients after LT, suggesting that liver disease plays a role, but may not be the only factor in the pathogenesis of prolonged QTc.

Cohort Studies↗