Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the last three decades, direct hepatotoxic effects of ethanol were established, some of which were linked to redox changes produced by NADH generated via the alcohol dehydrogenase (ADH) pathway and shown to affect the metabolism of lipids, carbohydrates, proteins, and purines. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving a specific cytochrome P-450; this newly discovered ethanol-inducible cytochrome P-450 (P-450 IIEi) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. Their activation by P-450IIEi now provides an understanding of the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, and chemical carcinogens. P-450 induction also explains depletion (and toxicity) of nutritional factors such as vitamin A. As a consequence, treatment with vitamin A and other nutritional factors is beneficial, but must take into account a narrowed therapeutic window in alcoholics who have increased needs for nutrients and also display an enhanced susceptibility to some of their adverse effects. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts, and causes glutathione depletion. Supplementation with S-adenosyl-L-methionine partly corrects the depletion and associated mitochondrial injury, whereas administration of polyunsaturated lecithin opposes the fibrosis. Thus, at the cellular level, the classic dichotomy between the nutritional and toxic effects of ethanol has now been bridged. The understanding of how the ensuing injury eventually results in irreversible scarring or cirrhosis may provide us with improved modalities for treatment and prevention.
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PMID:Metabolism of ethanol and associated hepatotoxicity. 1684 49

Volume retention in heart failure, nephrotic syndrome, and liver cirrhosis reflects pathological changes in homeostatic mechanisms that regulate the extracellular volume (sympathetic activity, renin-angiotensin-aldosterone system [RAAS], natriuretic peptides) and plasma osmolality (antidiuretic hormone [ADH]). In heart failure and liver cirrhosis, these changes are induced by a reduction of the effective circulating volume, which is the part of the extracellular fluid that is within the arterial system and effectively perfusing the tissues. This reduction in the effective circulating volume is caused by reduced cardiac output (heart failure), or by splanchnic vasodilatation with arterial underfilling (liver cirrhosis). In both cases, baroreceptors in both the carotid sinuses and in the glomerular afferent arterioles upregulate RAAS- and sympathetic activity, resulting in systemic vasoconstriction and renal sodium (and volume) retention. More severe reductions in the effective circulating volume may additionally stimulate ADH release, thus increasing the reabsorption of free water with subsequent hyponatriemia. In nephrotic syndrome, volume retention results either directly from the primary renal disease, which induces renal sodium and volume retention ("overfilling"), or indirectly from the reduced plasma oncotic pressure due to hypoalbuminemia, which induces a fluid shift from the intravascular to the interstitial space ("underfilling") with subsequent acitivation of baroreceptors and secondary sodium and volume retention.
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PMID:[Volume retention in heart failure, nephrotic syndrome, and liver cirrhosis]. 1700 41

Although the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome have steatosis, only a minority ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of liver fibrosis. For ALD, the dose and pattern of alcohol intake, coffee intake, and dietary and other lifestyle factors leading to obesity are the most important environmental determinants of disease risk. For NAFLD, dietary saturated fat and antioxidant intake, small bowel bacterial overgrowth, and obstructive sleep apnea syndrome may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the ADH and ALDH alcohol metabolizing genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor alpha, transforming growth factor beta, and angiotensinogen may be associated with steatohepatitis or hepatic fibrosis or both.
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PMID:Genetics of alcoholic liver disease and nonalcoholic fatty liver disease. 1729 76

Vasopressin is a critical regulator of water homeostasis. There are two major receptors for vasopressin: V1 and V2 receptors. Disturbances in water balance are commonly encountered in clinical practice and can be divided into disorders of urinary dilution and concentration. The major representatives of such disorders are diabetes insipidus and the syndrome of inappropriate secretion of antidiuretic hormone (SI ADH). Recent studies show that genetic forms of nephrogenic diabetes insipidus are due to mutations in the genes coding for the vasopressin V2 receptor (V2R) or aquaporin-2 (AQP2). Identification of the genes involved and analysis of the cellular fate of the V2R and AQP2 mutants are relevant for understanding the functioning of the V2R and AQP2 protein. These developments also have implications for future therapeutic options. The development of nonpeptide vasopressin receptor antagonists (VRAs) offers prospects for the treatment of euvolaemic (SI ADH) or hypervolaemic hyponatraemia (congestive heart failure or cirrhosis). Several nonpeptide VRAs are now in various stages of clinical trials. At present, only conivaptan is registered by the FD A for intravenous treatment of euvolaemic and hypervolaemic hyponatremia. A recent long-term study comparing tolvaptan with placebo in patients with chronic heart failure showed no reduction in risk of death and hospitalisation.
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PMID:Water in health and disease: new aspects of disturbances in water metabolism. 1795 51

Alcohol abuse is one of the major causes of liver fibrosis worldwide. Although the pathogenesis of liver fibrosis is a very complex phenomenon involving different molecular and biological mechanisms, several lines of evidence established that the first ethanol metabolite, acetaldehyde, plays a key role in the onset and maintenance of the fibrogenetic process. This review briefly summarizes the molecular mechanisms underlying acetaldehyde pro-fibrogenic effects. Liver fibrosis represents a general wound-healing response to a variety of insults. Although mortality due to alcohol abuse has been constantly decreasing in the past 20 years in Southern Europe and North America, in several Eastern-European countries and Great Britain Alcoholic Liver Disease (ALD) shows a sharply increasing trend [Bosetti, C., Levi, F., Lucchini, F., Zatonski, W.A., Negri, E., La, V.C., 2007. Worldwide mortality from cirrhosis: an update to 2002. J. Hepatol. 46, 827-839]. ALD has a complex pathogenesis, in which acetaldehyde (AcCHO), the major ethanol metabolite, plays a central role. Ethanol is mainly metabolized in the liver by two oxidative pathways. In the first one ethanol is oxidized to acetaldehyde by the cytoplasmic alcohol dehydrogenase enzyme (ADH), acetaldehyde is then oxidized to acetic acid by the mitochondrial acetaldehyde dehydrogenase (ALDH). The second pathway is inducible and involves the microsomal ethanol-oxidizing system (MEOS), in which the oxidation of ethanol to acetaldehyde and acetic acid also leads to generation of reactive oxygen species (ROS). Chronic ethanol consumption significantly inhibits mitochondrial ALDH activity while the rate of ethanol oxidation to acetaldehyde is even enhanced, resulting in a striking increase of tissue and plasma acetaldehyde levels [Lieber, C.S., 1997. Ethanol metabolism, cirrhosis and alcoholism. Clin. Chim. Acta 257, 59-84]. This review will focus on the molecular mechanisms by which acetaldehyde promote liver fibrosis.
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PMID:Alcohol induced hepatic fibrosis: role of acetaldehyde. 1816 54

The principal enzymes catalyzing the conversion of ethanol to acetate are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The activities of these enzymes are elevated in the serum during the course of alcoholism or cirrhosis. In previous investigations we have found elevated levels of ADH, ALDH, and class I ADH activity in liver cancer cells. It can suggest that these changes may be reflected by enzyme activity in the serum. In this work, the activity of ADH isoenzymes, and ALDH in the sera of patients with liver cancer was measured. Serum samples were taken from 64 patients (28 drinkers, 36 nondrinkers), with liver cancer. 25 patients had primary and 39 metastatic liver tumors. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorimetric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes we employed the fluorimetric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. A statistically significant increase of class I ADH isoenzymes was found in the sera of cancer patients. The median activity of this class isoenzyme in the total cancer group increased about 51% (2.94 mU/L) in the comparison to the control level (1.43 mU/L). The activity of the class I ADH isoenzyme was significantly higher in the sera of patients with metastatic tumors than with primary cancers. The activity of this class in the sera of drinkers and group of moderate drinkers was significantly higher in comparison to the control group and higher in the sera of heavy drinkers when compared with moderate drinking patients. The total ADH activity was significantly higher (44%) among patients with cancer than healthy ones. The activity of class I ADH isoenzymes was elevated only in the serum of patients with metastatic liver cancer. This increase of activity seems to be caused by the enzyme released from liver cancer cells and primary tumors originating in other organs.
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PMID:Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with liver cancer. 1848 58

Alcohol dependence and alcohol abuse or harmful use cause substantial morbidity and mortality. Alcohol-use disorders are associated with depressive episodes, severe anxiety, insomnia, suicide, and abuse of other drugs. Continued heavy alcohol use also shortens the onset of heart disease, stroke, cancers, and liver cirrhosis, by affecting the cardiovascular, gastrointestinal, and immune systems. Heavy drinking can also cause mild anterograde amnesias, temporary cognitive deficits, sleep problems, and peripheral neuropathy; cause gastrointestinal problems; decrease bone density and production of blood cells; and cause fetal alcohol syndrome. Alcohol-use disorders complicate assessment and treatment of other medical and psychiatric problems. Standard criteria for alcohol dependence-the more severe disorder-can be used to reliably identify people for whom drinking causes major physiological consequences and persistent impairment of quality of life and ability to function. Clinicians should routinely screen for alcohol disorders, using clinical interviews, questionnaires, blood tests, or a combination of these methods. Causes include environmental factors and specific genes that affect the risk of alcohol-use disorders, including genes for enzymes that metabolise alcohol, such as alcohol dehydrogenase and aldehyde dehydrogenase; those associated with disinhibition; and those that confer a low sensitivity to alcohol. Treatment can include motivational interviewing to help people to evaluate their situations, brief interventions to facilitate more healthy behaviours, detoxification to address withdrawal symptoms, cognitive-behavioural therapies to avoid relapses, and judicious use of drugs to diminish cravings or discourage relapses.
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PMID:Alcohol-use disorders. 1941 Jul 5

Liver fibrosis or cirrhosis is one of the representative liver diseases with a high morbidity and mortality worldwide. Over the past decades, many kinds of antifibrotic compounds have been investigated in vitro and in vivo for the treatment of liver cirrhosis. In this work, real-time bioimaging of hyaluronic acid (HA) derivatives was carried out using quantum dots (QDots) to assess the possibility of HA derivatives as target-specific drug delivery carriers for the treatment of liver diseases. HA-QDot conjugates with an HA modification degree of about 22 mol % was synthesized by amide bond formation between carboxyl groups of QDots and amine groups of adipic acid dihydrazide modified HA (HA-ADH). According to in vitro cell culture tests, HA-QDot conjugates were taken up more to the cells causing chronic liver diseases such as hepatic stellate cells (HSC-T6) and hepatoma cells (HepG2) than normal hepatocytes (FL83B). After tail-vein injection, HA-QDot conjugates were target-specific, being delivered to the cirrhotic liver with a slow clearance longer than 8 days. Furthermore, immunofluorescence and flow cytometric analyses of dissected liver tissues revealed the target-specific delivery of HA derivatives to liver sinusoidal endothelial cells (LSEC) and HSC. The results were thought to reflect the feasibility of HA derivatives as novel drug delivery carriers for the treatment of various chronic liver diseases including hepatitis, liver cirrhosis, and liver cancer.
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PMID:Bioimaging for targeted delivery of hyaluronic Acid derivatives to the livers in cirrhotic mice using quantum dots. 2051 53

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH)/syndrome of inappropriate antidiuresis is characterized by a hypotonic hyponatremia, with an insufficiently diluted urine given the plasmatic hypoosmolality, in the absence of hypovolemia (with or without a third space), hypotension, renal or heart failure, cirrhosis of the liver, hypothyroidism, adrenal insufficiency, vomiting, or other non-osmotic stimuli of ADH secretion. The response of ADH to the infusion of hypertonic saline divides SIADH into 4 different types. In type D, there is no alteration in ADH secretion. Rather, the defect is the maintained permeability of kidney aquaporin-2 channels to water. Activating mutations of the V2 receptor have been identified. The most frequent cause of SIADH is the use of drugs that induce secretion of the hormone. Old age is per se a risk factor for its development. SIADH is underdiagnosed, and hospitalization often worsens the clinical situation, due to an iatrogenic excess in the use of oral and i.v. liquids, often hypotonic, together with a reduction in salt intake. Treatment is directed towards normalization of natremia when possible, together with the avoidance of both hyponatremic encephalopathy as well as the osmotic demyelinization syndrome. Cases of "appropriate" secretion of ADH with normovolemic hyponatremia and high mortality rates should be treated with the same urgency as SIADH--such is the case of post-surgical hyponatremia.
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PMID:[Current considerations in syndrome of inappropriate secretion of antidiuretic hormone/syndrome of inappropriate antidiuresis]. 2113 Sep 59

The non-peptide vasopressin antagonists (VPA), called vaptans, were developed in the 1990s to antagonize both the pressor and antidiuretic effects of vasopressin. There are three subtypes of VPA receptors: V1a, V1b and V2. V1a receptors are widely distributed in the body, mainly the blood vessels and myocardium. The V1b receptors are located mainly in the anterior pituitary gland and play a role in ACTH release. V2 receptors are located in the collecting tubular renal cells. Both V1a and V1b receptors act through the intracellular phosphoinositol signalling pathway, Ca(++) being the second messenger. V2 receptors work through AMPc generation, which promotes aquaporin 2 (AQP2) trafficking and allows water to enter the cell. The vaptans act competitively at the AVP receptor. The most important are mozavaptan, lixivaptan, satavaptan and tolvaptan, all of which are selective V2 antagonists and are administered through the oral route. In contrast, conivaptan is a dual V1 and V2 antagonist administered through the endovenous route. The main characteristics of vaptans are their effect on free water elimination without affecting electrolyte excretion. There are several studies on the effects of these drugs in hypervolemic hyponatremia (heart failure, hepatic cirrhosis) as well as in normovolemic hyponatremia (inappropriate secretion of ADH [SIADH]). Current studies show that the vaptans are effective and well tolerated, although knowledge of these drugs remains limited. There are no studies of the use of vaptans in severe hyponatremia. Osmotic demyelination syndrome due to excessively rapid correction of hyponatremia has not been described.
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PMID:[Vasopressin receptor antagonists: the vaptans]. 2113 Sep 61


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