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- Alcoholic Liver Disease;
- Oxygen Transport in the Critically Ill Patient: Münster (FRG), 11–12 May, 1990?
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In this review, we discuss the pathogenesis and management of ALD, focusing on AH, its current therapies and potential treatment targets. Alcohol use disorders account for a significant cause of preventable disease worldwide, with resultant alcoholic liver disease ALD causing significant liver-related morbidity and mortality among adults with prolonged alcohol abuse [ 1 ].
ALD represents half of the cases of liver cirrhosis, therefore, making it the dominant cause of advanced liver disease globally [ 2 ]. The diagnosis of ALD is usually made at advanced stages of disease with higher rates of complications and mortality [ 1 ]. Early detection of initial forms of ALD in the primary care setting and subsequent behavioral interventions should be encouraged. However, there is a lack of characterization of the early stages of ALD in humans. Moreover, there is a clear need to define the natural history and prognostic factors as well as to develop reliable non-invasive markers for ALD.
The management of patients with ALD has evolved little due to many factors including difficulties of conducting clinical trials in patients with an active alcohol addiction, the lack of interest from drug companies, public funding for research and the drawbacks of existing experimental models. As a consequence, there are not approved targeted therapies to treat patients with severe ALD [ 3 ]. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of alcoholic hepatitis AH.
In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival [ 3 , 4 ]. The susceptibility to develop ALD among heavy drinkers depends on genetic and environmental factors. At similar levels of ethanol consumption, some patients only develop macrovesicular steatosis, while others develop progressive fibrosis and cirrhosis.
Although a positive correlation between cumulative alcohol intake and degrees of liver fibrosis has been reported, extensive variability in the histological response to alcohol abuse exists in individuals [ 5 ]. The environmental risk factors identified as promoters for the progression of ALD in patients with alcohol abuse include sex, obesity, drinking patterns, dietary factors, non-sex-linked genetic factors and cigarette smoking [ 6 , 7 , 8 ].
Epidemiological studies suggest that several genetic factors influence the severity of steatosis and oxidative stress, and that the cytokine milieu, the magnitude of immune response and the severity of fibrosis also modulate an individual's propensity to progress to advanced ALD [ 9 ].
Genes encoding the main alcohol metabolizing enzymes and proteins involved in the toxic effects of alcohol and its metabolites on the liver, such as antioxidants and pro-inflammatory cytokines, have been the focus of investigation [ 8 ]. Genetic factors that influence the activity of these enzymes and the rate of alcohol metabolism have been studied. Variations in the rate of generation of acetaldehyde, a promoter of fibrogenesis, could explain the differences in the susceptibility of individuals to ALD from alcohol abuse. Although polymorphisms in the genes encoding the main alcohol-metabolizing enzymes such as alcohol dehydrogenase, acetaldehyde dehydrogenase and cytochrome P 2E1 are accepted to be involved in an individual's susceptibility to alcoholism, their role in the progression of ALD remains controversial [ 10 ].
Recent studies indicate that variations in the patatin-like phospholipase domain-containing protein 3 PNPLA3 are strongly associated with increased risk of ALD. Future studies would clarify the role of PNPLA3 and identify it as a target for therapy [ 11 , 12 , 13 ]. Despite the large number of studies that have assessed the role of genetic variation in susceptibility to ALD, a large-scale, well-designed, genome-wide association study of factors associated with ALD remains to be performed. Consequently, a genetic test capable of identifying the patients who would be susceptible to advanced ALD is yet to be developed [ 3 ].
ALD comprises different stages of liver disease as a result of susceptibility factors and duration of alcohol abuse. These stages include steatosis, alcoholic steatohepatitis ASH , progressive fibrosis, cirrhosis, decompensated cirrhosis and superimposed hepatocellular carcinoma HCC; fig. Patients with underlying cirrhosis and ongoing alcohol abuse are predisposed to developing AH [ 14 , 15 ].
Exacerbations of AH occur at many of the later stages of disease.
Medical and nutritional complications of alcoholism : mechanisms and management
Predisposing risk factors to accelerated progression are listed. Steatosis is defined histologically as the deposition of fat in hepatocytes. Increased fatty acid and triglyceride synthesis, hepatic influx of free fatty acids from adipose tissue and chylomicrons from the intestinal mucosa, results in increased hepatic lipogenesis, decreased lipolysis and mitochondrial and microtubule damage [ 17 ]. Continued heavy alcohol consumption leads to ASH, characterized by polymorphonuclear cell infiltration and hepatocellular damage.
Acetaldehyde, a byproduct of alcohol metabolism, is implicated for the hepatocellular injury. It binds proteins and DNA, forming adducts that promote glutathione depletion, lipid peroxidation and mitochondrial damage [ 19 , 20 ]. Sustained alcohol misuse causes progression to liver fibrosis and cirrhosis, which leads to a high risk of complications such as ascites, variceal bleeding, hepatic encephalopathy, renal failure and bacterial infections [ 21 , 22 ].
Acetaldehyde promotes fibrogenesis directly by increasing the expression of collagen in hepatic stellate cells HSC [ 23 , 24 ]. The activation and biological actions of these mediators are largely due to reactive oxygen species ROS [ 26 ]. Alcohol abuse contributes to dysbiosis and inflammation of the intestinal tract with resulting translocation of microbial products such as lipopolysaccharide LPS to the liver [ 27 ]. LPS targets toll-like receptor-4 signaling in HSCs and sinusoidal endothelial cells, resulting in HSC activation and promotion of fibrogenesis through regulation of angiogenesis [ 28 ].
Patients typically present with rapidly progressive jaundice, which can be accompanied by fever, abdominal pain, anorexia and weight loss. In some cases, portal hypertension is severe, and the patient presents with ascites, encephalopathy or variceal bleeding. Alcohol use history can be quite variable. Often, there is a history of daily heavy alcohol use, which may have escalated in the weeks and months prior to presentation. Alternatively, as patients begin feeling ill, they may reduce or discontinue alcohol use in the preceding days or even weeks.
Physical examination findings are non-specific and may include fever, tender hepatomegaly, ascites, muscle wasting and other stigmata of chronic liver disease. The diagnosis of AH is made on clinical grounds, based on a history of excessive alcohol use with the typical physical examinations and laboratory findings. Other potential causes of acute hepatitis such as viral, drug-induced liver injury, spontaneous bacterial peritonitis or other infections should be considered and ruled out.
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Imaging is important to exclude biliary or vascular disorders and to evaluate for co-existing HCC. In many patients with ALD and clinical complications, the presence of a superimposed AH is not explored and therefore its real incidence is unknown. Population-based studies using administrative data estimate approximately 4. Prospective studies assessing the incidence, risk factors and clinical features of AH are clearly needed. The Maddrey's discriminant function DF is one of the several models that have been developed to help predict outcomes of patients with AH and to guide therapy.
Patients who develop severe AH usually require hospitalization for initial management. Primary prevention is aimed at alcohol abstinence; active management of alcohol use disorders is critical to achieving continued abstinence. For the successful management of these patients, a multidisciplinary team composed of hepatologists, psychologists, psychiatrists and social workers is highly recommended [ 29 ].
Significant protein calorie malnutrition and vitamin and mineral deficiencies including vitamin A, vitamin D, thiamine, folate, pyridoxine and zinc is common [ 6 , 30 , 31 ]. Nutritional support improves liver function, and short-term follow-up studies suggest that improved nutrition might improve survival times and histological findings in patients with AH [ 32 ].
Alcoholic hepatitis: Challenges in diagnosis and management
Most patients improve spontaneously with abstinence and supportive care. Medical treatment is considered for patients who present with a very severe clinical picture or continue to deteriorate. The management of AH depends on the severity of the episode fig. Both the American Association for the Study of Liver Disease and European Association for the Study of the Liver practice guidelines recommend the use of corticosteroids i. Moreover, clinical practice guidelines recommend stopping corticosteroids after 1 week in those with an unfavorable Lille score, as the risks of continued therapy likely outweigh the benefits.
Role of transjugular liver biopsy is dependent on the availability in the center and the presence of potential confounding factors. At week 1, the efficacy of prednisolone therapy should be evaluated using the Lille score www. Pentoxifylline is a phosphodiesterase inhibitor that inhibits the synthesis of tumor necrosis factor TNF , which is increased in patients with AH. In practice, pentoxifylline was typically reserved as a second-line agent for patients with contraindications to corticosteroid therapy.
The recent STOPAH trial, comparing prednisolone and pentoxifylline, has proven to be a definitive study for assessing the efficacy of these drugs for AH [ 34 ]. Current consensus regarding pentoxifylline is that it is not effective for rescue therapy in patients who do not respond to corticosteroids. The anti-TNF agents, infliximab and etanercept, were also investigated as potential therapies for patients with AH. TNF-alpha was theorized as a key culprit in potentiating hepatocyte inflammation. Studies did not support the hypothesis [ 35 ] and instead demonstrated adverse side effects such as increased rates of infection and increased mortality.
N-acetylcysteine replenishes glutathione in damaged hepatocytes and prevents cell death in ALD. A recent randomized trial performed using a combination of N-acetylcysteine with prednisolone showed a clear trend to improve survival, with decreased 1-month mortality 8 vs. The study, however, was underpowered to reach statistical significance and was found to have no effect on 6-month survival and primary outcome [ 37 ].
Its favorable safety profile renders N-acetylcysteine a potential option, in combination with corticosteroids, for patients with severe disease. AH results in massive hepatocyte cell death and apoptosis is a prominent feature of many of the preceding stages of ALD. Since caspase inhibitors are known to inhibit apoptosis, animal studies, in models of chronic liver injury from viral hepatitis secondary to hepatitis C infection, and non-ASH, using caspase inhibitors and have shown promising results in ameliorating liver injury and impeding progression to fibrosis [ 38 , 39 , 40 ].
Following activation, neutrophils undergo transmigration into the liver parenchyma where they destroy damaged hepatocytes through the release of ROS and proteases, supporting their prominent role in ALD [ 41 ]. This suggests that the modification of these chemokines, or their precursors or activators, may mediate neutrophil infiltration and perhaps attenuate AH.
The role of CXCL family of chemokines has been examined in translational studies, and discovered that elevated levels correlate with severity of disease, degree of portal hypertension and patient survival [ 35 , 44 ]. Given these promising findings, therapeutic agents that target CXC chemokines may be considered in the treatment of AH. A su turno, esta resistencia hace que la glucosa y la insulina se acumulen en la sangre.
Consumption of alcoholic beverages can influence intermediary metabolism leading to glucose intolerance 1 , hypertriglyceridaemia 2 and hypertension 3. Thus, alcohol consumption could elicit the metabolic changes observed in syndrome X, in which insulin resistance, hypertension and dislipidaemia are seen in glucose intolerant and prediabetic obese patients 4. These metabolic modifications and the accompanied changes in syndrome X risk factors have been associated with a high incidence of cardiovascular disease 5,6.
Alcohol and Nutrition - Alcohol Alert No.
In Africa, particularly Nigeria, the accumulating reports on the effect of alcohol on the biochemical features of syndrome X were documented in isolation, and most of the investigations involved testing male subjects but results were usually generalized for both gender. This present study examines the effect of alcohol on the characteristic biochemical features of syndrome X in both genders using apparently healthy subjects, which include light, moderate and heavy drinkers of alcohol.
It is hoped that this research report would provide clues on the potential prevalence and gender differences if any , in syndrome X risk factors induced by alcohol ingestion. Enlisted drinkers were between the ages of 20 and 40 years, and participation was restricted to apparently healthy individuals with no personal or familial history of coronary heart disease CHD , stroke, cancer or obvious hereditary disease. Selected subjects were then instructed to abstain from drinking alcohol two days to the scheduled period of study and only those who complied were selected and tested.
Testing exercise. Upon arriving in the laboratory as scheduled, the participants willingly endorsed the form approved by our local human experimentation committee as a means of seeking their consent. Their weights and heights were then taken. The measured heights and weights were recorded to the nearest 0. These values were used to derive the body mass index BMI. The subjects eventually selected were tested on two consecutive days.
They were advised to avoid alcohol intake but allowed to eat light supper because heavy foods alter alcohol bioavailability and consequent effects. Fasting whole blood was collected the next morning at about 8. The choice of alcohol dose and interval for experimental repetition and conduct were based on previous intervention studies 8,9.
Blood pressure measurements. Blood sample collection. Blood samples were collected the next morning around 8 am before breakfast. Sera samples were then obtained from the collected venous whole blood by centrifuging Vanguard V, SmithKline Beecham at x g for 5 min at room temperature. The separated supernatant serum was decanted into bijou bottle, stored frozen and analysed within 48 hours of collection.
Determination of serum glucose and triacylglycerol. Risk factor categories. Blood pressure was classified according to current guidelines Triacylglycerol levels were classified according to the National Cholesterol Education Program guidelines 13 , and based on fasting glucose levels, subjects were classified as having normal glucose, impaired fasting glucose or diabetes in accordance with the American Diabetes Association guideline Statistical analysis. Analysis of variance ANOVA was used to compare group mean values, followed by the Newman-Keuls post-hoc test 15 to determine statistical significance between the groups.
Evidence Table 1 suggests that illiteracy may influence the pattern of alcohol consumption. Illiterates are more likely to drink more, especially among the Urhobos and Ijaws. Majority of the participants had normal weight as judged by the BMI values.
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There were no marked gender differences in the socio-demographic statistics so presented. The experimental data obtained Table 2 show that the control values of serum glucose, triacylglycerol and blood pressure for the heavy drinkers were highest when compared with those of the light and moderate drinkers, and the degree of differences were more among the females. Similar trend was observed during the test experiment. It has been estimated that about one third of the adult population in the developed world have syndrome X, and they do not know it.
Syndrome X is the term used for a cluster of conditions that tend to appear in some individuals, and symptoms include glucose intolerance, hyperlipidaemia and hypertension, and it is common among prediabetic, obese individuals. The disease condition is also known as metabolic syndrome and many researchers think that it is genetically based, but poor lifestyle is likely to be the main cause.
Subsequent research findings have shown that even if one looks after oneself, eat a low-fat diet and are not obese, one could still be at a considerable risk. The biochemical features of syndrome X alter pathways involving the metabolism of both carbohydrates and lipids 4 , and these alterations may lead to glucose intolerance probably arising from insulin insensitivity , dyslipidaemia, and hypertension. The data obtained from this investigation show that alcohol consumption increases serum glucose, triacylglycerol and blood pressure Table 2 , and these present observations agree with earlier isolated reports on the effect of alcohol on blood glucose 1,16 , serum triacylglycerol 2 , and blood pressure 3,8.
Thus, apart from the positive relationship between central obesity and syndrome X, heavy consumption of alcohol by women especially, appears to be a potential predisposing lifestyle, this study suggests. The metabolic relationship between syndrome X risk factors and alcohol consumption is beginning to emerge 2.
Increase in glycerolphosphate also favours triacylglycerol synthesis and its hepatic accumulation 18 , and alcohol-induced increase in serum triacylglycerol has been reported Increases in blood triacylglycerol concentrations have been shown to reduce the number of insulin receptors Some researchers now think that plasma triacylglycerol levels may actually be more important than cholesterol levels in establishing heart disease risk. We conclude that heavy consumption of alcohol may be yet another cause of the metabolic adaptations that could promote fat formation. This could culminate in hypertriglyceridaemia, a condition known to induce poor glucose tolerance, oversecretions of insulin and higher risk of heart disease.
However, restricted carbohydrate diet has been reported to be beneficial in reducing the level of blood triacylglycerol in compliant patients The guidelines for this dietary intervention should be fully developed for possible therapeutic application, especially now that changing customs appear to condole women drinking of alcohol even publicly, and coupled with the fact that syndrome X can hardly be recognized by sufferers. Thus, such dietary approach to the treatment of syndrome X should be properly investigated, because it could be bestowed with the prowess of averting the progress of the subtle disease in alcoholics, when possibly coupled with the advise to reduce or avoid alcohol consumption.
The authors wish to appreciate the cooperation of the subjects, and the management of Vantex Research and Diagnostic Laboratory, Sapele, Delta State, Nigeria. Badawy A. A review of the effect of alcohol on carbohydrate metabolism. Br J Alcohol Alcoholism ; Abnormal glucose tolerance and alcohol consumption in three population at high risk of non-insulin dependent diabetes mellitus. Am J Epidemiol ; Influence of pattern of alcohol intake on blood pressure in regular drinkers: a controlled trial.