Alcoholic Liver Disease
Many interacting issues are at work when dealing with alcohol abuse: the medical sequelae, alcohol intoxication, alcohol tolerance, alcohol dependence, and alcohol withdrawal.
From a public health viewpoint, the diseases associated with alcohol abuse are preventable with abstention and such behavioral modifications as may be necessary should be considered the primary intervention. This article on www.indialivertransplant.com focuses on pharmacological interventions for alcohol dependence and alcohol’s hepatotoxic effects, in particular the spectrum of conditions known as alcoholic liver disease
Generally, the approaches currently used in the treatment of alcohol problems are based on three sources of information:
(1) The experiences of recovering alcoholics and the professional staff treating them,
(2) Research on human behavior, and
(3) Studies of potential medications (i.e., pharmacological research.)
The conditions that lead to excessive alcohol consumption in some individuals and not in others are very complex as they involve interactions among genetic, psychosocial, environmental, and neurobiological factors. Alcoholism is a multigenic disorder. The pharmacological effects of ethanol that support alcohol reward and alcohol seeking behavior involve actions at multiple receptors and neurochemical systems occurring throughout the body. Neuropharmacologic studies in animals have provided evidence for specific neurochemical mechanisms in the brain that are involved in alcohol dependence. There are many neurotransmitter systems that become dysregulated during the development of alcohol dependence, including gamma(γ)-aminobutryic acid (GABA), opioid peptides, glutamate, serotonin and dopamine systems.
Briefly, Alcohol has two major actions on the brain: increasing neuronal inhibition mediated through the inhibitory γ-aminobutyric acid (GABA)
, and other receptors
. Prolonged alcohol use down-regulates these receptors and decreases inhibitory neurotransmission. Prolonged alcohol use inhibits excitatory neurotransmission by inhibiting both N-methyl-d-aspartate (NMDA) and non-NMDA (e.g., α-amino-3-hydroxy-5-methisoxizole-4-propionic acid [AMPA]) receptors. Cessation or reduction of alcohol use initiates an imbalance between the decreased neuroinhibition and increased neuroexcitation. This causes the clinical manifestations of alcohol withdrawal: e.g., tremors, hallucinations, insomnia, anxiety or agitation, and possibly seizures. Alcohol also affects numerous other neurotransmitters.
Although about 30% of all alcohol-dependent patients are admitted to general hospitals, usually to treat the alcohol-related physical diseases, the alcohol dependence itself is often ignored or not diagnosed.
The spectrum of ALD ranges from fatty liver
(steatosis), present in most, if not all heavy drinkers, through steatohepatitis, fibrosis and ultimately cirrhosis.
Alcoholic Fatty Liver
Alcoholic fatty liver is predominantly an asymptomatic condition that develops in response to a short duration (a few days) of alcohol abuse. Patients with fatty liver are asymptomatic so that they rarely present with liver related problems. Fatty liver is reversible with abstention but it is a risk factor for progression to fibrosis and cirrhosis in those patients who continue drinking.
Between 20- 40% of persistent heavy drinkers will develop more serious liver disease. In some of these patients, they will get alcoholic hepatitis (AH) while others will present with complications of portal hypertension, and other conditions. People with advanced alcoholic liver disease (AALD) can also be asymptomatic and may even have normal liver blood tests.The level of alcohol consumption necessary for the development of these advanced forms of alcoholic liver disease is probably 80 g of alcohol per day, the equivalent to 6 to 8 drinks daily for several years.
Alcoholic hepatitis is usually accompanied by fatigue, anorexia, and weight loss, and other non-specific symptoms, such as nausea and vomiting.
Severe alcoholic hepatitis may be evidenced by gastrointestinal (GI) bleeding, and ascites. Other findings depend on the severity of liver insult and may include jaundice and other conditions.
Alcoholic cirrhosis may occur at any time before, during , after, or independent of a bout of alcoholic hepatitis.
Liver fibrosis and cirrhosis (clinically distinct conditions but, unless specifically mentioned, they are used interchangeably here) represent a continuous disease spectrum characterized by an increase in total liver collagen and other matrix proteins which disrupt the architecture of the liver and impair liver function. Fibrosis results from sustained wound healing in the liver in response to chronic or iterative injury. The wound healing response is an integral part of the overall process of inflammation and repair: it is dynamic and has the potential to resolve without scarring.The clinical history of alcoholic cirrhosis is similar to that of alcoholic hepatitis, and symptoms are similar to those observed with other forms of end stage liver disease. At present, there are few interventions available to alter the underlying fibrotic process in many patients with liver disease, although data from clinical and laboratory based research show that cirrhosis may be reversible.
About 40% of patients with cirrhosis are asymptomatic and may remain so for more than a decade, but progressive deterioration is inevitable once complications develop. In such patients there is a 50% 5-year mortality, with approximately 70% of these deaths directly attributable to liver disease. In asymptomatic individuals, cirrhosis may be first suggested during routine examination or diagnosed at autopsy, although biopsy is still required to establish the diagnosis postmortem. Cirrhosis affects hundreds of millions of patients worldwide. It is the most common non-neoplastic cause of death among the hepatobiliary and digestive diseases.
Specific Epidemiologic Issues Existing with the Main Types of Alcoholic Liver Disease
Disease frequency may be measured either by the pool of existing cases (prevalence) or by the occurrence of new cases (incidence). As the onset of many types of liver disease is insidious, there is often a long time interval (latent period) between disease occurrence and detection. Further, many patients with liver disease remain asymptomatic until their livers fail. Thus, it is very difficult, if not impossible, to accurately ascertain incidence rates of liver disease. While estimating prevalence may in general be more feasible than incidence rates, many epidemiologic investigations are conducted based on referral patients, which may not represent the true disease prevalence in entire populations.
Immunomodulatory Effects of Alcohol
There is an increased susceptibility to infections in alcohol related diseases. As a result, infection is one of the most common causes of death in patients with ALD, especially those with alcoholic hepatitis. Malnutrition, underlying liver cirrhosis, and aggressive in-hospital medical procedures all contribute to the risk of infection. Alcoholic liver disease and liver failure may even have a component of autoimmunity, in which the immune system turns on the body’s own tissues. Several important infectious diseases are also implicated in alcohol-related immunocompromised individuals. The incidence and severity of pulmonary tuberculosis (TB) is greater in alcoholics than in nonalcoholics.In the overall population, 16 percent of TB patients are alcohol abusers; the percentage ranges up to more than 35 percent in some marginalized populations. Significantly, long-term studies of drug and alcohol abusers who were followed for many years showed that these individuals had TB incidence rates from 15 to 200 times (!) the rates for reference populations. In recent years, the incidence of TB has been increased by the presence of human immunodeficiency virus (HIV) in drug and alcohol abusers. However, even after this added risk is taken into account, it is still clear that drug and alcohol abusers have increased rates of illness and death from TB.
Alcohol abusers are more susceptible than nonabusers to septicemia, urinary tract infections , bacterial peritonitislung abscess, empyema (an accumulation of pus in the chest), spontaneous bacterial peritonitis, diphtheria, cellulitis, and meningitis.
It is clear that the increased incidence of infectious diseases in alcohol abusers represents a significant toll of individual suffering and of medical expense to society. The risk of untreatable infections in alcohol abusers will also increase as antimicrobial resistance increases.
Most important , however, is the association of alcoholic liver disease with hepatitis C. Fully 25% of all patients with alcoholic liver disease have also markers of HCV infection, even in the absence of risk factors such as intravenous drug abuse. Alcohol may favor the acquisition, replication, or persistence of the virus so alcohol consumption is clearly a risk factor for the progression of liver disease caused by HCV. HCV infection multiplies the alcohol-associated risk of cirrhosis.
ALD and the Elderly
Alcohol use disorders in elderly people are common and associated with considerable morbidity. The ageing of populations worldwide means that the absolute number of older people with alcohol use disorders is on the increase even though the prevalence of alcohol use disorders in elderly people is generally lower than in younger people. Rates, however, may be underestimated because of under-detection and misdiagnosis. Age related changes in body composition means that equivalent amounts of alcohol produce higher blood alcohol concentrations in older people. Even so, elderly people have been shown to be at least as likely to benefit from treatment as younger people. Alcohol use disorders in elderly people may prove to be a silent epidemic, yet media attention and public health initiatives related to alcohol use disorders tend to focus almost exclusively on younger populations.
ALD and Women
There is marked regional variability in the extent of gender differences with regard to alcohol-related morbidity and mortality. Female alcohol-attributable mortality ranges from a negative value (more deaths prevented than caused) in established market economies of Western Europe (Europe A), North America (Americas A) and the Western Pacific Region (Western Pacific A) to more than 5% of all female deaths being attributable to alcohol in the former socialist countries of Eastern Europe around Russia (WHO Region Europe C). For comparison, female alcohol-attributable mortality is 18% in the former socialist countries of Eastern Europe (Europe C).
The differences among regions reflect the differences in the overall relationship between average volume of alcohol consumption and mortality generally. For DALY burdens, males have a far greater alcohol related DALY burden than females. It should be noted that for disease burden there is no region where alcohol has an overall beneficial impact on either gender.
The relationship between breast cancer risk and alcohol intake was first noted in the 1970’s among women participating in the third National Cancer Survey. Meta-analysis of case control studies (not randomized trials) have found that women who drank three or more alcoholic beverages per day (or 40 grams of alcohol, with about 13 grams in a standard drink) had a 69 percent higher risk of getting breast cancer compared with nondrinkers.A separate analysis of six prospective
cohort studies showed that those who had two to four drinks per day (30 to 60 grams of alcohol) had a 41 percent greater risk of getting breast cancer than those who did not drink.Remarkably, over a range of one to six drinks per day, the relationship of alcohol to breast cancer was linear.
Controversy remains over the interpretation of these studies as the effect is modest in magnitude and is not restricted to one type of alcoholic beverage. The risk is most pronounced at high intakes of alcohol. Increased exposure to estrogens and androgens with alcohol consumption is one plausible—but unconfirmed— biological mechanism to explain alcohol’s effect on breast cancer risk.
The mechanisms for the differential impact of alcohol on heart disease and mortality and on neurologic function in women and men are also still unclear. There remain possibilities at every level of alcohol processing: its metabolism by enzymes in the stomach and liver, its absorption into the bloodstream, and its actions on the physiology of end organs—that might explain mechanisms that could contribute to gender related differences in the health consequences of drinking.Adverse effects have been observed at levels of consumption that many would regard as low- between 7 to 13 drinks per week. It is important that research be aimed at identifying why women are so vulnerable to alcohol For any given level of alcohol intake, women have an increased susceptibility to alcoholic liver disease.
However, the threshold of alcohol necessary for the development of advanced alcoholic liver disease varies substantially among individuals, and factors other than absolute alcohol consumption clearly have an important role in determining who will develop alcoholic liver disease and who will not. These observations highlight the role of genetic factors that may predispose specific persons to greater propensity toward alcohol-induced liver toxicity.
ALD and Genetics
Alcoholism and alcohol-induced liver disease are partly genetic diseases. There is much information on alcohol dependence per se with regard to the biological mechanism of action; heritability studies; animal studies, and linkage and association studies. The potential new gene candidates for alcohol dependence is an important area of study.
One study has identified a stronger genetic component for male dependence on alcohol than for arterial hypertension. Sons of alcohol-dependent fathers tend to be more tolerant to alcohol and to have fewer hangovers, a fact which renders alcohol more pleasurable to them. The C2–promoter allele of the gene coding for the cytochrome 450CYP2E1 shows a significantly different distribution in heavy drinkers. This C2–allele, which leads to higher production of the cytochrome protein, is present in 6% of healthy heavy drinkers, in 19% of heavy drinkers with alcoholic liver disease and in 33% of heavy drinkers with cirrhosis. Similarly, two identical sections of the alcohol dehydrogenase gene (one on each chromosome) is found in 7% of healthy heavy drinkers and 31% in heavy drinkers with ALD. A change in a region of the DNA encoding human CD14 protein, has been linked to the development of fibrosis in alcoholic liver disease. Specific genetic polymorphisms have been detected in patients with alcoholic liver disease, most notably mutations in the tumor necrosis factor (TNF) promoter.
Diagnosis and Biochemical Markers
The major clinical assessment necessary for diagnosing alcoholic liver disease is determining whether the patient is abusing alcohol but this is not always easy. Alcoholic patients and even their family members often minimize or conceal alcohol use. Because of the inherent difficulties in obtaining a reliable history of alcohol use, various biochemical markers have been evaluated for their ability to detect surreptitious alcohol abuse. A comprehensive marker for alcohol dependence has not been identified although a series of successful markers exist for determining drinking status. Traditional serologic markers of alcohol abuse are based on liver injury and include elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and elevated AST/ALT ratios. These tests have diminished sensitivity and specificity, generally less than 70%. Other tests have been evaluated. Measuring urinary 5-hydroxytryptophol or ethyl glucuronide are more sensitive than measuring blood or breath ethanol. Carbohydrate-deficient serum transferrin protein is a more specific marker for identifying excessive alcohol consumption and monitoring abstinence.
Although hepatitis C virus (HCV) is a leading risk factor for liver fibrosis, there is no standard laboratory serum analyses, imaging tests or virologic assays that currently can distinguish those with hepatitis C, or any other condition, who are at risk for progressive fibrosis. Thus, increasing numbers of patients will require assessment of fibrosis, exposing them to the potential risks, inconvenience and cost of liver biopsy and its interpretation. If a non-invasive assay were developed that reliably excludes the possibility of significant fibrosis, then such patients may not require treatment with antiviral therapies, and, moreover, could be followed regularly to confirm lack of fibrosis progression. Increasing evidence that advanced fibrosis may be reversible, such that more frequent and refined analysis may render even severe disease amenable to therapy. The expectation that as antifibrotic therapies are developed, there will be a need for early and regular monitoring of response in order to establish effectiveness and optimize dosing.
Clinical assessment of interventions also relies on serial liver biopsies. Liver biopsy remains associated with a (small) morbidity and mortality and is prone to sampling error. It may not be an appropriate way of monitoring in a dynamic situation like a clinical trial. A panel of serum fibrosis markers has been developed which can be used to predict the stage of fibrosis and monitor disease progression or resolution without repeated liver biopsies.
Acetaldehyde is a toxic product of the metabolism of alcohol. Acetaldehyde will form a conjugate, both in vitro and in vivo, with the compound cysteinylglycine. Cysteinylglycine is derived from an antioxidant that plays a role in protecting the liver from alcohol-induced injury. The significance of the present finding is two-fold: first, the conjugation of acetaldehyde and cysteinylglycine may act as a means of scavenging the potentially toxic acetaldehyde; and second, the conjugate could potentially serve as a marker of alcohol consumption.
Comorbidities Associated with Alcohol Abuse and Dependence
The term "comorbidity" refers to the presence of any two or more illnesses in the same person. With respect to treatment, persons exhibiting comorbid alcohol-related and medical or psychiatric disorders often fall through the cracks of the health care system because of administrative distinctions among addiction, medical, and mental health-related services. Patients are often forced to choose between clinical settings, often resulting in neglect of one condition. Alcoholism and other disorders might be related in a number of ways, including the following:
- Alcoholism and a second disorder can co-occur, either sequentially or simultaneously, by coincidence.
- Alcoholism can cause various medical and psychiatric conditions or increase their severity.
- Comorbid disorders might cause alcoholism or increase its severity.
- Both alcoholism and the comorbid disorder may be caused, separately, by some third condition.
- Alcohol use or alcohol withdrawal can produce symptoms that mimic those of an independent psychiatric disorder.
Aside from the liver conditions that we focus on in this article, other medical conditions are associated with excessive alcohol use.
Alcohol-induced heart damage appears to increase with lifetime dose of alcohol.
Alcohol can damage the brain in many ways and the most serious effect is Korsakoff's syndrome, characterized in part by an inability to remember recent events or to learn new information. The incidence of alcohol-related brain damage is approximately 10 percent of adult dementias in the United States. Milder attention and memory deficits may improve gradually with abstinence.
Alcoholics are far more likely to also have a diagnosis of antisocial personality disorder, drug abuse, mania, and schizophrenia as compared with nonalcoholics.
Eating disorders are also associated with alcoholism. Between 33 and 83 percent of bulimics may have a first-degree relative suffering from alcohol abuse or alcoholism.
Studies indicate that approximately 10 to 30 percent of alcoholics have panic disorder, and about 20 percent of persons with anxiety disorders abuse alcohol. Among alcoholics entering treatment, about two-thirds have symptoms that resemble anxiety disorders.
Alcoholics are 35 times more likely than nonalcoholics to also use cocaine. Similar odds ratios for other types of drugs are: sedatives, 17.0 times; opioids, 13.0 times; hallucinogens, 12.0; stimulants, 11.0; and marijuana and related drugs, 6.0. Surveys of both clinical and nonclinical populations indicate that at least 90 percent of alcoholics are nicotine dependent.
- In developed countries alcohol is one of the ten leading causes of disease and injury. Worldwide, in 2000, alcohol caused about 3 per cent of all deaths (1.8 million) and about 4 per cent of ‘disability adjusted life years’ lost (DALYS) (58.3 million).
- Globally, almost half of the global burden of alcohol-related mortality is due to alcohol-related injuries, with 32% due to unintentional injuries and about 14% due to intentional injuries. Malignant neoplasms (liver cancer and stomach cancer) are the next most important category, accounting for about 20% of the overall alcohol-related mortality burden, followed by cardiovascular disease (15%) and other non-communicable disease [mainly alcoholic Liver Diseases (ALD)] such as liver cirrhosis –13% of all alcohol-attributable deaths.
- Alcoholic liver disease (ALD) is the commonest cause of cirrhosis in the Western world, and ALD is currently one of the ten most common causes of death. Liver fibrosis caused by alcohol abuse and its end stage, cirrhosis, represent enormous worldwide healthcare problems. Patients with cirrhosis and superimposed alcoholic hepatitis have a 4-year mortality of more than 60%.
- As the onset of many types of liver disease is insidious, there is often a long time interval (latent period) between disease occurrence and detection. Further, alcohol use lowers the immune response. Infection is one of the most common causes of death in patients with ALD, especially those with alcoholic hepatitis. Malnutrition, underlying liver cirrhosis, and aggressive in-hospital medical procedures all contribute to the risk of infection.
- Overall, stopping drinking has been shown to improve the survival of patients with all stages of ALD. This condition is eminently preventable. However, progress in developing specific treatments for acute alcoholic hepatitis has been hampered by a poor understanding of disease pathogenesis.
- Many treatment modalities have been tried in patients with alcoholic hepatitis, however, few have been consistently shown to have a beneficial effect and, accordingly, none have achieved consensus status among practising hepatologists. Thus, current therapy still focuses predominantly on supportive care.
- Current treatments for alcoholic cirrhosis are severely limited. One can attempt to have patients abstain from alcohol (where possible); eradicate existing viruses using interferon, ribavirin, and lamivudine in viral hepatitis; and transplant the liver. The vast majority of patients with ALD in clinical practice have advanced fibrosis or cirrhosis. No adjunctive pharma-co-therapies have been consistently shown to improve survival in more than one randomized controlled trial, although some have shown promise.
- Transplantation is a highly successful treatment, particularly for end stage cirrhosis, with a 75% five year survival rate. There is limited availability of organs, growing lists of patients needing a transplant, issues of compatibility, and co-morbid factors. Transplantation is also costly with ongoing anti-rejection drug costs. Effective anti-fibrotic treatments are needed urgently.
- In light of the high burden of disease, there are very few medicines in clinical trials specifically directed to reverse, inhibit or otherwise ameliorate alcoholic liver disease so there is a large “gap” between basic and applied research.
- There are many potential biological targets for anti-fibrotic therapies. Moreover, fibrosis of the liver is a paradigm for other fibrotic conditions in other organs of the body.
- There is little private-sector funding directed to alcoholic Liver Diseases. Public sector funding may be insufficient as well, particularly when compared to the enormous economic and social burdens placed on the healthcare system by ALD.
This article was posted on my blog by Dr. Mohit Bhardwaj.
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