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Home , Alcoholics Anonymous, Alcoholic liver disease, Alcoholism, Alcohol detoxification, Beer day, Chronic liver disease

-RELATED DISEASE: TREATMENT AND REHABILITATION

Introduction

For people who cope with , the specter of recovery relative to prevention of and injury to the body is ongoing. Of significance liver injury, or , is always a concern and can potentially severely impact the individual affected by an alcohol use disorder. Long-term alcohol use has been strongly connected to mental and physical disease states, and in the past few decades there has been a plethora of research related to patient education, treatments, disease management, and understanding the power of in peoples’ lives. The medical condition of alcohol-related cirrhosis is a major area of research and concern for all members of the interdisciplinary team. Liver transplant is the standard treatment for severe cases of alcohol use but this treatment may be limited. Relapsing episodes of alcohol use impacts an individual’s prognosis and treatment.

Overview Of Alcoholism And

There is a great deal of misunderstanding of the nature of alcoholism. For centuries, people who drank too heavily were considered weak or foolish. While alcoholism is now treated as a disease, clinicians are still struggling to fully understand alcoholism. The quandary confronting clinicians in dealing with alcoholic patients often entails not being able to accept why someone who requires medical treatment, possibly a transplant, to live would return to the very same behavior that led them to require treatment. This is the issue often facing clinicians as they struggle to cope with the high numbers

1 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com of people who cope with alcoholism and complications, such as (ALD).

Alcoholism may not only be a psychosocial disease but also a neurological one, and it may also have a genetic component. The question clinicians are trying to answer is what is alcoholism? One of the most highly recognized and respected organizations in the U.S., addressing issues of alcohol use and addiction is the Substance and Services Administration (SAMHSA). Another is the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada. These two organizations engage in research, public awareness, individual education, and empowerment for people who cope with addiction. Alcoholism is an addiction.32,60

Alcoholism as a Neurobiological Addiction

In March 2017, the Surgeon General of the U.S., published a report entitled Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. The report explored a number of key areas regarding alcoholism and other facets of addiction including the source of addiction itself. From the very first chapter, it acknowledges the neurobiological source of addiction. It states that a significant amount of research has been conducted to provide sufficient evidence to transform the way clinicians understand substance use disorders and its effects on the brain. With this knowledge, new ways of thinking about prevention and treatment of substance use disorders may be developed.

Clinicians are learning how substances such as alcohol produce changes in brain structure and function that promote and sustain addiction and contribute to relapse. We also know that there are similarities and

2 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com differences in how the various classes of addictive substances affect the brain and behavior.60

Breakthroughs in recent research are revolutionizing the ways in which clinicians now understand substance use disorders. Once they were viewed through the lens of a moral failing or character flaw but are now understood to be chronic illnesses characterized by clinically significant impairments in health, social function, and voluntary control over substance use. The latest research has aided clinicians to understand that while mechanisms may be different, addiction has many features in common with disorders such as diabetes, asthma, and . Each one of these diseases are subject to relapse, and influenced by genetic, developmental, behavioral, social, and environmental factors. They are all similar in that those individuals who cope with them may have difficulty in complying with the prescribed treatment.

The fact that health clinicians now know addiction is affected and driven by neurological changes helps to reduce the negative attitudes and stigma associated with substance use disorders, and supports the integration of treatment for substance use disorders into mainstream healthcare. The research into the neurobiology of addiction has led to the development of new and effective medications not just for alcohol use, but also and use disorders. All addictive substances have powerful effects on the brain. It is these effects that result in a pleasurable feeling people experience when they engage in their initial use of alcohol or other substances, and these feelings motivate people to use those substances repeatedly, despite the risks for significant harm.

The previous model for addressing substance use disorders was the criminal justice model. People were arrested and incarcerated for their use of alcohol

3 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com and other drugs. This has led to what many term as the war on drugs but it has never been successful, and certainly does not address the neurobiological model, which informs clinicians on how addiction develops in an individual.

ALD: Variables and Long-term Outcomes

Alcoholic liver disease is predominantly observed in males; this does not imply women do not contract ALD but they do in far lower numbers. In fact, the male to female ratio of patients with alcoholic liver cirrhosis has been reported as 9:1. A nationwide study in the U.S., that assessed patients discharged from the hospital following a diagnosis of ALD found that 4.5 per 100,000 persons had acute alcoholic . The male to female ratio was 1.83:1. In persons who have contracted chronic with cirrhosis, the male to female ratio is 2.64:1.61 Studies have also revealed a male predominance in the prevalence of NAFLD. An American study revealed that 58.9% of patients with NAFLD were male. Subsequently, a study was conducted in Japan which revealed that the male prevalence rates in NAFLD was 41.0% and 17.7% for females, respectively. Similar trends were observed in a study conducted in China.

One of the most common causes for alcoholic liver disease or ALD is excessive consumption of alcohol. Alcoholic liver disease in turn may lead to advanced liver cirrhosis. Alcohol-related cirrhosis is the second most common indication for , after cirrhosis caused by . Unfortunately, the high incidence of patients returning to heavy is approximately 20% - 30% even after they receive the transplant.30 This is a subject of some controversy in the medical community, as there are so many people waiting for liver transplants. Some

4 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com believe there must be protocols in place that put an emphasis on who receives transplants for ALD.

The high relapse rate is crucial because alcoholic recidivism has a negative impact on post-transplant compliance and long-term outcomes of liver transplant recipients. When a person receives a new liver but then back into drinking, this is strongly associated with increased damage to the transplanted liver and long-term outcomes may be poor for the patient. Thus, in evaluating candidates for liver transplant, there is a need for the clinician and patient to be clear and try to determine the risk of post- transplant relapse of alcohol use in patients with alcoholic liver disease.30

Alcohol-related Liver Disease

Alcohol has been reported to substantially contribute to the global burden of disease and is responsible for significant disability-adjusted life-years and deaths. Moreover, alcohol has a negative effect on socio-economic activities and the annual cost of excessive social drinking has been estimated to be an excessive amount in high-income countries.8,32,60,61

Development of ALD

The development of liver disease from alcohol ingestion depends on several factors. The first step is the person must reach a threshold regarding the duration of use and daily intake of alcohol. For someone drinking on a daily basis for 10–12 years with doses in excess of 40-80 g/day for males and of 20–40 g/day for females, these are the recognized thresholds. The truth is not all alcoholic beverages have the same content, and the threshold is different depending on the type of beverage. As an example, daily drinking of 3–6 cans (12 oz. each) of /day for males or 1.5–3 cans of beer/day

5 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com for females for 10 years or longer can cause ALD.62 Even if a person has reached the threshold mentioned here, it does not imply they will develop liver disease. In fact, only 10–35% of heavy, long-term alcohol drinkers will develop alcoholic hepatitis and only 8–20% will develop cirrhosis. As implied by these statistics, host attributes (i.e., and polymorphism(s) of alcohol-metabolizing ) and coexisting external factors (i.e., obesity and infection) combine to determine the likelihood of developing associated liver disease.62

The risk of serious liver disease always increases when the consumption of alcohol increases and in the presence of Hepatitis C infection. There are studies which reveal that women develop liver disease after exposure to lower quantities of alcohol and over shorter time periods. The correct diagnosis of ALD can usually be made on a clinical basis in conjunction with blood tests, and a is not usually required.

Alcoholic Liver Disease And Fatty Liver

Alcoholic liver disease and have become serious healthcare issues that also connect to world-wide social and economic problems. The amount of money that has to be spent to provide care, the lost hours of work, and the emotional toll are enormous. While they have similar pathology, they differ from each other in many characteristics, ranging from differences in clinical features to patient outcomes. A comparison of these diseases may result in a better understanding and management of both ALD and fatty liver disease.8,36-41

ALD versus NAFLD

6 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com There are two forms of fatty liver disease, one is alcohol-related (ALD) and the other is non-alcoholic related liver disease (NAFLD). Both of these diseases are problematic on a worldwide basis. They present with similar pathologies which range from simple hepatic to , liver cirrhosis, and . Most people who drink excessive alcohol or eat excessively will develop a simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, and these can range from including to a malignancy. Survival rates for people with either ALD or NAFLD depends on various disease-associated conditions. Excessive alcohol consumption is related to liver disease but it can cause other health problems as well, including cardiovascular disease, , and other serious issues. The causes of death have been found to differ in patients with ALD and NAFLD.

A long-term follow-up of patients with simple hepatic steatosis revealed that many of the patients with ALD and NAFLD died of extrahepatic, rather than hepatic causes. This supports the evidence, which was presented earlier, that ALD and NAFLD have the potential to cause a broad spectrum of additional, life-threatening health issues. Some of the main causes of death in ALD patients were arteriosclerosis (20%), liver cirrhosis (17%), unknown causes (16%), and extrahepatic (14%), whereas the main causes of death in NAFLD patients were arteriosclerosis (38%), unknown causes (19%), extrahepatic cancers (17%), and infections (8%).61 Mortality rates of patients with ALD and NAFLD have been found to be similar, even if sometimes the actual cause of death might be different. In comparison to those coping with Hepatitis C, larger percentages of patients with ALD and NAFLD have been found to die from extrahepatic causes. Still today, far too

7 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com many people with ALD are dying of infection and extrahepatic cancers, and many NAFLD patients die of cardiovascular disease.

Treatment Of Alcoholic Liver Disease

The standard for treatment of ALD is as the first line therapeutic intervention. Nutritional therapy, medication therapy, and the role of steroids in patients with moderate to severe alcoholic hepatitis is gaining increasing acceptance as well.8,36-41,61-63

Abstinence

The primary treatment for ALD is for the person to immediately cease drinking. Abstinence from alcohol leads to resolution of alcoholic fatty liver disease (benign steatosis) and abstinence improves survival in alcoholic cirrhotic patients, even those with decompensated liver function. Even when someone reduces their alcohol intake but does not completely abstain, they still show the ability to improve their survival rate although they are diagnosed with ALD.

The cumulative 5-year survival rates of patients with ALD were reported to be 83.3% in patients with simple hepatic steatosis and 74.9% in those with alcoholic steatohepatitis. Survival rates for patients with both compensated and decompensated alcoholic cirrhosis were reported to be 83.9% and 71.3%, respectively.61 The best way to increase survival rates is to engage in complete abstinence from alcohol. Abstinence has proven to increase the survival of patients with alcoholic cirrhosis.

Abstinence is not always as easy as it sounds. People who have been heavy drinkers for many years may have a great deal of difficulty in ending years

8 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com of drinking alcohol on a regular basis. They may require time in an inpatient facility to obtain the support they need to stop drinking on a permanent basis. However, that might not be the end of their journey. For many people with ALD, there can be serious damage to their liver. In that case, even after they enter permanent , they will need to engage in further treatments.

Withdrawal Symptoms

All people who have ALD will experience withdrawal symptoms as the alcohol leaves their bodies. Their system will crave the alcohol and this can be both physiologically and psychologically painful. There can also be other symptoms such as , insomnia, anger, frustration, and other issues related to their excessive use of alcohol for so long. It is well advised for such individuals to engage in a supportive network such (AA) to find the support they require in order to maintain sobriety. Many former alcoholics also find a sponsor, who is someone they work with 1-to-1 to work out many of their issues related to their alcoholism. Many also make the choice to live in a sober home, where they recover alongside other recovering addicts in a supportive, nonjudgmental environment.

Rehabilitation Programs

There are benefits to both inpatient and outpatient rehabilitation programs (discussed more later on) as they assist and empower patients in a proactive way to achieve and maintain sobriety. Referral to and communication with an addiction specialist, and the encouragement to attend AA meetings is one of the best methods of assisting patients with alcoholism and concomitant ALD. For patients who do not have these options available, for whatever

9 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com reason, patients have also shown improvement when they receive regular counselling.

Counselling has been demonstrated to encourage patients to modify their drinking habits. Another useful strategy is to assess patients for any such as a psychiatric condition to assist patients with alcohol use and addiction.

Pharmacotherapy

As with many other conditions, some pharmacotherapy alongside psychosocial supports and interventions can support and empower patients in maintaining abstinence from alcohol. These are discussed in more depth in a later section, however, a brief introduction here will include the more common pharmacy treatments for alcohol withdrawal of , acamposate, , and .8,36-41

Naltrexone and have been shown to assist in reducing or eliminating alcohol intake in chronic heavy drinkers. For example, Naltrexone is an opioid antagonist. It may be prescribed to patients who are struggling to abstain from alcohol. Naltrexone reduces the for alcohol that may be experienced by a patient using alcohol. Naltrexone blocks the effects of alcohol that a drinker usually experiences when drinking.58

Disulfiram, which has long been approved by the US Food and Drug Administration (FDA) for the treatment of alcoholism, continues to be used on a fairly consistent basis. Disulfiram can have favorable outcomes for patients. Disulfiram in a patient's system creates a negative reaction, similar

10 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com to a , when alcohol is consumed. This reaction is intended to discourage the patient from drinking alcohol.58

Topiramate has demonstrated safety and efficacy in multiple clinical trials. This drug aids patients by decreasing both craving and withdrawal symptoms, and this, in turn, increases quality of life measures among individuals using alcohol.58

Finally, baclofen has proven effective in promoting alcohol abstinence in addicted patients. Baclofen has a low liver metabolism rate so it passes through the body unchanged. It may be useful in controlling alcohol craving and thereby encourage abstinence in patients using alcohol. Because there are no reported cases of a hepatic adverse effect associated with baclofen, it may be effective and useful for patients with liver cirrhosis.58 In cases of chronic, heavy drinking, it becomes a life-long challenge to achieve and maintain sobriety. There is low margin for error in patients with ALD, the coordination of both pharmacotherapy and psychosocial intervention is best handled by an addiction specialist.

Other Lifestyle Changes

Patients with ALD should also consider making other changes such as and weight loss. Smoking, as we know, presents people with a high risk for many diseases and has been proven to be an independent for advancement of hepatic fibrosis, which can lead to more severe ALD, and may be linked to the development of HCC. Obesity, which can also cause fatty liver, non-alcoholic steatohepatitis, and cirrhosis, may be an independent risk factor for the progression of ALD.

Nutritional Therapy

11 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com It has long been established that patients with ALD (both severe ASH and cirrhosis) are almost all suffering from severe malnutrition, and the degree or severity of the malnutrition correlates with disease severity. In addition, complications of ALD (i.e., infections, encephalopathy, , and variceal bleeding) have been shown to be strongly associated with protein-calorie malnutrition (PCM). Micronutrient deficiencies of , vitamin B6, vitamin A and are among the most commonly encountered. Some patients show mineral or element alterations in their systems, such as selenium, , , and others. These are thought to be involved in its pathogenesis. In particular, zinc is decreased in patients with ALD. In animal models, zinc supplementation has been shown to improve, attenuate, and/or prevent ALD.62,63

Treatment Of In ALD

The role of steroids in patients with moderate to severe alcoholic hepatitis is gaining increasing acceptance, with the caveat that patients be evaluated for the effectiveness of therapy at 1 week. One drug which has proven to be effective is and especially so in people with renal dysfunction or . Biologics such as specific anti-TNFs have been disappointing and should probably not be used outside of the clinical trial setting. There is always the possibility of a transplant for people with end- stage ALD who have stopped drinking (usually for ≥6 months), and both long-term graft and patient survival are excellent.58,59,63

Glucocorticoids

Glucocorticoids have been in use for decades but their use in the treatment of liver disease, and most specifically alcoholic hepatitis has been intensely studied and hotly debated. There are studies on glucocorticoids to treat

12 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com severe alcoholic hepatitis going back to the 1970s and despite this there is still controversy regarding its use.

The primary reason for using steroids is to reduce the inflammatory pathways in alcoholic hepatitis. They have actually been shown to decrease proinflammatory and intercellular cell molecule 1 expression and inhibit activation. As a result, the use of this drug has shown it can provide only short-term histological improvement in patients with alcoholic hepatitis.

Results of any studies for ALD are going to vary and they will certainly depend on the nature of the trial. The patients recruited for the study are also an important factor. Among glucocorticoids, researchers have investigated various steroidal medications, for a wide range of durations and different criteria used for treatment. Steroid use in alcoholic hepatitis has been extremely controversial for the reason that it contains a high risk of infection in an already immunocompromised host. In some clinical studies, there have actually been higher rates of mortality in the group using the glucocorticoid compared to the placebo group. The factors connected to this higher rate of mortality was a greater incidence of fungal infections among patients receiving glucocorticoids.

A meta-analysis on this subject, although published decades in the past, provided evidence that glucocorticoids were effective in high quality trials. This was especially so in studies that excluded patients with gastrointestinal bleeding but included those with . However, alongside this research, another meta-analysis revealed absolutely no benefits when they attempted to control for confounders. An additional meta-analysis of 15 trials with 721 randomized patients concluded that their

13 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com study demonstrated favorable results with the use of glucocorticoids was based on heterogeneous trials of low quality.64

Recently using individual patient data from more than 400 patients, Mathurin, et al., demonstrated improved survival with treatment. The long-term benefit of steroids is still uncertain and not yet completely accepted in the medical community. It is difficult to assess, follow-up can be challenging, and only when the patient abstains from alcohol completely is there hope for recovery. Otherwise, alcoholic hepatitis is likely to recur. The survival benefit of corticosteroid therapy has not been found to persist beyond 1 year, which means it is at best a short-term benefit.64

However, even after 13 randomized controlled trials and 6 meta-analyses of steroids as a treatment for ASH, there are concerns in the medical community regarding their continued use. While are probably beneficial in patients with severe disease, mortality on treatment remains high, and this is especially true when the patient also has a renal impairment and treatment is contraindicated in patients with concomitant infection and gastrointestinal bleeding.

In another study, the reduction in 28-day mortality observed among patients treated with prednisolone did not reach the conventional threshold of statistical significance, and no significant differences were observed in 90- day or 12-month outcomes. After a secondary analysis which provided adjustments for baseline determinants of prognosis, the results then showed a significant advantage with respect to 28-day mortality with prednisolone. The survival differences may have been a chance finding or may represent a benefit of prednisolone for short-term mortality that did not translate to

14 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com longer-term benefit. In this study, researchers used the same threshold of disease severity that has been used in most other trials of alcoholic hepatitis (a score of 32 or higher for discriminant function), the 28-day mortality overall in STOPAH (STEROIDS OR PENTOXYFYLLINE FOR ALCOHOLIC HEPATITIS) was appreciably lower than the 28-day mortality in the trials included in other analyses.64,65

Since, many studies took place decades ago, mortality reported in two more recently published trials was similar to those previously reported. In this trial, researchers found lower incidences of infection and acute kidney injury, which possibly resulted in lower mortality rates. In this particular study, the mean age was slightly younger; possibly a factor in the mortality rate. In one study, the reduction in 28-day mortality observed among patients treated with prednisolone did not reach the conventional threshold of statistical significance. As a result, there were no important 90-day or 12- month outcomes.

In a secondary analysis that included adjustments for baseline determinants of prognosis, a significant advantage with respect to 28-day mortality was seen with prednisolone. These differences in survival rates may be a chance finding, but there is still the possibility they may represent a benefit of prednisolone for short-term mortality that did not translate to longer-term benefit. While the same threshold of disease severity adhered to is used in most other trials of alcoholic hepatitis (a score of 32 or higher for discriminant function), the 28-day mortality overall in STOPAH was appreciably lower than the 28-day mortality in the trials included in other analyses.64,65

Potential Side Effects of Glucocorticoids

15 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com One of the cautionary notes about glucocorticoids for patients with alcoholic hepatitis is the possibility of multi-organ failure. Since infection is always a crucial issue for patients with alcoholic hepatitis, it is worth noting that in a trial published in 2011, the addition of N-acetylcysteine to prednisolone was associated with a reduced rate of infection. The results of this trial showed that after 28 days, neither prednisolone nor pentoxifylline influenced mortality. Furthermore, the cumulative mortality at 90 days and at 1 year in this group of patients was alarming. Self-reported alcohol consumption revealed complete abstinence in 37% of the patients at 1 year of follow-up. However, data on alcohol consumption are difficult to collect, and this fact is reflected in the high proportion of missing data.58,63-65

The higher rate of infection among the patients treated with prednisolone is expected, but mortality attributed to infection tends to be similar across groups, regardless of whether prednisolone was administered. Investigators attribute deaths to infection in approximately one-fourth of patients, but infection also probably has played a role in deaths attributed to other causes, such as multi-organ failure. Since infection plays such an important role in the outcome of alcoholic hepatitis, it is worth noting that in a trial published in 2011, the addition of N-acetylcysteine to prednisolone was associated with a reduced rate of infection. The results of this trial showed that after 28 days, neither prednisolone nor pentoxifylline influenced mortality. Furthermore, the cumulative mortality at 90 days and at 1 year in this group of patients was alarming.64,65

Self-reported alcohol consumption revealed complete abstinence in approximately one-third of the patients at 1 year of follow-up. However, data on alcohol consumption are difficult to collect, and this fact is reflected in the high proportion of missing data. No matter what the exact figures are,

16 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com more clearly needs to be done to prevent recidivism in this group of patients.

Corticosteroids in the Treatment of Alcoholic Hepatitis

The treatment of choice for patients with severe alcoholic hepatitis (AH) is the use of corticosteroids. Many randomized well-designed studies have been reported from all over the world on the use of corticosteroids in the treatment of AH. However, the data on the efficacy of corticosteroids in these patients have been conflicting. Initial meta-analyses also failed to show beneficial effects of corticosteroids.58,59,63-65

Individual data meta-analysis showing clear benefit of corticosteroids amongst patients with severe AH led the American College of to recommend use of corticosteroids as the first line treatment option amongst patients with severe AH. However, corticosteroids are relatively contraindicated amongst patients with severe AH and coexistent sepsis, gastrointestinal bleeding, and acute . These patients may be candidates for second line treatment with pentoxifylline. Further, specific treatment of AH with corticosteroids is far from satisfactory with as many as 40%-50% of patients failing to respond to steroids, and are thus classified as non-responsive to steroids. The management of these patients is a continuing challenge for physicians.64-65

Better treatment modalities need to be developed for this group of patients in order to improve the outcome of patients with severe AH. This section describes at length the available trials on the use of corticosteroids and pentoxifylline with their current status. Route of administration, dosage, adverse effects, and mechanisms of action of these two drugs are also

17 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com discussed. Finally, an algorithm with a clinical approach to management of patients who present with clinical syndrome of AH is elaborated on here.

Corticosteroids act by reducing in the body. They are widely used in the treatment of conditions such as arthritis and lupus. Inflammation is a major characteristic of AH. Many agents have been tested in clinical trials, and although prednisolone is preferred, it is not necessarily more effective. It is usually provided to patients as an oral dose of 40-60 mg/day for a total duration of 4 weeks. After that, the patient is asked to taper off over a period of about 2-3 weeks. If the patient cannot tolerate the drug due to and/or vomiting, they may receive it intravenously with a preparation known as methylprednisolone. The patient may continue this until they can tolerate the oral dose.63-65

Prior to putting a patient on steroids, all patients should be screened for any contraindication. An important contraindication is the presence of infection, which is fairly common among patients with severe AH. In earlier times, this was considered to be the marker as an absolute contraindication for steroids. However, the latest data from France had shown that if a patient is adequately treated for an established infection, steroids can be safely started and even improve the outcome in these patients. In this study, all 246 patients studied prospectively were treated with steroids. Patients with infection (25% of the group) were treated adequately with antibiotics prior to starting steroids. Survival with steroids at 2 months was similar, irrespective of the presence of infection prior to starting steroids.

Some of the contraindications are an active gastrointestinal bleeding, renal failure, , active , uncontrolled diabetes and . Clinicians must always take care to assess their patients for their

18 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com response to steroids. Patients should also be screened for possible infections, which can be a common while on steroids. When patients develop either sepsis and/or infective complications when taking steroids, the clinician should take this as a poor prognostic sign. In one study, 57 patients developed infection after starting steroids. And this was a far more frequent occurrence among non-responders than responders to steroids.

Pentoxifylline

For patients who have contraindications to steroids, the second option for treatment is oral pentoxifylline (PTX). The first time PTX demonstrated its efficacy was in a study for people with AH. This particular study showed survival benefit at 1 month with the use of PTX in comparison with the group which used a placebo, with a rate of 76% vs 54%. This benefit was attributed mainly to the prevention of the hepatorenal syndrome (HRS). After this, additional studies were conducted and these studies provided confirmation that there are beneficial effects in using PTX in the prevention of HRS.58,59,63-65

A study published recently comparing steroids to PTX showed superiority in the treatment of AH patients with better survival rate at 3 months. However, the latest Cochrane systematic review of 5 RCTs (4 reported as abstracts) concluded that there is not enough evidence for survival benefit of PTX in the treatment of AH. However, the problem with these studies is a small sample size. Further, four of these five studies were reported as abstracts.

The question of whether PTX is a salvage option for patients with NRS was answered by a study in which patients were identified as NRS at 1 wk. The use of additional PTX failed to demonstrate survival advantage at 2 mo. Further to these studies, other clinical research revealed no benefits as

19 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com shown on the biochemical parameters. Clearly, PTX was not shown to be an option for patients with NRS. It is important to note that PTX has not been studied in patients with NRS without additional steroids. It’s already known that many patients with NRS are prone to develop infections, so this may have affected the overall benefit of PTX.

While there is evidence as to the benefits of PTX for severe AH, some in the medical field believe it is weak and it should only be used as a second line option, and only until such time as more effective agents are developed. The protocol for PTX is as an oral medication and no higher a dose of 400 mg three times a day for a total duration of 28 days. Even after all the studies conducted on PTX, the exact mechanism of action of this drug is not completely understood and therefore not entirely clear.

ALD, Liver Transplant And Relapse

The issue of organ transplants as a life-saving measure for people with ALD continues to be one of great controversy in the medical field. As noted above the liver transplant procedure is the common indicator for ALD but it is much debated due to organ shortage, and the potential of relapse. The world-wide acceptance of six-month abstinence before transplantations is used to try and decrease relapse rates. This does not work well for patients who have severe hepatitis or decompensated patients who won’t survive six months. This leaves the medical field in a quandary because the first rule of medicine is do no harm. Long-term care of these patients is also difficult because they may or may not return to pre-transplant behaviors and habits.45-48,60-63

Sometimes, the patient is in an emergency predicament, and there is no time for that discussion. In those instances, the surgeon and patient, plus

20 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com the patient’s family will need to make a very fast decision. Emergency surgery carries all kinds of risks, not the least of which is the emotional toll it takes on the patient to be suddenly thrust into the operating room for life- altering surgery. The majority of patients do not end up in that situation, but some do, and for them, surgical intervention may be the only option.

It is obvious that the liver transplant procedure can save lives but it does not treat alcoholism and recipients may relapse again, sometimes to harmful levels of drinking, and pre-transplant sobriety does not confirm sobriety after liver transplant. There are many stages to relapse, which can take the form of occasional slips or harmful drinking pattern for a prolonged period; the later affects graft and patient survival.

One study aimed to identify the factors which would predict the chances of post-transplant alcohol relapse. These factors included: • Absence of a structured management program for sobriety • Prior alcohol rehabilitation • Poor social support • Lack of a partner • Poor psychosomatic prognosis • Psychiatric co-morbidity • Gender • Non-acceptance of the problem by partner and/or family/friends • Low motivation for alcohol treatment • Presence of a first-degree relative with alcohol use disorder • Continued engagement in social activities with presence of alcohol

Additional research has provided evidence that the active involvement of a psychiatrist may decrease the chances of a relapse after liver transplant. In

21 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com at least one study the patients’ management relapse rates were lower when they were managed within a unit with access to psychiatric services.

ALD, Psychopathology And Abstinence

The literature on alcoholism and relapse is enormous with a number of excellent criteria and screening procedures developed to try and predict a return to alcohol use. Globally there is an accepted protocol that a person must have a minimum of six months of alcohol abstinence prior to liver transplant. Patients who can maintain this six-month abstinence have been reported to be at lower risk of alcohol use relapse than those who are abstinent for less than six months.

Unfortunately, this selection criterion has been highly criticized, because this method does not account for other factors that may influence alcoholic behavior. One of the strongest issues in the life of alcoholics are the psychosocial factors that influence and impact them. These are much more difficult to establish.

There is a real need in clinical trials to develop tools to assess the risks of post-transplant relapse of alcohol use beforehand. One such study took place between 2003 and 2015 with 102 individuals with ALD. The widely- accepted diagnosis of ALD is based on a history of habitual and excessive consumption of alcohol. In reviewing the patients’ records, pre-transplant levels of alcohol consumption were reviewed. The tool used was the High- Risk Alcoholism Relapse scale, developed following treatment of U.S., . It contains three items: duration of heavy drinking, usual number of drinks per day, and number of previous inpatient admissions for treatment of alcoholism. Each item is scored 0, 1, or 2, resulting in total possible scores ranging from 0 to 6; high scores, ranging from 3 to 6, have

22 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com been found to correlate positively with the risk of relapse. In this study, the key psychosocial factors identified were 1) the absence of psychiatric , except for alcohol-related mental disease, 2) adherence to medical treatment, 3) understanding of and agreeing to transplant and support by the patient’s family, 4) being employed or willing to work, and 5) having an HRAR score ≤ 2 points, indicating a lower risk of return to drinking.30

The psychopathology of ALD frequently includes denial, both by patients and their families. This makes it difficult and sometimes impossible to evaluate risks of alcohol relapse following an initial interview with ALD patients. One of the recommendations from the above study is that patients need re- evaluation for risk of alcohol relapse one month after their initial evaluation, with further re-evaluations required if the risk of alcohol relapse is great. Timely, repeated patient follow-up is important because it may reveal alcohol-related pathology within the family, including the patient's intentions and whether the family is supportive.

There should also be psychiatric or psychological follow-up. In addition to evaluation pre- and post-transplant, it has been determined that counseling may minimize the relapse of alcoholism after liver transplant. In the follow- up stage one out of seven relapsed and returned to heavy drinking after liver transplant. In this study, the rate of alcohol relapse was 14.3% and was lower than in previous studies.30

It is not the aim of sobriety programs is not simply abstention from alcohol or to tell people to stop drinking. People who cope with addiction require everyday life instruction to prevent a relapse after liver transplant. It is recommended that patients in liver transplant programs be introduced to a

23 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com self-help group such as Alcoholics Anonymous. Unfortunately, it is not unusual for people with ALD and their family members to strongly deny problems with alcohol, as denial is a psychological mechanism to exclude painful thoughts. A set of psychosocial evaluation criteria may be useful in assessing risk of alcohol relapse in patients with ALD who are candidates for liver transplant. This is likely to result in improvements in the selection of ALD patients for transplantation and may increase the liver transplant success rate.

Addiction Treatment

When a person seeks help for an issue of addiction there are various programs available to offer support and to intervene before further physical and psychological harm is done. Family and associations can be helpful facilitators and provide meaningful collateral information to clinicians involved in the treatment team planning in an addiction program. Available substance use counselors, social workers, and physicians often work collaboratively to develop addiction treatment plans for addicted patients.

Knowing the extent of alcohol use and possible combination with other harmful substances the person is taking should be included in the overall risk assessment. Suspected other substance use may initially be only one substance in addition to alcohol, but further investigation may reveal that the person is more than one other substance, such as prescription drugs. A list of clinicians prescribing for a patient in alcohol treatment is helpful, especially for patients who are elderly or disabled enough to be unable to provide a clear history. When an older person is suspected of use, the addiction treatment team will need to completely review those and list the different types of prescriptions used, including names, dosages, and times of use.

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It is important to note that the process of treatment may be slower for disabled or older individuals in an alcohol recovery program. The changes that are associated with aging, such as slowing of body processes and decreased sensory perception may make the process of overcoming addiction more complicated and extend the time of recovery. It is also important for clinicians to be aware of the cognitive changes that can occur with prolonged alcohol use when making decisions on for the treatment plan. It may be necessary to develop a treatment program and education for those with cognitive changes in a way that reinforces teaching topics in repetitive and calming methods. The following discussion highlights both the inpatient and outpatient venue for alcohol recovery treatment and progress.63-66

Inpatient Programs

Inpatient programs are designed for more intensive treatment of drug and alcohol use. Patients in recovery may need treatment at an inpatient program if not improving in outpatient therapy, including attempts at counseling or outpatient rehabilitation in the past. Some patients experience severe symptoms of withdrawal, including associated with alcohol withdrawal. In these cases, inpatient treatment is also warranted to protect the patient’s health until he or she reaches a more stable state.

Inpatient is a process of assisting a patient during a period of alcohol withdrawal. The patient is admitted to a hospital or detoxification center and monitored closely during the period of withdrawal. Clinicians caring for a patient undergoing withdrawal and detoxification must monitor and intervene to treat patient symptoms as the body goes through withdrawal, as well as attend to the emotional and psychological state of

25 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com patients experiencing intense feelings of grief, anger, frustration, and . When caring for individuals in an inpatient detoxification program, clinicians also need to provide care for chronic medical conditions raised earlier, such as diabetes and cardiovascular disease.

When a patient is an inpatient at a detoxification center for withdrawal from alcohol, the clinician should focus interventions on providing a quiet environment that is safe for the patient. This may mean keeping the patient in an area that is not overstimulating, such as by keeping the lights low and minimizing outside noise. The patient may need precautions to avoid becoming injured during the acute phase of withdrawal. Another aspect of clinical care in an inpatient program may be to administer medications that will manage symptoms if the patient is going through withdrawal. This often means giving drugs as scheduled to minimize the effects of , hypertension, or agitation that can develop and to help the patient overcome the physical effects of withdrawal. Only after the physical effects have been managed can the patient begin to negotiate therapy and rehabilitation required to overcome addiction.

Inpatient rehabilitation is also an option that can provide addiction care for individuals who are past the point of detoxification, but who are still needing ongoing care to avoid relapsing into alcohol use. Inpatient programs are specialized facilities that have programs designed to provide psychological counseling and case management services for patients. Individuals may be admitted for care at an inpatient rehabilitation center for a period of 3 to 6 weeks, depending on the program available.

Rehabilitation programs may have different approaches to management of alcohol use; these often involve psychoeducation for the patient about the ill

26 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com effects of using as well as treatment for emotional or psychological effects of alcohol addiction. Psychoeducation refers to the education of a patient with a mental health condition to teach about the patient’s condition and to help the patient as well as family cope and manage the patient’s condition. The addicted person is often not only physically addicted to alcohol and possibly other substances when entering a treatment program, but also often needs psychological counseling to address the underlying reasons for using alcohol in the first place.

Several approaches are available for providing counseling and inpatient therapy, such as cognitive-behavioral therapy, which helps individuals to consider how their thoughts affect behavior; if patients can recognize how thoughts contribute to behavior, they may be able to change dysfunctional habits, such as turning to alcohol when feeling depressed. Psychological counseling helps patients to talk about their feelings of why they started using substances, but also for any other factors that may be causing feelings of shame, grief, or depression.

Group therapy may also be available, and often with others who are also residents of the rehabilitation center and who need counseling for their addiction. This allows patients to meet with others who may share similar problems. Group therapy with family members is an important part of healing for many people and their loved ones. Facilitated by a staff member, allows patients and family members to meet together to talk about how addiction has impacted their lives, as well as to arrive at solutions for how they can relate to each other in the future without using alcohol.

The amount of time that a person spends in inpatient treatment varies, depending on the type of program and the point at which the patient is

27 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ready to be discharged to home. A case manager can work with the patient throughout the time of inpatient hospitalization to set goals for treatment and to develop plans for continuing care after discharge. The case manager can provide discharge-planning right from the start so that the patient is ready to be discharged back to home after meet goals of treatment. For older or disabled patients, they should not be dismissed from the facility until resources and help for continuing care have been arranged after returning home. This may mean referrals to outpatient programs for counseling, recommendations for Alcoholics Anonymous, or standing appointments for home care to follow up and check in with the patient after discharge.

Outpatient Programs

The patient with a alcohol use problem may be able to undergo therapy with a trained counselor who specializes in alcohol use in the community. This can take place in such locations as a community center, outpatient rehabilitation center, or a private counseling office. The purpose of one-to- one counseling is to give the patient time to talk with a therapist about alcohol use and having an addiction problem, the reasons for why a problem had developed, and what can be done to cut back or completely eliminate using alcohol.

Brief intervention strategies describe situations that involve meeting with the patient to provide psychoeducation. These are often suitable interventions that involve motivational interviewing to promote change in the patient, which can be effective as part of outpatient treatment. Psychoeducation may be offered in counseling sessions with the patient and family to discuss methods of cutting back on alcohol consumption and to talk about its effects. These sessions are opportunities to further provide a plan for abstinence or

28 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com at least an appropriate use of prescription drugs and alcohol, with guidelines for combating triggers that may cause the patient to slip in behavior and go back to old patterns of substance use. Bogunovic had showed that between 10 and 30 percent of adults who were older and that struggled with alcohol throughout life were able to reduce their drinking after 1 to 3 sessions of psychoeducation.66

Alcoholics Anonymous may be options for some patients as part of outpatient therapeutic treatment. While some people may cringe at the idea of attending such a meeting, these groups are made up of people of all ages and backgrounds. Joining a group such as AA may foster new friendships with others that can help a person with . These groups provide a sense of support and help during times when it may be difficult to stop using alcohol. If the person is drinking more because of loneliness or isolation, a group such as NA can also provide a social outlet and more contact with others, particularly with those who are also experiencing struggles with stopping use.

Some outpatient programs are more intensive than occasional counseling or therapy sessions. These programs may require a greater commitment from the patient, many appointments with a therapist, and dedicated time at group sessions, such as by attending AA meetings. Intensive outpatient programs often consist of the patient participating in alcohol use rehabilitation for several hours each day; for instance, a patient may live at home, but may spend the majority of the day at a treatment center for intensive therapy and then return home in the evening. The benefit of using an outpatient program for treatment of substance use is that the patient can still live at home and continue to see family and friends while attending treatment sessions.

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Group therapy may be provided as part of outpatient programs. Similar to such settings as AA, group therapy is a chance to meet and talk with others who also struggle with alcohol or other substance use problems. Group therapy provided as part of outpatient drug or a trained counselor, who can lead discussions and foster conversations between group members, may facilitate alcohol rehabilitation. Patients may feel more comfortable meeting in a group of other patients who are also older adults and who struggle with similar problems and may be more likely to attend group sessions and comply with the treatment regimen.

Clinicians who prescribe outpatient treatment must consider the practical aspects of providing care to patients with disabilities. For example, an older adult who has difficulty with mobility or who lacks transportation may not be the best candidate for meetings at various locations scheduled several times per week. The potential barriers associated with disabled patients who require addiction therapy should be weighed against the benefits of using outpatient versus inpatient treatment.

Medical and Pharmacological Intervention

Medical intervention, often through administration of medications, may be given as part of detoxification protocol to protect the safety of the patient who is experiencing withdrawal symptoms. These are briefly reviewed here for the clinician and/or therapist involved with patient care during acute phases of detoxification.58-64

Traditionally, abstaining from alcohol was the only method of recovery for the patient with an alcohol use disorder; when undergoing detoxification and recovery, the patient stopped using the substance of addiction and slowly

30 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com and painfully recovered, if at all. Research now indicates that administering certain medications during recovery provides better neurological stabilization for the affected patient and is a much safer approach to care. Because multiple substances are often part of the clinical picture, and not just alcohol use, the common medical treatments that may be encountered are covered.

A patient who is going through alcohol withdrawal can have debilitating symptoms that require appropriate treatment to avoid critical complications, such as or . Alcohol withdrawal symptoms start to develop within 4 to 12 hours of the last drink, but they tend to worsen with time to the point that they peak in severity between 48 and 72 hours after stopping alcohol intake.

Medications used as intervention for the treatment of a are most effective when supported by counseling or intensive therapy as part of a recovery program. Because acute withdrawal symptoms can be dangerous or life threatening, detoxification is best performed in an inpatient setting where patients can be closely monitored and given medications that prevent seizures and other complications of withdrawal.

Benzodiazepines

The initial period may result in delirium tremens, which can cause , disorientation, tremor, fever, tachycardia, and hypertension. The patient may experience nausea, vomiting, sweating, hallucinations, and seizures. Because of the severity of these symptoms, initial treatment for delirium tremens is administration of , which provide a effect. Patients should be given short-acting benzodiazepines with dosages adjusted for age and condition. Elderly patients may have a slower process of metabolizing and excreting drugs in

31 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com the body, and dose adjustments are important in this age group. Examples of drugs to consider for acute withdrawal symptoms include and . Naltrexone and Acamprosate

As the addicted patient continues through the process of recovery, other medications may also be given to combat cravings for alcohol or drugs. These medications are designed for use over a longer period of time after the patient has come through the initial stages of acute withdrawal and is receiving ongoing care. Naltrexone is an antagonist that may be given for some patients who struggle with alcohol use. This type of drug has been approved for use in patients trying to overcome opioid addiction as well. Naltrexone has been shown to be safe to use among older patients with alcoholism, as well. Among patients who use Naltrexone for alcohol addiction, it reduces cravings for alcohol and decreases the risk of excess alcohol intake or . It is available as an oral tablet or as a monthly, extended-release injection.

The mechanism of how naltrexone works for alcohol addiction is not entirely clear. Because it is an , researchers believe that it impacts neurotransmitters in the brain that cause an addicted person to want to drink alcohol. Injectable, extended-release naltrexone was approved for management of alcohol addiction by the U.S. Food and Drug Administration in 2006. Additionally, naltrexone is also used for the management of drug addiction, specifically addiction to . Naltrexone binds to opioid receptors and blocks them, thereby blocking the effects of the drugs. It has also been shown to reduce cravings for opioids, which can decrease the risk of opioid addiction or relapse after the patient has stopped taking the drugs. It can be taken in tablet or injectable form for treatment and has been approved for treatment of opioid addiction by the U.S. FDA.

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Acamprosate has been shown to be effective in treating substance use and addiction disorders. It has been approved by the U.S. FDA for the management of alcohol addiction among people who have stopped drinking. It most likely reduces alcohol cravings by balancing neurotransmitters in the brain, which diminishes the desire for alcohol. Acamprosate can also be helpful for managing some other effects associated with alcohol withdrawal, such as anxiety, mood swings, and disturbances. The drug is typically administered as an oral tablet but it should be used carefully among patients who have kidney disease, and the dose may need to be modified in these situations. The patient who takes acamprosate must be compliant with the medication regimen, as it often requires several doses per day and takes at least 5 days to reach therapeutic levels in the body.

The administration of medications for the treatment of drug or alcohol addiction requires further intervention from the clinical staff than simply monitoring vital signs and laboratory levels and giving a patient medication. Clinicians who work with addicted patients must be cognizant of the negative emotional effects that substance use and recovery can have on the patient. Many patients feel shame and stigmatized by admitting that they have a problem with alcohol or drugs, and may also suffer from homeless, or lack family and social supports. Clinicians must recognize how difficult it can be for the patient to accept that he or she needs to take medication and receive treatment for substance use.

Psychotherapy During Recovery Process

A significant part of the safety and efficacy of using medications to treat substance use disorders is the concurrent use of therapy or counseling for the patient. While many medications are successful in reducing cravings for

33 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com alcohol or certain drugs, a patient is more likely to continue with taking medications and going through the recovery process when there are other supports in place. In addition to administering medication, clinicians caring for patients during rehabilitation will facilitate meetings and coordinate referrals for patients to attend group counseling or to talk about life outside of addiction as well as the effectiveness of medical therapy. A standard part of interventions when caring for patients with an addiction is to assess the effectiveness of all support given, including pharmacological factors and non- pharmacological interventions as well.

More of the literature emphasizes the effects of alcohol and an addiction disorder upon individuals as they age and across the lifespan. Life changes can be painful and challenging for individuals who may be faced with sudden periods of loneliness, isolation, or grief. As individuals begin to move at a slower pace, spend more time alone, and have fewer activities to do, adjustment to life changes are often very difficult in comparison to earlier times of feeling more vibrant and active. Some individuals are able to turn to more activities and become involved with others to fill their time and to find purpose in life, while others turn to using substances.

Because of the growing aging population worldwide, there are also growing numbers of individuals with alcohol and other substance use and addiction disorders. The harmful effects of alcohol addiction and medical comorbidities have become a growing burden as well on the health system. Whether through inpatient care, outpatient treatment, or ongoing counseling, combined medical and psychotherapeutic approaches providing support for individuals of all ages may help to reduce the biopsychosocial burden of alcohol use and addiction across the lifespan.

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Summary

Long-term alcohol use has been strongly connected to comorbid diseases and in the past few decades there has been a plethora of research related to patient education, treatments, disease management, and understanding the power of addiction in peoples’ lives. Alcohol-related cirrhosis is a major cause of this disease. The gold standard for treatment is abstinence as the first line therapeutic intervention. Nutritional therapy, medication therapy, and the role of steroids in patients with moderate to severe alcoholic hepatitis is gaining increasing acceptance.

A liver transplant is the standard treatment for severe cases but this treatment may be limited for patients who are alcoholics. Patients with alcoholic liver disease must agree to a term of sobriety in order to receive a donor liver. Relapsing episodes impacts the prognosis for a liver transplant patient. Maintaining abstinence is best supported by interdisciplinary approaches of medical and mental health care, such as ongoing counseling.

People who have been heavy drinkers for many years may have a great deal of difficulty in ending years of drinking alcohol on a regular basis. They may require time in an inpatient facility to obtain the support they need to stop drinking on a permanent basis. However, that might not be the end of their journey. For many people with ALD, there can be serious damage to their liver. In that case, even after they enter permanent sobriety, they will need to engage in further treatments.

35 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com Alcoholic liver disease and fatty liver disease have become serious healthcare issues that also connect to world-wide social and economic problems. The amount of money that has to be spent to provide care, the lost hours of work, and the emotional toll are enormous. While they have similar pathology, they differ from each other in many characteristics, ranging from differences in clinical features to patient outcomes. A comparison of these diseases may result in a better understanding and management of both ALD and fatty liver disease. In most people who drink excessive alcohol or eat excessively will develop a simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease.

The psychopathology of ALD frequently includes denial, both by patients and their families, complicating efforts to evaluate risks of alcohol relapse in ALD patients. Patients are recommended for re-evaluation of the risk of alcohol relapse following initial evaluation, with further re-evaluations required if the risk of alcohol relapse is great. Timely, patient is critical, including medical and psychiatric or psychological follow-up. Counseling may minimize the relapse of alcoholism, and is especially indicated in patients with alcoholic liver disease that have undergone extensive medical treatment and/or liver transplant.

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The References below include published works and in-text citations of published works that are intended as helpful material for your further reading. [References are for a multi-part series on .]

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