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\def\RunningAuthor{Sujana D. et al.}
\firstPage{2009}
\articleType{Review Article}
\receivedDate{01 Aug 2020}
\acceptedDate{09 Oct 2020}
\revisedDate{28 Sep 2020}
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\title{\textbf{A Review on Alcoholic Liver Disease}}
\author{Sujana~D\textsuperscript{*}\textsuperscript{1},  
            Sarathchandiran~I\textsuperscript{1}, 
            Kumar~B\textsuperscript{2}~\\[5pt]{\textsuperscript{1}Department of Pharmacy, Sri Balaji Vidypeeth University, Puducherry - 607403, Tamilnadu, India}~\\{\textsuperscript{2}Department of Pharmacy Practice, Ratnam Institute of Pharmacy, Nellore, Andhra Pradesh - 524346, India}}

\begin{abstract}
Alcoholic disorders affect millions of people worldwide. Alcohol consumption directly affects the liver, which causes morbidity and fatality and elucidates exalted social and economic worth. Alcohol liver disease (ALD) can cause acute liver disease (e.galcoholic hepatitis) or chronic/protracted liver disease (e.g. steatosis/ alcoholic hepatomegaly, steatohepatitis/alcoholic hepatitis, alcoholic fibrosis/ cirrhosis). The morbidity/fatality of alcoholic liver disease build upon the amounts, concentration and extent of alcohol intake, along with other co-factors, include a history of hepatic disease, improper diet and genetic and physiological predispositions of personnel. Alcoholic hepatomegaly is a reversible disease after abstinence of alcohol, and alcoholic liver cirrhosis is associates with morbidity and fatality. The average survival rate of patients with severe cirrhosis is up to 2 years. The common signs and symptoms are jaundice, right upper abdominal pain, fatigue, anorexia and arthritis. It can be diagnosed with patient history, signs and symptoms and imaging studies. It has been treated with corticosteroids, pentoxifylline, antioxidants, anti-emetics, and enteral nutrition. Complete self-restraint is the main treatment for acute/chronic ALD. Patients with severe alcoholic hepatic cirrhosis who completely self-restraint can be referred for liver transplantations, which markedly lengthened life expected period. The important step in the prevention of ALD is abstinence of overconsumption of alcohol, quit smoking, normal weight, while the prevention of liver damage in active alcohol over consumers is not clinically applicable.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Alcohol,\newline Alcohol liver disease,\newline hepatic cirrhosis,\newline Steatohepatitis,\newline Steatosis,\newline cirrhosis,\newline liver fibrosis,\newline corticosteroids,\newline pentoxifylline,\newline jaundice
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Sujana~D~\\ Phone:\ ~\\  Email:\ sujana.devireddy9@gmail.com
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\section{Introduction}
Alcohol/ethanol is a clear, volatile liquid that burns easily. It has a slight characteristic odour that is easily soluble in water. Alcohol is an organic compound consist of carbon, oxygen, hydrogen, and its chemical formula is C\ensuremath{_{2}}H\ensuremath{_{5}}OH. 

Pharmacology of alcohol is important for its presence in beverages alcoholism and for alcoholic intoxication. \unskip~\citep{1203705:23116467,1203705:23116465,1203705:23116454}

\textbf{Alcoholic beverages}

There are large varieties of alcoholic beverages.


  
  \begin{enumerate}
  \item \relax Malted liquors: - These are obtained by fermentation of germinating cereals. E.g. beers and stout
  \item \relax Wines: - It is produced by fermentation of natural sugars as present in grapes and other fruits.
  \end{enumerate}
  

\begin{itemize}
  \item \relax Light wines: claret, cider alcohol content 9-12\%, cannot exceed 15\%.
  \item \relax Fortified wines: port, sherry alcohol content is 16-22\%.
  \item \relax Effervescent wines: champagne alcohol content is 12-16\%.
\end{itemize}
  3. Spirits: - Gin, rum, brandy, vodka, whiskey etc. the alcohol content of these can vary from 40-55\%.

The taste, flavour and value of alcoholic beverages not only depends on alcohol content but also on the presence of higher alcohols, higher ether, esters, and aldehydes. Polymers and volatile oils. \unskip~\citep{1203705:23116463,1203705:23116472,1203705:23116451}

\textbf{Other forms of alcohol}


  
  \begin{enumerate}
  \item \relax Absolute alcohol:- 99\%w/w ethanol
  \item \relax Rectified spirit: - 90\%w/w ethanol produced from fermented molasses.
  \item \relax Proof spirit: - 100\% proof spirit is 49.29\%w/w or 57.1\%v/v alcohol.
  \end{enumerate}
  \textbf{Mechanism of action}

GABA release at GABA locations in the brain is increased by alcohol. It also inhibits excitatory amino acid receptors of the NMDA and kainite types. Ethanol can also block voltage-sensitive neuronal Ca channels, which can decrease neurotransmitter release indirectly. \unskip~\citep{1203705:23116467,1203705:23116452,1203705:23116459}

\textbf{Safe limits for alcohol intake}


  
  \begin{enumerate}
  \item \relax Males = 21 units per week (1 unit = glass or half pint)
  \item \relax Females = 14 units per week
  \end{enumerate}
  \textbf{Alcoholic liver disease}

The liver is one of the largest and complex organs in the human body, with several functions. These include detoxifies various metabolites, storing energy, synthesizes hormones or biochemical and proteins, and regulating cholesterol and blood sugar. \unskip~\citep{1203705:23116467,1203705:23116463,1203705:23116447}

It is a term that explains the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, cirrhosis. \unskip~\citep{1203705:23116462,1203705:23116453,1203705:23116465}  The major cause of it is drinking too much alcohol that is above the recommended limits. \unskip~\citep{1203705:23116457,1203705:23116468} There are also other factors that are used to increase the risk of liver disease along with alcohol, those include viral liver diseases, genetics and other hepatotoxins like drugs. \unskip~\citep{1203705:23116466,1203705:23116448}

According to the Centers for Disease Control and Prevention (CDC), there were 19,388 fatalities in the United States in 2014 owing to alcoholic liver disease and cirrhosis. In the United States in 2015, roughly 20\% of all liver transplants were due to alcoholic liver disease.

\textbf{Pathogenesis}

The absorption of Alcohol is easy from the lining of the stomach, but the small intestine will absorb most of the amount. The body cannot store alcohol. A little quantity will be degraded in traverse through the mucosa of the gut, but the max amount will be catabolized by the liver, by the enzyme alcohol dehydrogenase (ADH) and also by liver enzyme cytochrome P\ensuremath{_{450}} 2E1 (C\ensuremath{_{YP}}2E1), the microsomal enzyme oxidation systems (MEOS).

The aetiology of liver damage caused by alcohol use is unknown. Because the liver metabolises the majority of consumed alcohol, chronic alcohol consumption leads to the development of liver disease. 

Pathogenesis includes a variety of factors below,


  
  \begin{enumerate}
  \item \relax Alcohol metabolism variations 
  \item \relax Centrilobular hypoxia
  \item \relax Infiltration and activation of inflammatory cells 
  \item \relax Formation of antigenic adducts
  \end{enumerate}
  \textbf{Variation in alcohol metabolism}

Several pathways have been involved in the metabolism of alcohol \unskip~\citep{1203705:23116450,1203705:23116469,1203705:23116440}. The major pathway is by breaking ethanol into acetaldehyde by the enzyme alcohol dehydrogenase (ADH), and again it breaks down into acetate by the enzyme acetaldehyde dehydrogenase (ALDH). \unskip~\citep{1203705:23116467,1203705:23116458,1203705:23116465} Although genetic variability in both of these enzymes may cause variations in blood alcohol levels, it does not indicate the likelihood of developing liver disease. \unskip~\citep{1203705:23116439,1203705:23116455} When the alcohol concentration rises in the ADH pathway, the microsomal ethanol oxidising system (MEOS) and catalase are responsible for the majority of the oxidation. Chronic alcohol intake increases the expression of cytochrome p-450 2E1 (CYP2E1), an essential enzyme in MEOS. CYP2E1 polymorphisms are also seen, and they are linked to increased vulnerability to liver injury. \unskip~\citep{1203705:23116467,1203705:23116469,1203705:23116466}

\textbf{Centrilobular hypoxia}

The most common type of liver damage is protuberant in the zonal area surrounding the central vein. This region is the furthest from oxygenated blood and has the greatest CYP2E1 concertation. Injury is exacerbated by an oxygen deficit.

\textbf{Inflammatory cell infiltration and activation}

Pro-inflammatory cytokines and inflammatory cells are frequently detected in the blood and liver cells of alcoholic hepatitis patients. However, studies have focused on interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha), which both show an inverse relationship with illness prognosis. These mediators may play a role in damage by encouraging leucocyte adhesion. Alcohol-induced activation of Kupffer cells or macrophages in the liver might result in damage owing to the release of inflammatory and fibrogenic cytokines. Chronic alcohol intake increases intestinal permeability, allowing endotoxins to enter the portal bloodstream. Alcohol-primed kupffer cells may produce more cytokines and oxygen free radicals as a result of this.

\textbf{Antigenic adduct formation}

When ethanol is converted to acetaldehyde, hydroxyethyl free radicals are produced. \unskip~\citep{1203705:23116467,1203705:23116452} These radicals will attach to hepatic proteins, changing them and triggering an immunological response. Antibodies to these adducts have been detected in the serum of alcoholics. \unskip~\citep{1203705:23116459,1203705:23116442}

\textbf{Stages of Alcoholic Liver Disease}

The stages of alcoholic liver disease include four stages 

\textbf{Fatty liver}

Fatty liver is the initial stage of alcoholic liver disease, which is also known as steatosis. It is a highly prevalent stage of liver disease, which is mainly characterized by increased deposition of fat inside the liver cells. Heavy or abusive drinkers will get this fatty liver stage in the early alcoholic abuse stage; it can be reversible when alcohol is stopped.

\textbf{Alcoholic hepatitis}

It is the second stage of alcoholic liver disease, which is characterized by liver inflammation resulting in the degeneration or degradation of the hepatocytes. This stage generally lasts for some years and eventually progress to damage of the liver if the patient continues to take alcohol and treatment is not given in proper time. In severe cases, it leads to complications like liver cirrhosis and severe liver damage. The symptoms include Abdominal tenderness and pain, jaundice, nausea, vomiting, loss of appetite, anorexia, weakness, weight loss, fatigue.

\textbf{Fibrosis}

Fibrosis is a gradual accumulation of protein in the liver, including collagen. Mild to moderate forms of fibrosis may be reversible. Continuous fibrosis and inflammation are irreversible, and they may lead to liver cancer.

\textbf{Cirrhosis}

Cirrhosis is the last and final stage of alcoholic liver disease, and it causes the permanent scarring of healthy liver tissue. It is a severe and irreversible process. The symptoms in this stage include spleen enlargement, fluid accumulation in the abdomen, confusion, bleeding from veins. Figure~\ref{f-fb025e580b58}


\bgroup
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\centering \makeatletter\IfFileExists{images/59feebf7-19f1-4a0e-ae99-3084541fbbd1-upicture1.png}{\includegraphics{images/59feebf7-19f1-4a0e-ae99-3084541fbbd1-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Stages of alcoholic liver disease}}
\label{f-fb025e580b58}
\end{figure*}
\egroup
\textbf{Signs and symptoms}

Nausea, Loss of appetite, Jaundice, Fatigue, Increased thirst, Abdominal discomfort, Swelling in the legs and abdomen, Weight loss, Darkening or lightening of the skin, Red hands or feet, Dark bowel movements, Unusual agitation, Fainting, Mood swings, Confusion, Bleeding gums Enlarged breasts (in men) \unskip~\citep{1203705:23116451,1203705:23116456,1203705:23116459}

\textbf{Risk factors}

Daily intake of alcohol for 10{\textendash}12 years with doses in excess of 40{\textendash}80 g/day for males and of 20{\textendash}40 g/day for females, Genetic variations, Diet and nutrition, Infection with hepatitis C virus, Tobacco and coffee, female Gender, overconsumption of alcohol, Drinking without food, previous history of liver disease. \unskip~\citep{1203705:23116463,1203705:23116453,1203705:23116454}

\textbf{Complications}

Enlarged veins\textbf{, } Ascites\textbf{, } Hepatic encephalopathy\textbf{, } Kidney failure\textbf{, } Cirrhosis. \unskip~\citep{1203705:23116457}

\textbf{Diagnosis}

Signs and symptoms\textbf{, } Blood tests\textbf{ -}Liver function test (AST, ALT, Serum bilirubin), \ensuremath{\gamma }-Glutamyl transferase, Carbohydrate deficient transferrin, Bilirubin, Prothrombin time, Albumin, Serum fibrosis markers: procollagen III propeptide, laminin, type IV collagen, Ultrasound, Computed tomography (CT) scan of the liver, Magnetic resonance imaging (MRI) scan of the liver and Liver biopsy. \unskip~\citep{1203705:23116465,1203705:23116444}. 
    
\section{\textbf{Management}}
\textbf{Non-pharmacological treatment}

Avoid alcohol consumption, Treat comorbid diseases,\textbf{\space }Maintain mean body weight, quit smoking, maintain a balanced diet, Take nutrition and fluids

\textbf{Abstinence}

This may aid in the reversal of some early-stage liver damage. Stopping drinking after being diagnosed with fatty liver disease, for example, may be able to reverse the illness in 2 to 6 weeks. Because alcohol dependency can make quitting drinking more difficult, it's important to cut back on alcohol consumption gradually.

Those who frequently consume more alcohol than the suggested daily limit should seek medical help before quitting. Withdrawing from alcohol can be dangerous. To properly manage alcohol withdrawal, individuals should seek medical assistance.\textbf{\space }

In a person who is addicted to alcohol, cognitive behavioural therapy (CBT) and medicines such as benzodiazepines can be utilised to reduce withdrawal symptoms. People who are suffering from severe alcoholism may be admitted to an inpatient rehabilitation centre for closer supervision. \unskip~\citep{1203705:23116464,1203705:23116439} To avoid alcohol withdrawal symptoms, patients frequently require a lowering dosage of chlormethiazole or chlordiazepoxide. In extremely agitated patients, intravenous chlormethiazole is occasionally utilised, but only when careful cardiorespiratory monitoring is available. \unskip~\citep{1203705:23116441,1203705:23116468,1203705:23116445}

\textbf{Nutrition}

Oral supplementation may not be effective because of poor intake and compliance due to anorexia, dysgeusia, impaired absorption, and continued hypermetabolic states \unskip~\citep{1203705:23116451,1203705:23116452}. Enteral tube feedings have been shown to be helpful, well-tolerated, and may enhance hepatic system function. They may overcome the effects of anorexia and dysgeusia but not poor enteral absorption. In hepatic patients, a complete protein formula with 35-40 K calories of energy per day and 1.2-1.5 gm/Kg of protein per day is advised for enteral feeding. \unskip~\citep{1203705:23116454,1203705:23116441,1203705:23116469}

\textbf{Pharmacological treatment}

Corticosteroids are used to suppress the inflammatory cytokine production that causes the propagation of liver disease through chronic inflammation. Corticosteroids have been observed to suppress cytokine production, interfere with adduct formation, and inhibit collagen production, thereby reducing hepatocellular injury. Corticosteroids, primarily prednisolone, is one of the best therapies recommended by the American Association for the Study of Liver Disease and the European Association for the Study of the Liver. Mostly prednisolone is preferred over prednisone as prednisone requires hepatic conversion to the active form of prednisolone. \unskip~\citep{1203705:23116458,1203705:23116456} This conversion process may be decreased in patients with alcoholic hepatitis. The treatment course mostly consists of prednisolone 40 mg per day for 28 d, followed by a taper for 2 to 4 weeks. \unskip~\citep{1203705:23116449,1203705:23116439,1203705:23116448}

Because of its favourable safety profile and the absence of other alternatives to corticosteroids, pentoxifylline has been recommended as an alternate therapy for individuals with severe alcoholic hepatitis. The evidence for using pentoxifylline, on the other hand, is poor. \unskip~\citep{1203705:23116462,1203705:23116465,1203705:23116439}  Pentoxifylline works by changing gene transcription to decrease the generation of TNF- (which is elevated in alcoholic hepatitis). Orally, 400 mg pentoxifylline three times a day. \unskip~\citep{1203705:23116446,1203705:23116443,1203705:23116469}

Anti-TNF-antibodies were thought to be one of the most promising therapy for alcoholic hepatitis. \unskip~\citep{1203705:23116462,1203705:23116456,1203705:23116457} The cytokine's levels were linked to the severity of the disease in alcoholic hepatitis, while low levels were linked to liver regeneration. \unskip~\citep{1203705:23116450}

Antioxidants - Oxidative stress may also play an important role in the pathogenesis of ALD. Alcohol causes oxidative stress through a variety of mechanisms, including lipid peroxidation, the formation of reactive oxygen species, and the decrease of endogenous antioxidant capacity. Based on this, it has been theorized that high antioxidant therapy would improve outcomes in ALD. \unskip~\citep{1203705:23116462,1203705:23116465,1203705:23116459}

Vitamin B deficiency, in particular, thiamine, folate, pyridoxine, and riboflavin, is very common in ALD. \unskip~\citep{1203705:23116442,1203705:23116461} Because of poor absorption of oral preparations in the stomach owing to alcoholism and malnutrition, parenteral vitamin B therapy is preferable. 

Because it eliminates the ethanol-induced increase in liver oxygen consumption that occurs after long-term ethanol administration, propylthiouracil has been utilised as a therapy for ALD. Propylthiouracil (300 mg daily) will lower the death rate in patients with chronic liver disease. 

Malotilate has been proposed in the treatment of ALD because it will inhibit CYP2E1 production by alcohol consumption.  

S-adenosyl-L-methionine is a dietary supplement that has been used to treat ALD by restoring glutathione levels in the liver mitochondria. Ethanol extracts the glutathione pool in the mitochondria, causing a deficit in glutathione transport from the cytosol to the mitochondria. 10, 19, and 27. By boosting the production of reactive oxygen species inside hepatocyte mitochondria, it makes ethanol-fed hepatocytes more vulnerable to the lethal effects of inflammatory cytokines like IL and TNF-\ensuremath{\alpha }. 

Saturated fatty acids are also protective against ALD. Polyunsaturated fatty acids potentiate alcohol-induced liver injury by inducing cytochrome\textit{ P}-450 2E1. Fatty acid saturation decreases CYP2E1 activity and lipid peroxidation.  

Oxandrolone has been utilised for a long time because of its anabolic properties (increased nitrogen balance) and potential to speed up the reversal of fatty liver in ALD patients. It has only been demonstrated to help patients with mild to severe illness. 

Because it may restore phosphatidylcholine levels and prevent fibrosis in baboons given alcohol, soya bean lecithin is also utilised in therapy. \unskip~\citep{1203705:23116461,1203705:23116460,1203705:23116469}

\textbf{Liver (hepatic) transplantation (LT)} \textbf{\space }

Liver transplantation will be the final management of choice of end-stage liver disease patients that is cirrhosis, and it will be the only option of their survival. LT for ALD has been a controversial situation due to the continuously increasing demand for organ donors and the inadequate possibility of organ donation, which is collaborating with the matter that persons with severe alcohol consumption might get a relapse, further deterioration of the already transplanted liver. Hepatic transplantation is usually only considered for those who have totally stopped drinking for at least six months before the procedure and who have healthy other organ systems enough to withstand surgery. Liver transplantation is a difficult procedure that requires the availability of a suitable donor. Following transplantation, immune suppressant medications will be administered, which might increase the risk of severe infections and cancer. \unskip~\citep{1203705:23116463,1203705:23116462,1203705:23116471}
    
\section{Conclusion }
Alcohol is an organic compound, most of the amount metabolised by the liver and causes toxicity to the liver. Alcoholic liver disease is caused by overconsumption of alcohol for years. The most common symptoms of ALD are jaundice and tremors. ALD occurs in 3 stages, and those are alcoholic steatosis, steatohepatitis, progressive fibrosis and alcoholic cirrhosis. Most of the Deaths of alcohol consumption due to ALD (alcoholic cirrhosis) Treatment options include lifestyle changes, medications (example. Hepato protectors, pentoxifylline and corticosteroids), and surgery.
\section*{Acknowledgement}The authors are grateful to the authorities of the university and faculty. 

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.
    

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