Alcoholic liver disease (ALD) is characterized by a fatty liver, hepatitis, fibrosis, and cirrhosis. Binge drinking is on the rise worldwide, and is particularly common in the U.S. A review of studies addressing the effects of binge drinking on the liver underscores the complex interactions among various immune, signaling pathways, epigenetic, and metabolic responses of the liver to binge drinking.
Results will be published in the April 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
“The liver is the main metabolic site in the body,” said Shivendra D. Shukla, Margaret Proctor Mulligan Professor at the University of Missouri, School of Medicine as well as corresponding author for the study. “It is involved in nutrient and drug metabolism and disposition, and in the production of a myriad of agents needed for the physiological functions of organs such as the heart, kidney, blood vessels, and brain. ALD-affected liver chemicals can also influence immunity, cardiovascular health, and coagulation. Thus, ALD can have a ‘domino effect’ on many organs.”
“The liver is also the major organ for alcohol metabolism, and as such, is the first line of defense against excessive alcohol consumption,” added Samir Zakhari, senior vice president in the Office of Science at Distilled Spirits Council of the United States. “The effects of binge drinking on the liver depend on whether binge drinking is superimposed on chronic heavy drinking, or is done on an empty stomach especially after a period of fasting or starvation.”
“Binge abuse is on the rise globally,” said Shukla. “For example, about 43 percent of college students have reported at least one binge episode during the previous months. It is therefore necessary to fully understand its consequences at molecular levels. This is the first review that highlights the molecular pharmacology of binge drinking and how this may offer insight into binge-induced injury and its wider implications.”
Some of the review’s key themes are:
- Binge consumption of alcohol is implicated in the pathophysiology of ALD. New studies from both experimental animals and humans indicate that binge drinking has profound effects on immunological, signaling, and epigenetic parameters of the liver. This is in addition to the known metabolic effects of acute levels of alcohol.
- “Chronic alcohol consumption renders the liver highly susceptible to binge-induced liver damage,” said Shukla. “Binge-induced liver injury impacts other organs as well, a view rather poorly appreciated by the public.”
- Binge drinking alters the levels of several cellular components and dramatically amplifies liver injury in the chronically alcohol-exposed liver.
“This review, the first of its kind, emphasizes the importance of molecular and epigenetic mechanisms in binge-induced liver injury,” said Shukla. “This review also sets the stage for additional investigations in this field. The cross-organ implications of binge-induced liver damage must be explored.”
“Binge drinking influences all the mechanisms mentioned above, but can also cause mitochondrial damage, which may result in cell death and disturbances in bioenergetics,” added Zakhari. “Therefore, people should not binge drink, especially on an empty stomach, and if they are chronic heavy drinkers, binge drinking will exacerbate liver injury, especially if comorbid conditions such as obesity, Hepatitis C, or HIV infection exist.”
The authors stress the importance of additional molecular investigations into the binge effects of alcohol for a better understanding of ALD. They also suggest that future research address the development of therapeutic strategies to control binge drinking.
“Our review highlights the effects of ALD on multiple molecules that in turn have effects on various organs,” said Shukla. “We hope this will encourage research and development of newer approaches and tools to control and ameliorate binge-induced health effects.”
According to the AASLD, roughly 2,000 Americans develop ALF-formally called fulminant hepatitis-each year, with many of these cases caused by acetaminophen (Tylenol) overdose, drug-induced liver injury, autoimmune liver disease, or viral hepatitis. Previous studies report patient survival from ALF was less than 15% before the era of liver transplantation and significantly better at more than 65% following transplantation.
LDLT-when a portion of a healthy liver from a living donor is used for transplantation-was developed as an alternative treatment option to overcome the shortage of deceased donor organs. A 2007 study by de Villa et al. found that LDLT accounts for less than 5% of liver transplants in the U.S. and Europe compared to more than 90% in Asia excluding mainland China.
“ALF is a rare, life-threatening condition where the rapid deterioration of liver function causes changes in mental activity and disrupts the body’s blood clotting capabilities,” explains lead author Dr. Yasuhiko Sugawara, Associate Professor in the Graduate School of Medicine at the University of Tokyo in Japan. “Expanding knowledge of treatment options, such as LDLT, that improve patient outcome is imperative.”
Using data from the Intractable Liver Disease Study Group of Japan, researchers identified 209 ALF candidates who underwent living donor liver transplantation. The authors report that in patients who underwent LDLT the cumulative one-year, five-year and ten-year survival rates following transplantation were 79%, 74%, 73%, respectively. Patient age impacted short-term and long-term mortality, while donor age only affected long-term patient mortality.
“Our study demonstrates the benefit of LDLT in a Japanese population, which has less access to deceased donor organs,” concludes Dr. Sugawara. “Prospective studies are needed to determine the overall impact of LDLT in all patients with ALF.”
In a related editorial also published in Liver Transplantation, Professor Chung-Mau Lo with the University of Hong Kong and Queen Mary Hospital in Hong Kong, China, notes that LDLT for ALF patients has generated debate among experts in several areas: (1) reports in Western countries of inferior outcome with LDLT in high-urgency situations; (2) likelihood of ALF patients receiving a liver in countries with developed deceased organ donation programs; and (3) concern with coercion of donors and a possible increase of donor risk when the evaluation process is rushed in such an urgent situation.
“Deceased donor liver transplantation is dictated by the availability of the organ, and high-risk marginal grafts are frequently used. LDLT allows for early transplant to avoid waitlist mortality and better timing of the operation, which can be performed at the first sign of patient deterioration,” concludes Professor Lo. “LDLT for ALF has developed in Asia because there is no choice. Is it possible that it may in fact be a better choice?”
The results of this study appear in the October 2006 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). Published by John Wiley & Sons, Inc., Hepatology is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/hepatology.
Patients with NAFLD, one of the most common causes of liver disease worldwide, often have elevated liver enzymes but no symptoms of the disease. Obesity has been established as a major risk factor for NAFLD and since it is reaching epidemic proportions worldwide, the number of people at risk for developing chronic liver disease is likely to increase in the future. Studies conducted on NAFLD to date have either had small numbers of patients or relatively short follow-up periods. The current study involved the largest reported number of NAFLD patients originally referred because of elevated liver enzymes and followed the patients for more than ten years.
Led by Stergios Kechagias, M.D. of the Division of Internal Medicine at University Hospital in Linkping, Sweden, the study involved 212 patients between 1988 and 1993 who had chronically elevated liver enzymes. All of the patients underwent liver biopsy, and only the 129 patients who had confirmed fatty liver without excessive alcohol consumption or other liver disease participated in the study. A total of 88 patients accepted follow-up at an average of almost 14 years from when they were diagnosed with NAFLD. Of these, 68 patients underwent repeat liver biopsy.
The results showed that NAFLD was found to be associated with a significant risk of developing end-stage liver disease and that death from liver-related causes and cardiovascular diseases was significantly more common in the 71 patients with NASH than in the general population. In addition, 78 percent of NAFLD patients were diagnosed with diabetes or impaired glucose tolerance at follow-up. “Given the strong association between insulin resistance and NAFLD it is reasonable to recommend lifestyle modifications in all patients with NAFLD,” the authors state. “Not only do lifestyle modifications reduce the risk of developing type 2 diabetes, intense dietary intervention may also improve liver histology in NAFLD.”
In an accompanying editorial in the same issue, Vlad Ratziu and Thierry Poynard of the Universite Pierre et Marie Curie and Assistance Publique-Hopitaux de Paris in Paris, highlight the widespread misconception that NAFLD in its various forms is largely considered to be a mild disease with a good prognosis. They note that NAFLD patients are usually not referred to hepatologists and the only way to accurately diagnose the disease (liver biopsy) is not practical as a screening tool for large populations. Nonetheless, NASH is an important cause of advanced liver disease and it is important to prevent its progression to cirrhosis because once liver failure occurs in these cases the outcome is often fatal. They note that the current study is important not only because of its long follow-up period, but because the authors were able to identify the outcome of different forms of NAFLD. “Remarkably, and possibly because of the longer follow-up, the authors were able to show that even patients without cirrhosis developed ESLD [end-stage liver disease], thus refuting the claim that non-cirrhotic NASH is ‘benign.'” They add that the study, along with previously published data, points to the necessity of studying the risk of increased cardiovascular deaths in NASH patients. They conclude that treating NASH is a “major unmet medical need,” and that strategies for screening patients with risk factors for liver disease, including obesity, diabetes and heart disease, should be developed.
In the UK, about 10% of the adult population have liver problems, mainly due to heavy drinking and obesity/overweight.
The liver has hepatic myofibrobrlasts, these are cells that create scar tissue when the organ is injured. Hepatic myofibrobrlasts produce proteins which makes it more difficult to break down the scar tissue. In a healthy liver the scars gradually disappear and new healthy ones replace them. This does not happen when the liver tissue is diseased – and the scar tissue spreads.
The scientists found that Sulphasalazine stops the hepatic myofibrobrlasts from producing the protein that protects the scar tissue cells. In other words, it helps the scar tissue to gradually melt away.
If human trials show similar results, it could mean treating and-stage patients with Sulphasalazine rather than having them undergo a liver transplant. The scientists say they will start trials with heavy drinkers who no longer drink, but whose livers are not able to recover on their own.
This drug could be a Godsend for alcoholics who have given up drinking. Even a seemingly small recovery of 10% can make a huge difference to the patient’s general health and quality of life, say the researchers.
The researchers say Sulphasalazine could halve the cirrhosis death rate in the UK. Treatment would cost �10 ($18.50) per week.
Some Facts About Cirrhosis
— Responsible for 1.4 million deaths per year worldwide
— Responsible for 5,000 – 10,000 deaths per year in the UK
— Early stages are symptom free (so damage accumulates unnoticed)
— There is currently no cure. The only end-stage treatment is a liver transplant
— Most common causes are Hepatitis C (globally) and excessive alcohol consumption (developed countries)
— Scotland has particularly high rates among developed countries
The study “Chronic alcohol ingestion renders the lung epithelium susceptible to acute injury by alteration in granulocyte-macrophage colony-stimulating factor signaling and alveolar epithelial permeability,” was carried out by David Guidot, Pratibha Joshi, Jesse Roman, Lou Ann Brown and Michael Koval of Emory University in Atlanta. Guidot and Joshi are also associated with the Veterans Affairs Medical Center in Atlanta.
“We’re trying to understand what’s happening with the alcoholic lung at the molecular level,” said Koval, who presented the findings at The American Physiological Society lung disease conference on Nov. 2-5 in Fort Lauderdale.
Beyond the liver
Although chronic alcohol abuse is closely associated with liver disease, the condition affects many of the body’s organs. In recent years, researchers have turned their attention to the ‘alcoholic lung.’
Alcoholics are more susceptible to pneumonia and more than twice as likely to develop ARDS compared to non-alcoholics, Koval said. The alcoholic lung has been found to have lower levels of glutathione, an antioxidant that helps protect the lung from oxidative stress.
The Emory research team has found that alcohol disrupts claudins, a family of proteins that helps maintain a tight air-fluid barrier. This barrier allows air into the lung, while keeping blood and other potentially smothering fluids out.
When the claudin proteins are disrupted, the lung leaks more, the researchers have found. The lung can usually pump out this excess fluid, but when the lung suffers an injury or infection it is unable to handle the greater volume, Koval explained. And that’s when pneumonia or ARDS may develop.
The researchers also previously found that the alcoholic lung has fewer granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors and a dampened response to signaling by GM-CSF in the epithelial cells, which form the lining inside the lung. GM-CSF is a hormone that plays a role in immunity within the lung.
The researchers keyed into GM-CSF after a clinical study found that GM-CSF treatment appeared to decrease acute lung injury in patients with septic shock. They have found that lung epithelial cells depend on GM-CSF signaling to maintain the tight barrier that is critical for gas exchange. They have also found that the air-fluid barrier is enhanced when the alcoholic lung is treated with GM-CSF.
GM-CSF connection strengthened
With these findings in mind, the researchers fed rats an alcohol-containing liquid diet for six weeks to mimic chronic alcohol abuse. They then applied GM-CSF to epithelial cells impaired by the rats’ alcohol ingestion. They found that GM-CSF restores claudin protein function and the cells’ air-fluid barrier function improved. These findings complement their recently published study showing that this same GM-CSF treatment restores immune function in alcohol-fed rats.
“These findings suggest that alcohol abuse dampens GM-CSF signaling, which, in turn, contributes to the alcoholic lung phenotype and renders the lung susceptible to edematous injury,” the authors wrote. Treating lung epithelial cells with GM-CSF can reverse the deleterious effects of alcohol, the authors concluded. “GM-CSF treatment, in part by restoring tight junction protein assembly, may decrease the risk of acute lung injury in susceptible patients.”
These results are sufficiently intriguing that a clinical study in which ARDS patients are being treated with GM-CSF is now taking place, Koval said. An important next step is to understand how different elements of the lung respond to GM-CSF at the molecular level, to better optimize treatment of alcoholic lung disease.
The research was funded by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health.
The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has 10,500 members and publishes 14 peer-reviewed journals containing almost 4,000 articles annually.
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Contact: Christine Guilfoy
What is the liver?
The liver is the largest gland in the human body. It weighs approximately 3 lb (1.36 kg). It is reddish brown in color and is divided into four lobes of different sizes and lengths. It is also the largest internal organ (the largest organ is the skin). It is below the diaphragm on the right in the thoracic region of the abdomen. Blood reaches the liver through the hepatic artery and the portal vein. The portal vein carries blood containing digested food from the small intestine, while the hepatic artery carries oxygen-rich blood from the aorta.
The liver is made up of thousands of lobules, each lobule consists of many hepatic cells – hepatic cells are the basic metabolic cells of the liver.
The liver has a wide range of functions, including:
- Detoxification (filters harmful substances form the blood, such as alcohol)
- Stores vitamins A, D, K and B12 (also stores minerals)
- Protein synthesis (makes certain amino acids – the building blocks of proteins)
- The production of biochemicals needed for digestion, such as bile
- Maintains proper levels of glucose in the blood
- Produces 80% of your body’s cholesterol (cholesterol is vital)
- The storage glycogen (also converts glucose to glycogen)
- Decomposing red blood cells
- Synthesizing plasma protein
- The production of hormones
- Produces urea (the main substance of urine)
Hepatitis can heal on its own with no significant consequence, or it can progress to scarring of the liver. Acute hepatitis lasts under six months, while chronic hepatitis lasts longer.
Most liver damage is caused by 3 hepatitis viruses, called hepatitis A, B and C. However, hepatitis can also be caused by alcohol and some other toxins and infections, as well as from our own autoimmune process (the body attacks itself).
About 250 million people globally are thought to be affected by hepatitis C, while 300 million people are thought to be carriers of hepatitis B.
Not all forms of hepatitis are infectious. Alcohol, medicines, and chemical may be bad for the liver and cause inflammation. A person may have a genetic problem, a metabolic disorder, or an immune related injury. Obesity can be a cause of liver damage which can lead to inflammation. These are known as non-infectious, because they cannot spread form person-to-person.
How many types of hepatitis are there?
There are five main types of hepatitis that are caused by a virus, A, B, C, D, and E – plus types X and G.
- Hepatitis A – this is caused by eating infected food or water. The food or water is infected with a virus called HAV (Hepatitis A Virus). Anal-oral contact during sex can also be a cause. Nearly everyone who develops Hepatitis A makes a full recovery – it does not lead to chronic disease.
- Hepatitis B – this is an STD (sexually transmitted disease). It is caused by the virus HBV (Hepatitis B Virus) and is spread by contact with infected blood, semen, and some other body fluids. You get Hepatitis B by:
- Unprotected sexual intercourse with an infected person (unprotected sex means without using a condom) Using a syringe that was previously used by an infected person (most commonly happens with drug addicts and people who inject steroids).
- Having your skin perforated with unsterilized needles, as might be the case when getting a tattoo, or being accidentally pricked. People who work in health care risk becoming infected by accident in this way. Sharing personal items, such as a toothbrush or razor, with an infected person.
- A baby can become infected through his mother’s milk if she is infected.
- Being bitten by someone who is infected.
The liver of a person infected with Hepatitis B swells. The patient can suffer serious liver damage due to infection, resulting in cancer. For some patients the hepatitis becomes chronic (very long-term or lifelong). Donated blood is always tested for Hepatitis B.
- Hepatitis C – Hepatitis C is usually spread through direct contact with the blood of a person who has the disease. It is caused by the virus HCV (Hepatitis C Virus). The liver can swell and become damaged. In hepatitis C, unlike hepatitis B, liver cancer risk is only increased in people with cirrhosis and only 20% of hep C patients get cirrhosis. Feces is never a route of transmission in hepatitis C. Donated blood is also tested for Hepatitis C.
- Hepatitis D – only a person who is already infected with Hepatitis B can become infected with Hepatitis D. It is caused by the virus HDV (Hepatitis D Virus). Infection is through contact with infected blood, unprotected sex, and perforation of the skin with infected needles. The liver of a person with Hepatitis D swells.
- Hepatitis E – a person can become infected by drinking water that contains HEV (Hepatitis E Virus). The liver swells but there is no long-term consequence. Infection is also possible through anal-oral sex.
- Hepatitis X – if a hepatitis cannot be attributed to the viruses of hepatitis A, B, C, D, or E, it is called Hepatitis X. In other words, hepatitis of an unknown virus.
- Hepatitis G – this is a type of hepatitis caused by the Hepatitis G virus (HGV). Usually there are no symptoms. When there are symptoms they are very mild.
What are the signs and symptoms of hepatitis?
Many people with Hepatitis experience either mild symptoms or none at all. Remember that an infected person’s feces are always infectious to other people. When symptoms appear, they usually do so about 15 to 180 days after the person has become infected.
The acute phase of hepatitis – symptoms
The initial phase of hepatitis is called the acute phase. The symptoms are like a mild flu, and may include:
- Loss of appetite
- Mild fever
- Muscle or joint aches
- Slight abdominal pain
- Weight loss
The acute phase is not usually dangerous, unless it develops into the fulminant or rapidly progressing form, which can lead to death.
As the patient gets worse, these symptoms may follow:
- Circulation problems (only toxic/drug-induced hepatitis)
- Dark urine
- Dizziness (only toxic/drug-induced hepatitis)
- Drowsiness (only toxic/drug-induced hepatitis)
- Enlarged spleen (only alcoholic hepatitis)
- Headache (only toxic/drug-induced hepatitis)
- Itchy skin
- Light colored feces, the feces may contain pus
- Yellow skin, whites of eyes, tongue (jaundice)
Patient outcomes after the acute phase depend on various factors, especially the type of hepatitis.
Treatments for hepatitis
- Hepatitis A – There is no treatment specifically for hepatitis A. Doctor will advise the patient to abstain from alcohol and drugs during the recovery. The vast majority of patients with Hepatitis A will recover spontaneously.
- Hepatitis B – A patient with Hepatitis B needs to rest. He will require a diet that is high in protein and carbohydrate – this is to repair damaged liver cells, as well as to protect the liver. If this is not enough, the doctor may prescribe interferon. Interferon is an antiviral agent.
- Hepatitis C – A patient with Hepatitis C will be prescribed pegylated interferon and ribavirin.
- Hepatitis D or E – So far, there is no effective treatment for either Hepatitis D or E.
- Non-Viral Hepatitis – If the patient has non-viral hepatitis, the doctor needs to remove the harmful substance. It will be flushed out of the stomach by hyperventilation or induced vomiting. Patients with drug-induced hepatitis may be prescribed corticosteroids.
How to prevent hepatitis
How to prevent Hepatitis A
- Wash your hands with soap after going to the toilet
- Only consume food that has just been cooked
- Only drink commercially bottled water, or boiled water if you unsure of local sanitation
- Only eat fruits that you can peel if you are somewhere where sanitation is unreliable
- Only eat raw vegetables if you are sure they have been cleaned/disinfected thoroughly
- Get a vaccine for Hepatitis A if you travel to places where hepatitis may be endemic
How to prevent Hepatitis B
- Tell the partner if you are a carrier or try to find out whether he/she is a carrier
- Practice safe sex
- Only use clean syringes that have not been used by anyone else
- Do not share toothbrushes, razors, or manicure instruments
- Have a Hepatitis B series of shots if you are at risk
- Only allow well sterilized skin perforating equipment (tattoo, acupuncture, etc.)
How to prevent Hepatitis C
- If you are infected do not let others share your toothbrush, razor, manicure equipment
- If you are infected cover open wounds
- Do not share needles, toothbrushes, or manicure equipment
- If your skin is to be pierced, make sure equipment is well sterilized (tattoo, etc.)
- Go easy on the alcohol
- Do not share drug equipment
How to prevent Hepatitis D
- Use the same guidelines as for Hepatitis B. Only a person who is infected with Hepatitis B can become infected with Hepatitis D.
How to prevent Hepatitis E
- Do the same as you would to protect yourself from Hepatitis A infection.
How to prevent Alcoholic Hepatitis
- Go easy on the alcohol, or abstain from consuming alcohol
How to prevent Toxic/Drug Induced Hepatitis
- Make sure you know about the lethal contents of all chemicals
- Make sure the spray is not pointing at you
- Make sure you wear protective gear if you have to