Title 4. ALCOHOLIC LIVER DISEASE.pdf ✅

PHARMD GURU Page 1 INTRODUCTION:  Alcoholic Liver Disease is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of alcohol.  The pathogenesis is not completely understood. Though alcoholic liver disease is most likely to occur in people who drink heavily over many years, the relationship between drinking and alcoholic liver disease is complex.  Not all heavy drinkers develop alcoholic liver disease, and the disease can occur in people who drink only moderately.  Patients who are severely affected present with sub-acute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (e.g., jaundice, coagulopathy), and manifestations of portal hypertension (e.g., ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic liver disease often do not cause any symptoms.  Alcoholic liver disease usually persists and progresses to cirrhosis if heavy alcohol use continues.  If alcohol use ceases, alcoholic liver disease resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis.  Of all chronic heavy drinkers, only 15–20% develops hepatitis or cirrhosis, which can occur concomitantly or in succession. ALCOHOLIC LIVER DISEASE
PHARMD GURU Page 2 EPIDEMIOLOGY: Alcohol abuse is the most common cause of serious liver disease in Western societies. The true prevalence of alcoholic liver disease, especially of its milder forms, is unknown, because patients may be asymptomatic and never seek medical attention. ETIOLOGY: Alcoholic liver disease occurs when the liver is damaged by the excessive consumption of alcohol. How alcohol damages the liver and why it does so only in a minority of heavy drinkers is not clear. It is known that the process of breaking down ethanol; the alcohol in beer, wine and liquor produces highly toxic chemicals, such as acetaldehyde. These chemicals trigger inflammation that destroys liver cells. Over time, web-like scars and small knots of tissue replace healthy liver tissue, interfering with the liver’s ability to function. This irreversible scarring, called cirrhosis, is the final stage of alcoholic liver disease. Heavy alcohol use can lead to liver disease, and the risk increases with the length of time and amount of alcohol drink. But because many people who drink heavily or binge drink never develop alcoholic liver disease or cirrhosis, it is likely that factors other than alcohol play a role. These include:  Other types of hepatitis: Long-term alcohol abuse worsens the liver damage caused by other types of hepatitis, especially hepatitis C.  Malnutrition: Many people who drink heavily are malnourished, either because they eat poorly or because alcohol and its toxic by-products prevent the body from properly absorbing and breaking down nutrients, especially protein, certain vitamins and fats. In both cases, the lack of nutrients contributes to liver cell damage.  Sex: Women have a higher risk of developing alcoholic liver disease than men do. This disparity may result from differences in the way alcohol is processed by women.  Genetic factors: A number of genetic mutations have been identified that affect the way alcohol is broken down in the body. Having one or more of these mutations may increase the risk of alcoholic liver disease.  Other factors which may increase risk include:
PHARMD GURU Page 3  Type of beverage (beer or spirits are riskier than wine)  Binge drinking  Obesity - Alcohol and obesity may have a synergistic effect on the liver; that is, their combined effect is worse than the effect of either of them alone. PATHOPHYSIOLOGY:
PHARMD GURU Page 4 Some signs and pathological changes in liver histology include:  Alcoholic liver disease is characterized by the inflammation of hepatocytes. Between 10% and 35% of heavy drinkers develop alcoholic liver disease. While development of hepatitis is not directly related to the dose of alcohol, some people seem more prone to this reaction than others. This is called alcoholic steato-necrosis and the inflammation appears to predispose to liver fibrosis. Inflammatory cytokines (TNF- alpha, IL6 and IL8) are thought to be essential in the initiation and perpetuation of liver injury by inducing apoptosis and necrosis. One possible mechanism for the increased activity of TNFalpha is the increased intestinal permeability due to liver disease. This facilitates the absorption of the gut-produced endotoxin into the portal circulation. The Kupffer cells of the liver then phagocytose endotoxin, stimulating the release of TNF-alpha. TNFalpha then triggers apoptotic pathways through the activation of caspases, resulting in cell death.  Mallory’s hyaline body: A condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.  Ballooning degeneration: Hepatocytes in the setting of alcoholic change often swell up with excess fat, water and protein; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby biliary ducts, leading to diffuse cholestasis.  Inflammation: Neutrophilic invasion is triggered by the necrotic changes and presence of cellular debris within the lobules. Ordinarily the amount of debris is removed by Kupffer cells, although in the setting of inflammation they become overloaded, allowing other white cells to spill into the parenchyma. Chronic liver disease also shows the conditions, such as fibrosis and cirrhosis.  Fibrosis: Fibrosis of the liver is excessive accumulation of scar tissue that results from ongoing inflammation and liver cell death that occurs in most types of chronic liver diseases. Nodules, an abnormal spherical areas of cells, form as dying liver cells are replaced by regenerating cells. This regeneration of cells causes the liver to become hard. Fibrosis refers to the accumulation of tough, fibrous scar tissue in the liver.