ALCOHOL RELATED DISEASES. DISCUSS THERAPY OF ALCOHOL DEPENDENCE

1. ALCOHOL RELATED DISEASES.DISCUSS THERAPY OF ALCOHOL DEPENDENCE Presented by Dr. ChandanBansal Moderator : Raveesha A

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5. Introduction • Ethanol is a weakly charged molecule that moves easily through cell membranes, rapidly equilibrating between blood and tissues. • The level of alcohol in the blood is expressed as milligrams or grams of ethanol per deciliter (e.g., 100 mg/dLor 0.10 g/dL), • In round figures, 340 mL of beer, 115 mL of non fortified wine, and 43 mLwhisky, gin, or vodka each contain ~10–15 g of ethanol. • The ethanol content of different alcoholic beverages varies with spirits such as whisky, brandy ram and gin, and distilled liquors such as arrack containing 35-50% alcohol, wines about 12% alcohol and beers ordinarily contain 4 - 5% alcohol. The higher the alcoholic content of the beverage, higher is the blood alcohol concentration (BAC).

6. Contd… • These beverages also have additional components, called congeners, that affect the taste and effects. • Congeners include low-molecular-weight alcohols (e.g., methanol and butanol), aldehydes, esters, histamine, phenols, tannins, iron, lead, and cobalt. Such congeners might also contribute to the adverse health consequences associated with heavy drinking. • Lifetime prevalence rates for alcohol use in the general population in India vary from 24- 74% among males and from 10-58% among students.

7. Contd… • One standard unit is equal to 30 ml of spirits, 60 ml of wine or half a bottle of beer. Each standard drink is equal to about 10 gm of ethanol. • It takes approximately one hour for one unit of alcohol to be completely metabolised by the body. • Blood alcohol peaks 30 to 60 minutes after consumption on an empty stomach. • While absorption patterns are similar, higher blood alcohol levels are achieved for the same dose in women (lesser body water), and persons with a higher fat content. • The legal limit for drink driving in India is 30 mg/dl (one bottle of beer or two small pegs of whisky consumed within an hour is likely to produce a BAC above the legal limit).

8. Pharmacokinetics ABSORBTION • Alcohol is absorbed from mucous membranes of the mouth and esophagus (in small amounts), from the stomach and large bowel (in modest amounts), and from the proximal portion of the small intestine (the major site). • The rate of absorption is increased by rapid gastric emptying (as can be induced by carbonated beverages); by the absence of proteins, fats, or carbohydrates (which interfere with absorption); by the absence of congeners; and by dilution to a modest percentage of ethanol (maximum at ~20% by volume).

9. Contd… • EXCRETION • Between 2% (at low blood alcohol concentrations) and 10% (at high blood alcohol concentrations) of ethanol is excreted directly through the lungs, urine, or sweat, but the greater part is metabolized to acetaldehyde, primarily in the liver. • METABOLISM • The most important pathway occurs in the cell cytosol where alcohol dehydrogenase(ADH) produces acetaldehyde, which is then rapidly destroyed by aldehydedehydrogenase(ALDH) in the cytosol and mitochondria . • A second pathway in the microsomes of the smooth endoplasmic reticulum (the microsomal ethanol-oxidizing system, or MEOS), is responsible for 20% of ethanol oxidation at high blood alcohol concentrations.

11. Nutritional and Metabolic Effects • While 1 gm of ethanol can provide 7.1 k calories of energy, these are 'empty calories', devoid of nutrients such as proteins, minerals and vitamins. • Common vitamin deficiencies associated with alcohol abuse include deficiency of thiamine (Beriberi or Wernicke-Korsakoff's syndrome), Niacin (pellagra), pyridoxine (peripheral neuropathy), folate and vitamin A deficiencies. • It also produces metabolic disturbances including hypoglycaemia, ketoacidosis, hypocalcaemia, hypophosphataemia and hypomagnesaemia.

12. Receptors involved • The intoxicating effects of alcohol reflect the actions of this drug on a wide range of neurotransmitters, receptors, and transporters. Most prominently, alcohol acutely enhances actions at -aminobutyric acid A (GABAA) receptors and inhibits N-methyl-D-aspartate(NMDA) receptors. • There are also effects on adenosine, with an inhibition of uptake of this transmitter, and a translocation of the cyclic AMP–dependent protein kinase catalytic subunit from the cytoplasm to the nucleus. • Alcohol also affects opioid systems and cannabinolreceptors, enhances activity of the dopamine-rich reward system, increases serotonin actions, and directly or indirectly affects most other neurochemical systems

13. Tolerance • Tolerance is a complex phenomenon involving at least three types of compensatory mechanisms. • After 1–2 weeks of daily drinking, metabolic or pharmacokinetic tolerancecan be seen. This alteration disappears almost as rapidly as it develops. • Cellular or pharmacodynamic tolerancedevelops through neurochemical changes that maintain relatively normal physiologic functioning despite the presence of alcohol. Subsequent decreases in blood levels contribute to symptoms of withdrawal. • Individuals learn to adapt their behavior so that they can function better than expected under influence of the drug (behavioral tolerance). • The resulting withdrawal syndrome is most intense during the first 5 days, but some symptoms (e.g., disturbed sleep and anxiety) can take up to 4–6 months to resolve.

15. The Effects of Ethanol on Organ Systems

16. Nervous System • Approximately 35% of drinkers experience a blackout, an episode of temporary anterograde amnesia, in which the person forgets all or part of what occurred during a drinking evening. • Although alcohol might initially help a person to fall asleep, it disrupts sleepthroughout the rest of the night. • The stages of sleep are also altered, and time spent in rapid eye movement (REM) and deep sleep is reduced. • Alcohol relaxes muscles in the pharynx, which can cause snoring and exacerbate sleep apnea; symptoms of the latter occur in 75% of alcoholic men over age 60. • Another common consequence of alcohol use is impaired judgment and coordination,increasing the risk of accidents and injury.

17. Contd… • Heavy drinking can also be associated with headache, thirst, nausea, vomiting, and fatigue the following day, a hangover syndromethat is responsible for significant financial losses in most work environments. • Peripheral neuropathy occurs in about 5-15% of chronic alcohol abusers and can be the consequence of dietary thiamine and other vitamin deficiencies. A glove and stocking distribution of tingling and numbness and paraesthesia is common. Polyneuropathies(sensory, motor and autonomic components being involved) are most common, but mononeuropathiescan also occur due to pressure symptoms (the classical 'Saturday night palsy').

18. Wernicke’skorsakoff’s syndrome • very few alcoholics (perhaps as few as 1 in 500) develop Wernicke's(ophthalmoparesis, ataxia, and encephalopathy) and Korsakoff's(retrograde and anterograde amnesia) syndromes • These occur as the result of thiamine deficiency, especially in predisposed individuals, e.g., those with transketolase deficiency. • Acute glucose load must therefore be avoided in alcoholic patients as this can deplete thiamine stores and precipitate Wernicke's syndrome. • Whenever necessary, glucose supplementation must be accompanied by thiamine supplementation.

19. Contd… CENTRAL PONTINE MYELINOSIS • It is a rare disorder occuring in alcoholics and a number of other disorders(liver, renal, metabolic disorders). It is characterised by rapid onset of flaccid or spastic quadriplagia with involvement of bulbar muscles(dysarthria, dysphagia). MARCHIAFAVA-BIGNAMI SYNDROME • It is described in italian drinkers of crude red wine and other alcoholics. It presents as a subacutedementing illness, and later progress rapidly to fits, rigidity, paralysis, coma and death. It is due to demyelination and axonal damage in the corpus callosum, cerebral white matter, optic chiasma and middle cerebellar peduncle. CEREBELLAR DEGENERATION OR ATROPHY. • Approximately 1% of alcoholics develop This is a syndrome of progressive unsteady stance and gait often accompanied by mild nystagmus; neuroimaging studies reveal atrophy of the cerebellarvermis.

20. PSYCHIATRIC PROBLEMS • As many as two-thirds of alcohol-dependent individuals may have psychiatric problems. • Half of these relate to a preexisting antisocial personality manifesting as impulsivity and disinhibition and conditions such as schizophrenia or manic depressive disease and anxiety disorders such as panic disorder. • Another common co-morbidity occurs with dependence on illicit substances. • Many psychiatric syndromes can be seen temporarily during heavy drinking and subsequent withdrawal . These include an intense sadnesslasting for days to weeks in the midst of heavy drinking seen in 40% of alcoholics (alcohol-induced mood disorder); • temporary severe anxietyin 10–30% of alcoholics, often beginning during alcohol withdrawal, and which can persist for a month or more after cessation of drinking (alcohol-induced anxiety disorder) • and auditory hallucinations and/or paranoid delusions in a person who is alert and oriented, seen in 3–5% of alcoholics (alcohol-induced psychotic disorder).

21. The Gastrointestinal System ESOPHAGUS AND STOMACH • Alcohol intake can result in inflammation of the esophagus and stomach causing epigastric distress and gastrointestinal bleeding • Alcohol is one of the most common causes of hemorrhagic gastritis. • Violent vomiting can produce severe bleeding through a Mallory-Weiss lesion, a longitudinal tear in the mucosa at the gastroesophageal junction. PANCREAS AND LIVER • The incidence of acute pancreatitis is almost threefold higher in alcoholics than in the general population. • Alcohol impairs gluconeogenesisin the liver, resulting in a fall in the amount of glucose produced from glycogen, increased lactate production, and decreased oxidation of fatty acids. This contributes to an increase in fat accumulation in liver cells.

22. Alcoholic Liver Disease

23. Introduction • Chronic and excessive alcohol ingestion is one of the major causes of liver disease. • The pathology of alcoholic liver disease comprises three major lesions, with the injury rarely existing in a pure form: (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. • Fatty liver is present in >90% chronic drinkers. A much smaller percentage of heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis. • Although alcohol is considered a direct hepatotoxin, only between 10 and 20% of alcoholics will develop alcoholic hepatitis. • The explanation for this apparent paradox is unclear but involves the complex interaction of facilitating and comorbid factors such as gender, heredity, and immunity.

24. Etiology and Pathogenesis • Quantity and duration of alcohol intake are the most important risk factors involved in the development of alcoholic liver disease . • Women are more susceptible to alcoholic liver injury when compared to men. They develop advanced liver disease with substantially less alcohol intake. • In general, the time it takes to develop liver disease is directly related to the amount of alcohol consumed. • The threshold for developing alcoholic liver disease in men is an intake of >60–80 g/d of alcohol for 10 years, while women are at increased risk for developing similar degrees of liver injury by consuming 20–40 g/d. • Ingestion of 160 g/d is associated with 25–fold increased risk of developing alcoholic cirrhosis.

25. Contd.. • Gender-dependent differences result from poorly understood effects of estrogen and the metabolism of alcohol. Social, immunologic, and heritable factors have all been postulated to play a part in the development of the pathogenic process. • Patients with both alcoholic liver injury and HCV infection develop decompensated liver disease at a younger age and have poorer overall survival. • Increased liver iron stores and, rarely, porphyriacutaneatardacan occur as a consequence of the overlapping injurious processes secondary to alcohol abuse and HCV infection. In addition, alcohol intake of >50 g/d by HCV-infected patients decreases the efficacy of interferon-based antiviral therapy.

26. Contd… • Alcohol is a direct hepatotoxin, but ingestion of alcohol initiates a variety of metabolic responses that influence the final hepatotoxic response. • The initial concept of malnutrition as the major pathogenic mechanism has been replaced by the understanding that the hepatic metabolism of alcohol initiates a pathogenic process involving production of toxic protein-aldehyde adducts, endotoxins, oxidative stress, immunologic activity, and pro-inflammatory cytokine release (Fig. 301-1). • Tumor necrosis factor (TNF-) and intestine-derived endotoxemia facilitate hepatocyte apoptosis and necrosis. Stellate cell activation and collagen production are key events in hepatic fibrogenesis. The resulting fibrosis determines the architectural derangement of the liver following chronic alcohol ingestion.

29. Fatty liver • Fatty liver is the initial and most common histologic response to hepatotoxic stimuli, including excessive alcohol ingestion. • The accumulation of fat within the perivenularhepatocytescoincides with the location of alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism. Continuing alcohol ingestion results in fat accumulation throughout the entire hepatic lobule. • Despite extensive fatty change and distortion of the hepatocytes with macrovesicular fat, the cessation of drinking results in normalization of hepatic architecture and fat content within the liver. • Alcoholic fatty liver has traditionally been regarded as entirely benign, but similar to the spectrum of nonalcoholic fatty liver disease the appearance of steatohepatitis and certain pathologic features such as giant mitochondria, perivenular fibrosis, and macrovesicular fat may be associated with progressive liver injury.

30. Alchoholic hepatitis • The transition between fatty liver and the development of alcoholic hepatitis is blurred. • The hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and fibrosis in the perivenular and perisinusoidal space of Disse. • Alcoholic hepatitis is thought to be a precursor to the development of cirrhosis. • However, like fatty liver, it is potentially reversible with cessation of drinking. • Cirrhosis is present in up to 50% of patients with biopsy-proven alcoholic hepatitis and its regression is uncertain, even with abstention.

31. Alcoholic Cirrhosis • Excessive chronic alcohol use can cause several different types of chronic liver disease, including alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. • Furthermore, use of excessive alcohol can contribute to liver damage in patients with other liver diseases, such as hepatitis C, hemochromatosis, and those patients who have fatty liver disease related to obesity. • Chronic alcohol use can produce fibrosis in the absence of accompanying inflammation and/or necrosis. Fibrosis can be centrilobular, pericellular, or periportal. When fibrosis reaches a certain degree, there is disruption of the normal liver architecture and replacement of liver cells by regenerative nodules. • In alcoholic cirrhosis, the nodules are usually <3 mm in diameter; this form of cirrhosis is referred to as micronodular. • With cessation of alcohol use, larger nodules may form, resulting in a mixed micronodular and macronodular cirrhosis.

35. Clinical Features • Previously unsuspected hepatomegalyis often the only clinical finding. • Occasionally, patients with fatty liver will present with right upper quadrant discomfort, tender hepatomegaly, nausea, and jaundice. • Cytokine production is thought to be responsible for the systemic manifestations of alcoholic hepatitis. • Fever, spider nevi, jaundice, and abdominal pain simulating an acute abdomen represent the extreme end of the spectrum, while many patients will be entirely asymptomatic. • Portal hypertension, ascites, or variceal bleeding can occur in the absence of cirrhosis.

36. Laboratory Features • Patients with alcoholic liver disease are often identified through routine screening tests. • The typical laboratory abnormalities seen in fatty liver are nonspecific and include modest elevations of the aspartateaminotransferase(AST), alanineaminotransferase(ALT), and -glutamyltranspeptidase(GGTP), accompanied by hypertriglyceridemia, hypercholesterolemia, and occasionally hyperbilirubinemia. • In alcoholic hepatitis and in contrast to other causes of fatty liver, the AST and ALT are usually elevated two- to sevenfold. They are rarely >400 IU, and the AST/ALT ratio >1. • Hyperbilirubinemia is common and is accompanied by modest increases in the alkaline phosphatase level. • Derangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemia and coagulopathyare common in advanced liver injury. • Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size.

38. Prognosis • Critically ill patients with alcoholic hepatitis have short-term (30 day) mortality rates >50%. • Severe alcoholic hepatitis is heralded by coagulopathy (prothrombin time > 5 s), anemia, serum albumin concentrations < 2.5 mg/dL, serum bilirubin levels > 8 mg/dL, renal failure, and ascites. • A discriminant function calculated as 4.6 x [prothrombin time control (seconds)] + serum bilirubin (mg/dL) can identify patients with a poor prognosis (discriminant function > 32). • The presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal syndrome predicts a dismal prognosis. • The pathologic stage of the injury can be helpful in predicting prognosis. Liver biopsy should be performed whenever possible to confirm the diagnosis, to establish potential reversibility of the liver disease, and to guide the therapeutic decisions.

39. Treatment • Complete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. • Attention should be directed to the nutritional and psychosocial states during the evaluation and treatment periods. • Because of data suggesting that the pathogenic mechanisms in alcoholic hepatitis involve cytokine release and the perpetuation of injury by immunologic processes,glucocorticoids have been extensively evaluated in the treatment of alcoholic hepatitis. • Patients with severe alcoholic hepatitis, defined as a discriminant function > 32, were given prednisone, 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks followed by a steroid taper .

40. Contd… • Exclusion criteria included active gastrointestinal bleeding, sepsis, renal failure, or pancreatitis. Women with encephalopathy from severe alcoholic hepatitis may be particularly good candidates for glucocorticoids. • Newer understanding of the role of TNF- expression and receptor activity in alcoholic liver injury has led to an examination of TNF inhibition as an alternative to glucocorticoids for severe alcoholic hepatitis. The nonspecific TNF inhibitor, pentoxifylline, recently demonstrated improved survival in the therapy of severe alcoholic hepatitis .

41. Contd… • Preliminary trials of neutralizing monoclonal antibody specific for TNF have been disappointing because of increased deaths secondary to infection. • Because of inordinate surgical mortality and the high rates of recidivism following transplantation, patients with alcoholic hepatitis are not candidates for immediate liver transplantation. • The transplant candidacy of these patients should be reevaluated after a defined period of sobriety.

43. Hematopoietic System • Ethanol causes an increase in red blood cell size [mean corpuscular volume, (MCV)], which reflects its effects on stem cells. • Heavy drinking is accompanied by folic acid deficiency, there can also be hypersegmentedneutrophils, reticulocytopenia, and a hyperplastic bone marrow. • Chronic heavy drinking can decrease production of white blood cells, decrease granulocyte mobility and adherence, and impair delayed-hypersensitivity responses.(with a possible false-negative tuberculin skin test). • Many alcoholics have mild thrombocytopenia, which usually resolves within a week of abstinence unless there is hepatic cirrhosis or congestive splenomegaly.

44. Cardiovascular System • ACUTE EFFECTS • Ethanol decreases myocardial contractility and causes peripheral vasodilation, with a resulting mild decrease in blood pressure and a compensatory increase in cardiac output. • Exercise-induced increases in cardiac oxygen consumption are higher after alcohol intake. • These acute effects have little clinical significance for the average healthy drinker but can be problematic in men and women with pre existing cardiac disease. • CHRONIC EFFECTS. • The consumption of three or more drinks per day results in a dose-dependent increase in blood pressure, which returns to normal within weeks of abstinence. • Chronic heavy drinkers have a sixfoldincreased risk for coronary artery disease as well as an increased risk for cardiomyopathy.

45. Contd… • Symptomsrange from unexplained arrhythmias in the presence of left ventricular impairment to heart failure with dilation of all four heart chambers and hypocontractility of heart muscle. • Perhaps one-third of cases of cardiomyopathy are alcohol-induced. • Mural thrombi can form in the left atrium or ventricle, while heart enlargement >25% can cause mitral regurgitation • Atrial or ventricular arrhythmias, especially paroxysmal tachycardia, can also occur after a drinking binge in individuals showing no other evidence of heart disease—a syndrome known as the "holiday heart." This condition is observed transiently in the majority of alcoholics entering treatment.

46. BENEFITS FOR CARDIOVASCULAR SYSTEM • A maximum of one to two drinks per day may decrease the risk for cardiovascular death, perhaps through an increase in high-density lipoprotein (HDL) cholesterol or changes in clotting mechanisms. • In one large national study, cardiovascular mortality was reduced by 30–40% among individuals reporting one or more drinks daily compared to nondrinkers, with overall mortality lowest among those consuming approximately one drink per day. • Recent data have also corroborated that regular light drinking decreases the risk for ischemic, but not hemorrhagic, stroke.

47. Genitourinary System & Sexual Functioning. MEN • Acutely, modest ethanol doses (e.g., blood alcohol concentrations of 0.06 gm/dL) can increase sexual drive but also decrease erectile capacity in men. • Even in the absence of liver impairment, a significant minority of chronic alcoholic men show irreversible testicular atrophy with shrinkage of the seminiferous tubules, decreases in ejaculate volume, and a lower sperm count . WOMEN • The repeated ingestion of high doses of ethanol by women can result in amenorrhea,a decrease in ovarian size, absence of corpora lutea with associated infertility, and an increased risk of spontaneous abortion.

48. Pregnancy and alcohol • Heavy drinking during pregnancy results in the rapid placental transfer of both ethanol and acetaldehyde, which may have serious consequences for fetal development • The fetal alcohol syndromecan include any of the following: • facial changes with epicanthal eye folds; (aankhmeechnashemein) • poorly formed ear concha; • small teeth with faulty enamel; (daru pee kedant sad gaye) • cardiac atrial or ventricular septal defects; • an aberrant palmar crease and limitation in joint movement; darupakadne se ek hi crease • and microcephaly with mental retardationdaru pee peekemoohaurdimagdonochote ho gaye • The amount of ethanol required and the time of vulnerability during pregnancy have not been defined, making it advisable for pregnant women to abstain completely

49. Endocrinal effects Hormonal changes include • Increase in cortisol levels, which can remain elevated during heavy drinking; • Inhibition of vasopressin secretion at rising blood alcohol concentrations and enhanced secretion at falling blood alcohol concentrations (with the final result that most alcoholics are likely to be slightly overhydrated); • A modest and reversible decrease in serum thyroxine (T4); and a more marked decrease in serum triiodothyronine (T3). • Hormone irregularities should be reevaluated after a month of abstinence.

50. MUSCULO SKELETAL SYSTEM • Between one-half and two-thirds of alcoholics have skeletal muscle weakness caused by acute alcoholic myopathy, a condition that improves but which might not fully remit with abstinence. • Effects of repeated heavy drinking on the skeletal systeminclude • changes in calcium metabolism, • lower bone density, and decreased growth in the epiphyses, • leading to an increased risk for fractures and osteonecrosis of the femoral head