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I.

ABSTRACT

An alcoholic beverage is a drink containing ethanol, commonly known as alcohol, although in

chemistry the definition of alcohol includes many other compounds. Alcoholic beverages are

divided into three general classes, beers, wines, and spirits.

Ethanol is only slightly toxic compared to other alcohols, but has significant psychoactive

effects. A significant blood alcohol content may be considered legal drunkenness as it reduces

attention and slows reaction speed. Alcoholic beverages can be addictive and the state of

addiction to ethanol is known as alcoholism.

Chronic alcoholism can cause cirrhosis, it’s called Laennec’s cirrhosis. This condition should

be renamed "alcoholic cirrhosis". Laennec's cirrhosis has three stages. The pathologic features of

this form of cirrhosis change with time. Therefore, it is helpful to break the disease down into

three stages, the fatty liver stage, the fibrotic liver stage and, the nodular liver stage.

Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver

tissue by fibrous scar tissue as well as regenerative nodules (lumps that occur as a result of a

process in which damaged tissue is regenerated), leading to progressive loss of liver function.

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II. INTRODUCTION

Each year, excessive alcohol consumption kills about 79.000 people in the United States and

do not close the possibility in Indonesia will also be like that. consumption of alcohol will be

increased, particularly among the young. Has been known that consume alcohol frequently will

influence our health condition. alcohol is very toxic to our body organs, especially the Liver.

Alcohol affect the heart condition because all the volume of alcohol that we drink will be

processed there and toxic substances. That substances will accelerate the occurrence of liver

cirrhosis. therefore, I am interested as a writer to create this paper. with the title "The relationship

between alcohol consumption and liver cirrhosis in men".

Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver

tissue by fibrous scar tissue as well as regenerative nodules. Cirrhosis is most commonly caused

by alcoholism, hepatitis B and C and fatty liver disease and many other possible causes.

Alcoholism is the first causes of this disease, but now in Indonesia hepatitis B is more often. But

perhaps in 10 years, causes of cirrhosis in Indonesia will be changed from hepatitis B to

alcoholism. It can occur because of globalization and westernization.

Alcohol users will be increasing from day to day, especially among the young. This claim is

supported by the lifestyle nowdays. Of course this habit is affecting the health of youth in the last

10 years. changes will happen quickly to their liver because the substances that exist in the

alcohol.

Rate of absorption of alcohol depends on several factors. It is quickest, for example, when

alcohol is drunk on an empty stomach. Alcohol is distributed throughout the water in the body, so

that most tissues such as the heart, brain, and muscles are exposed to the same concentration of

alcohol as the blood. The exception is the liver, where exposure is greater because blood is

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received direct from the stomach and small bowel via the portal vein. Alcohol diffuses rather

slowly, except into organs with a rich blood supply such as the brain and lungs.

An alcoholic beverage is a drink containing ethanol, commonly known as alcohol, although in

chemistry the definition of alcohol includes many other compounds. Alcoholic beverages are

divided into three general classes, beers, wines, and spirits.

The consumption of large doses results in drunkenness or intoxication that may lead to a

hangover as the effect wears off and depending on the dose and regularity of use, can cause acute

respiratory failure or death and with chronic use has medical repercussions, especially to the

liver.

Blood alcohol concentration varies according to sex, size and body build, phase of the

menstrual cycle, previous exposure to alcohol, type of drink, whether alcohol is taken with food

or drugs or not. More than 90% of alcohol is eliminated by the liver, 2-5% is excreted unchanged

in urine, sweat, or breath. The first step in metabolism is oxidation by alcohol dehydrogenases.

Women may have lower levels of alcohol dehydrogenases in the stomach than men, so that less

alcohol is metabolised before absorption.

Chronic alcoholism can cause cirrhosis, it’s called Laennec’s cirrhosis. This condition should

be renamed "alcoholic cirrhosis". Laennec's cirrhosis has three stages. The pathologic features of

this form of cirrhosis change with time. Therefore, it is helpful to break the disease down into

three stages. In early stages the liver is large and fatty, and then the liver becomes scarred

(fibrotic). In the final stage, the liver becomes lumpy (nodular). Substances that contained in the

alcohol will accelerate the process.

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III. ALKOHOL

Ethanol is a psychoactive drug that has a depressant effect. Most countries restrict and

regulate its sale and consumption. For example, they place legal drinking-age restrictions upon

the sale of alcoholic drinks to young people. The manufacture and consumption of alcohol

occurs in most cultures and societies of the world, from hunter-gatherer peoples to nation-states.

The drinking of alcoholic beverages is very often an important part of social events in such

societies, and it can be an important aspect of a community’s culture.(1)

Types of alcoholic beverage

Alcoholic beverages that have a lower alcohol content (beer and wine) are produced by

fermentation of sugar or starch containing plant material. Beverages of higher alcohol content

(spirits) are produced by fermentation followed by distillation.

a. Beer

The process of making beer defines the finished product. Beer involves a short (incomplete)

fermentation process and a short aging process (a week or two), typically resulting in an alcohol

content of 4%–6% ABV. Beer is a naturally carbonated beverage.

b. Wine

Wine involves a longer (complete) fermentation process, and a relatively long aging process

(months or years, sometimes decades) resulting in an alcohol content between 7-18%. Sparkling

wine is generally made by adding a small amount of sugar before bottling, which causes a

secondary fermentation to continue in the bottle.

c. Spirits

Spirits contain at least 20% ABV. Liqueurs are characterized by the way in which their

flavors are infused and typically have high sugar content. (1)

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Alcoholic content

The concentration of alcohol in a drink may be specified in percent alcohol by volume

(ABV), in percentage by weight (sometimes abbreviated w/w for weight for weight), or in proof.

In the USA, the 'proof' measurement is twice the percentage of alcohol by volume at 60 degrees

Fahrenheit (e.g., 80 proof = 40% ABV). Degrees proof were formerly used in the UK where 100

degrees proof was 57.1% ABV (historically, the most dilute spirit which would sustain the

combustion of gunpowder). Common distillation cannot exceed 191.2 proof (USA) because at

that point ethanol is an azeotrope with water. Alcohols of this purity are commonly referred to as

grain alcohol and are not meant for human consumption, with the notable exception of neutral

grain spirits.

Most yeasts cannot grow when the concentration of alcohol is higher than about 18% by

volume, so that is a practical limit for the strength of fermented beverages such as wine, beer,

and sake. Strains of yeast have been developed that can survive in solutions of up to 25% alcohol

by volume, but these were bred for ethanol fuel production, not beverage production. Spirits are

produced by distillation of a fermented product, concentrating the alcohol and eliminating some

of the by-products.

Unsweetened, distilled alcoholic beverages with an alcohol content of more than 30% ABV

are called spirits. Sweetened beverages with a high alcohol content are called liqueurs. Spirits

can be added to wines to create fortified wines, such as port and sherry. (1)

Toxicity

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Alcohols often have an odor described as 'biting' that 'hangs' in the nasal passages. Ethanol in

the form of alcoholic beverages has been consumed by humans since pre-historic times, for a

variety of hygienic, dietary, medicinal, religious, and recreational reasons. The consumption of

large doses results in drunkenness or intoxication (which may lead to a hangover as the effect

wears off) and, depending on the dose and regularity of use, can cause acute respiratory failure or

death and with chronic use has medical repercussions. Because alcohol impairs judgment, it can

often be a catalyst for reckless or irresponsible behavior.(2)

Alcohol in the body

Rate of absorption of alcohol depends on several factors. It is quickest, for example, when

alcohol is drunk on an empty stomach and the concentration of alcohol is 20-30%. Thus, sherry,

with an alcohol concentration of about 20% increases the levels of alcohol in blood more rapidly

than beer (3-8%), while spirits (40%) delay gastric emptying and inhibit absorption. Drinks

aerated with carbon dioxide, for example whisky, soda and champagne. They get into the system

quicker. Food, and particularly carbohydrate, retards absorption. Blood concentrations may not

reach a quarter of those achieved on an empty stomach. The pleasurable effects of alcohol are

best achieved with a meal or when alcohol is drunk diluted, in the case of spirits.

Alcohol is distributed throughout the water in the body, so that most tissues such as the heart,

brain, and muscles are exposed to the same concentration of alcohol as the blood. The exception

is the liver, where exposure is greater because blood is received direct from the stomach and

small bowel via the portal vein. Alcohol diffuses rather slowly, except into organs with a rich

blood supply such as the brain and lungs.

Very little alcohol enters fat because of fat's poor solubility. Blood and tissue concentrations

are therefore higher in women, who have more subcutaneous fat and a smaller blood volume,

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than in men, even when the amount of alcohol consumed is adjusted for body weight. Women

also may have lower levels of alcohol dehydrogenases in the stomach than men, so that less

alcohol is metabolised before absorption. Alcohol enters the fetus readily through the placenta

and is eliminated by maternal metabolism.

Blood alcohol concentration varies according to sex, size and body build, phase of the

menstrual cycle (it is highest premenstrually and at ovulation), previous exposure to alcohol, type

of drink, whether alcohol is taken with food or drugs, such as cimetidine (which inhibits gastric

alcohol dehydrogenase) and antihistamines, phenothiazines, and metoclopramide (which enhance

gastric emptying, thus increasing absorption).(3)

Metabolism of Alcohol

More than 90% of alcohol is eliminated by the liver; 2-5% is excreted unchanged in urine,

sweat, or breath. The first step in metabolism is oxidation by alcohol dehydrogenases, of which at

least four isoenzymes exist, to acetaldehyde in the presence of cofactors. Acetaldehyde is a

highly reactive and toxic substance, and in healthy people it is oxidised rapidly by aldehyde

dehydrogenases to harmless acetate.

The first step in the metabolism of alcohol takes place in the hepatocytes, where conversion to

acetaldehyde occurs. Acetaldehyde is then metabolised to acetate by aldehyde dehydrogenase

(ALDH). The toxic substance, acetaldehyde, and its derivatives are implicated in alcoholic

cirrhosis of the liver. The liver alcohol dehydrogenase (ADH), ALDH, and cytochrome

P4502E1(P4502E1) are polymorphic at the ADH2, ADH3, ALDH2 loci, and the 5’-flanking

region of the P4502E1. Further, ethnic variations have been reported. The ß2ß2 enzyme encoded

by ADH2 2*2 is approximately 20-fold more active in ethanol oxidation than the ß1ß1 enzyme.

Individuals who inherit the ADH2*2 allele have homodimeric and heterodimeric ß2-containing

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isozymes and could be expected to have faster rates of alcohol metabolism and possibly higher

concentrations of acetaldehyde production after alcohol consumption. Many studies have

attempted to explain susceptibility to alcoholism and alcohol induced liver disease in terms of

differences in these alcohol-metabolizing enzymes. However, the specific mechanisms involved

in the different alcohol-induced organ-specific diseases, such as those involving the liver,

pancreas, heart and skeletal system, are not yet clear.

Alcohol (ethanol) is a drug, and health professionals should know something of its

physiological and pathological effects and its handling by the body. It is a small, water soluble

molecule that is relatively slowly absorbed from the stomach, more rapidly absorbed from the

small intestine, and freely distributed throughout the body. Alcoholic drinks are a major source of

energy, for example, six pints of beer contain about 500 kcal and half a litre of whisky contains

1650 kcal. The daily energy requirement for a moderately active man is 3000 kcal and for a

woman 2200 kcal.(3)

Heavy drinkers

Two mechanisms dispose of excess alcohol in heavy drinkers and account for "tolerance" in

established drinkers. Firstly, normal metabolism increases, as shown by high blood

concentrations of acetate. Secondly, the microsomal ethanol oxidising system is brought into

play; this is dependent on cytochrome P450, which is normally responsible for drug metabolism,

and other cofactors. This process is called enzyme induction, and the effect is also produced by

other drugs that are metabolised by the liver and by smoking.

The two mechanisms lead to a redox state, in which free hydrogen ions build up and have to

be disposed of by several different pathways. Some of the resultant metabolic aberrations can

have clinical consequences: hepatic gluconeogenesis is inhibited, the citric acid cycle is reduced,

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and oxidation of fatty acids is impaired. Glucose production is thus reduced, with the risk of

hypoglycaemia. Overproduction of lactic acid blocks uric acid excretion by the kidneys and

accumulated fatty acids are converted into ketones and lipids.(3)

Behavior effect

Alcohol is a sedative and mild anaesthetic. It is believed to activate the pleasure or reward

centres in the brain by triggering release of neurotransmitters such as dopamine and serotonin.

Alcohol produces a sense of wellbeing, relaxation, disinhibition, and euphoria. These feelings are

accompanied by physiological changes such as flushing, sweating, tachycardia, and increases in

blood pressure, probably because of stimulation of the hypothalamus and increased release of

sympathomimetic amines and pituitary-adrenal hormones. The kidneys secrete more urine, not

only because of the fluid drunk but also because of the osmotic effect of alcohol and inhibition of

secretion of antidiuretic hormone.

Increasing consumption leads to a state of intoxication, which depends on the amount drunk

and previous experience of drinking. Even at a low blood alcohol concentration of around 6.5

mmol/l (30 mg/100 ml), the risk of unintentional injury is higher than in the absence of alcohol,

although individual experience and complexity of task have to be taken into account. In a

simulated driving test, for example, bus drivers with a blood alcohol concentration of 10.9

mmol/l (50 mg/100 ml) thought they could drive through obstacles that were too narrow for their

vehicles.

People become garrulous, elated, and aggressive at concentrations above 21.7 mmol/l (100

mg/100 ml) and then may stop drinking as drowsiness supervenes. After effects ("hangover")

include insomnia, nocturia, tiredness, nausea, and headache.

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If drinking continues, slurred speech and unsteadiness are likely at around 43.4 mmol/l (200

mg/100 ml), and loss of consciousness may result. Concentrations above 86.8 mmol/l (400

mg/100 ml) commonly are fatal as a result of ventricular fibrillation, respiratory failure, or

inhalation of vomit (this is particularly likely when drugs have been taken in addition to alcohol).
(3)

IV. CIRRHOSIS

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The word "cirrhosis" derives from Greek kirrhos, meaning "tawny" (the orange-yellow colour

of the diseased liver). While the clinical entity was known before, it was René Laennec who gave

it the name "cirrhosis" in his 1819 work in which he also describes the stethoscope.(4)

Cirrhosis is most commonly caused by alcoholism, hepatitis B and C and fatty liver disease

and many other possible causes. Some cases are cryptogenic, but most of these are probably due

to previously unrecognised fatty liver disease.

Ascites (fluid retention in the abdominal cavity) is the most common complication of

cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-

term outcome. Other potentially life-threatening complications are hepatic encephalopathy

(confusion and coma) and bleeding from esophageal varices. Cirrhosis is generally irreversible

once it occurs, and treatment generally focuses on preventing progression and complications. In

advanced stages of cirrhosis the only option is a liver transplant.(5)

Causes (4,5,6)

Cirrhosis has many possible causes, sometimes more than one cause is present in the same

patient. In the Western World, chronic alcoholism and hepatitis C are the most common causes.

- Alcoholic liver disease (ALD)

Alcoholic cirrhosis develops in 15% of individuals who drink heavily for more than a decade.

There is great variability in the amount of alcohol needed to cause cirrhosis (as little as 3-4

drinks a day in some men and 2-3 in some women. Alcohol seems to injure the liver by blocking

the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent

alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. AST and ALT are both

elevated but less than 300 IU/L with a AST : ALT ratio > 2.0, a value rarely seen in other liver

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diseases. Liver biopsy may show hepatocyte necrosis, Mallory bodies, neutrophilic infiltration

with perivenular inflammation.

- Chronic hepatitis C

Infection with this virus causes inflammation of and low grade damage to the liver that over

several decades can lead to cirrhosis. Can be diagnosed with serologic assays that detect hepatitis

C antibody or viral RNA. The enzyme immunoassay, EIA-2, is the most commonly used

screening test in the US.

- Chronic hepatitis B

The hepatitis B virus is probably the most common cause of cirrhosis worldwide, especially

South-East Asia, but it is less common in the United States and the Western world. Hepatitis B

causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D

is dependent on the presence of hepatitis B, but accelerates cirrhosis in co-infection. Chronic

hepatitis B can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG

and HBV DNA are determined to assess whether patient will need antiviral therapy.

- Non-alcoholic steatohepatitis (NASH)

In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis

appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and

treatment with corticosteroid medications. This disorder is similar to that of alcoholic liver

disease but patient does not have an alcohol history. Biopsy is needed for diagnosis.

- Primary biliary cirrhosis

May be asymptomatic or complain of fatigue, pruritus, and non-jaundice skin

hyperpigmentation with hepatomegaly. There is prominent alkaline phosphatase elevation as

well as elevations in cholesterol and bilirubin. Gold standard diagnosis is antimitochondrial

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antibodies with liver biopsy as confirmation if showing florid bile duct lesions. It is more

common in women.

- Primary sclerosing cholangitis

PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble

vitamin deficiencies, and metabolic bone disease. There is a strong association with

inflammatory bowel disease (IBD), especially ulcerative colitis. Diagnosis is best with contrast

cholangiography showing diffuse, multifocal strictures and focal dilation of bile ducts, leading to

a beaded appearance. Non-specific serum immunoglobulins may also be elevated.

- Autoimmune hepatitis

This disease is caused by the immunologic damage to the liver causing inflammation and

eventually scarring and cirrhosis. Findings include elevations in serum globulins, especially

gamma globulins. Therapy with prednisone +/- azathioprine is beneficial. Cirrhosis due to

autoimmune hepatitis still has 10-year survival of 90%+. There is no specific tool to diagnose

autoimmune but it can be beneficial to initiate a trial of corticosteroids.

- Hereditary hemochromatosis

Usually presents with family history of cirrhosis, skin hyperpigmentation, diabetes mellitus,

pseudogout, and/or cardiomyopathy, all due to signs of iron overload. Labs will show fasting

transferrin saturation of > 60% and ferritin > 300 ng/mL. Genetic testing may be used to identify

HFE mutations. If these are present, biopsy may not need to be performed. Treatment is with

phlebotomy to lower total body iron levels.

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- Wilson's disease

Autosomal recessive disorder characterized by low serum ceruloplasmin and increased

hepatic copper content on liver biopsy. May also have Kayser-Fleischer rings in the cornea and

altered mental status.

- Alpha 1-antitrypsin deficiency (AAT)

Autosomal recessive disorder. Patients may also have COPD, especially if they have a history

of tobacco smoking. Serum AAT levels are low. Recombinant AAT is used to prevent lung

disease due to AAT deficiency.

- Cardiac cirrhosis

Due to chronic right sided heart failure which leads to liver congestion.

- Other, there are Galactosemia, Glycogen storage disease type IV, Cystic fibrosis, Drugs or

toxins, Certain parasitic infections (such as schistosomiasis)

Pathophysiology

The liver plays a vital role in synthesis of proteins (e.g. albumin, clotting factors and

complement), detoxification and storage (e.g. vitamin A). In addition, it participates in the

metabolism of lipids and carbohydrates.

Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the cause. If

the cause is removed at this stage, the changes are still fully reversible.

The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal

parenchyma, blocking the portal flow of blood through the organ and disturbing normal function.

Recent research shows the pivotal role of stellate cell, a cell type that normally stores vitamin A,

in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the

stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the

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circulation. In addition, it secretes TGF-β1, which leads to a fibrotic response and proliferation of

connective tissue. Furthermore, it disturbs the balance between matrix metalloproteinases and the

naturally occurring inhibitors (TIMP 1 and 2), leading to matrix breakdown and replacement by

connective tissue-secreted matrix.

The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the

entire liver architecture, leading to decreased blood flow throughout. The spleen becomes

congested, which leads to hypersplenism and increased sequestration of platelets. Portal

hypertension is responsible for most severe complications of cirrhosis.

Signs and symptoms (4,5,6)

Some of the following signs and symptoms may occur in the presence of cirrhosis or as a

result of the complications of cirrhosis. Many are nonspecific and may occur in other diseases

and do not necessarily point to cirrhosis. Likewise, the absence of any does not rule out the

possibility of cirrhosis.

- Spider angiomata or spider nevi

Vascular lesions consisting of a central arteriole surrounded by many smaller vessels due to

an increase in estradiol. These occur in about 1/3 of cases.

- Palmar erythema

Exaggerations of normal speckled mottling of the palm, due to altered sex hormone

metabolism.

- Muehrcke's nails

Paired horizontal bands separated by normal color due to hypoalbuminemia (low production

of albumin).

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- Terry's nails

Proximal two thirds of the nail plate appears white with distal one-third red, also due to

hypoalbuminemia

- Clubbing

Angle between the nail plate and proximal nail fold > 180 degrees

- Hypertrophic osteoarthropathy

Chronic proliferative periostitis of the long bones that can cause considerable pain.

- Dupuytren's contracture

Thickening and shortening of palmar fascia that leads to flexion deformities of the fingers.

Thought to be due to fibroblastic proliferation and disorderly collagen deposition. It is relatively

common (33% of patients).

- Gynecomastia

Benign proliferation of glandular tissue of male breasts presenting with a rubbery or firm

mass extending concentrically from the nipples. This is due to increased estradiol and can occur

in up to 66% of patients.

- Hypogonadism

Manifested as impotence, infertility, loss of sexual drive, and testicular atrophy due to

primary gonadal injury or suppression of hypothalamic or pituitary function.

- Liver size

Can be enlarged, normal, or shrunken.

- Splenomegaly

Increase in size of the spleen. Due to congestion of the red pulp as a result of portal

hypertension.

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- Ascites

Accumulation of fluid in the peritoneal cavity giving rise to flank dullness (needs about 1500

ml to detect flank dullness). It may be associated with hydrocele and penile flomation (swelling

of the penile shaft) in men.

- Caput medusa

In portal hypertension, the umbilical vein may open. Blood from the portal venous system

may be shunted through the periumbilical veins into the umbilical vein and ultimately to the

abdominal wall veins, manifesting as caput medusa.

- Cruveilhier-Baumgarten murmur

Venous hum heard in epigastric region (on examination by stethoscope) due to collateral

connections between portal system and the remnant of the umbilical vein in portal hypertension.

- Fetor hepaticus

Musty odor in breath due to increased dimethyl sulfide.

- Jaundice

Yellow discoloring of the skin, eye, and mucus membranes due to increased bilirubin (at least

2-3 mg/dL or 30 mmol/L). Urine may also appear dark.

- Asterixis

Bilateral asynchronous flapping of outstretched, dorsiflexed hands seen in patients with

hepatic encephalopathy.

- Other

Weakness, fatigue, anorexia, weight loss.

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Lab findings (4,6)

The following findings are typical in cirrhosis:

- Aminotransferases

AST and ALT are moderately elevated, with AST > ALT. However, normal

aminotransferases do not preclude cirrhosis.

- Alkaline phosphatase

usually slightly elevated.

- GGT

Correlates with AP levels. Typically much higher in chronic liver disease from alcohol.

- Bilirubin

May elevate as cirrhosis progresses.

- Albumin

Levels fall as the synthetic function of the liver declines with worsening cirrhosis since

albumin is exclusively synthesized in the liver

- Prothrombin time

Increases since the liver synthesizes clotting factors.

- Globulins

Increased due to shunting of bacterial antigens away from the liver to lymphoid tissue.

- Serum sodium

Hyponatremia due to inability to excrete free water resulting from high levels of ADH and

aldosterone.

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- Thrombocytopenia

Due to both congestive splenomegaly as well as decreased thrombopoietin from the liver.

However, this rarely results in platelet count < 50,000/mL.

- Leukopenia and neutropenia

Due to splenomegaly with splenic margination.

- Coagulation defects

The liver produces most of the coagulation factors and thus coagulopathy correlates with

worsening liver disease.

Other laboratory studies performed in newly diagnosed cirrhosis may include Serology for

hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, anti-mitochondria, anti-LKM)

Ferritin and transferrin saturation (markers of iron overload), copper and ceruloplasmin (markers

of copper overload), Immunoglobulin levels (IgG, IgM, IgA), Cholesterol and glucose, Alpha 1-

antitrypsin.

Imaging (4)

- Ultrasound

Ultrasound is routinely used in the evaluation of cirrhosis, where it may show a small and

nodular liver in advanced cirrhosis along with increased echogenicity with irregular appearing

areas. Ultrasound may also screen for hepatocellular carcinoma, portal hypertension and Budd-

Chiari syndrome (by assessing flow in the hepatic vein).

- FibroScan (transient elastography)

Fibroscan is a new type of device, uses elastic waves to determine liver stiffness which

theoretically can be converted into a liver score based on the METAVIR scale. The FibroScan

produces an ultrasound image of the liver (from 20-80mm) along with a pressure reading (in

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kPa.) The test is much faster than a biopsy (usually last 2.5-5 minutes) and is completely

painless. It shows reasonable corellation with the severity of cirrhosis.

- CT scan and MRCP

Other tests performed in particular circumstances include abdominal CT and liver/bile duct

MRI (MRCP). Rarely diseases of the bile ducts, such as primary sclerosing cholangitis, can be

causes of cirrhosis. Imaging of the bile ducts, such as ERCP or MRCP (MRI of biliary tract and

pancreas) can show abnormalities in these patients, and may aid in the diagnosis.

Endoscopy (6)

Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is

performed in patients with established cirrhosis to exclude the possibility of esophageal varices.

If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and beta

blocker treatment may be commenced.

Pathology (4,5,6)

Macroscopically, the liver may be initially enlarged, but with progression of the disease, it

becomes smaller. Its surface is irregular, the consistency is firm and the color is often yellow (if

associates steatosis). Depending on the size of the nodules there are three macroscopic types:

micronodular, macronodular and mixed cirrhosis. In micronodular form (Laennec's cirrhosis or

portal cirrhosis) regenerating nodules are under 3 mm. In macronodular cirrhosis (post-necrotic

cirrhosis), the nodules are larger than 3 mm. The mixed cirrhosis consists in a variety of nodules

with different sizes.

Microscopically, cirrhosis is characterized by regeneration nodules, surrounded by fibrous

septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central

veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may

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present inflammatory infiltrate (lymphocytes, macrophages) If it is a secondary biliary cirrhosis,

biliary ducts are damaged, proliferated or distended - bile stasis. These dilated ducts contain

inspissated bile which appear as bile casts or bile thrombi (brown-green, amorphous). Bile

retention may be found also in the parenchyma, as the so called "bile lakes."

Diagnosis (4)

The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous,

transjugular, laparoscopic, or fine-needle approach. Histologically cirrhosis can be classified as

micronodular, macronodular, or mixed, but this classification has been abandoned since it is

nonspecific to the etiology, it may change as the disease progresses, and serological markers are

much more specific. However, a biopsy is not necessary if the clinical, laboratory, and radiologic

data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and

cirrhosis itself predisposes for complications due to liver biopsy.

Grading (4,5)

The severity of cirrhosis is commonly classified with the Child-Pugh score. This score uses

bilirubin, albumin, INR, presence and severity of ascites and encephalopathy to classify patients

in class A, B or C; class A has a favourable prognosis, while class C is at high risk of death. It

was devised in 1964 by Child and Turcotte and modified in 1973 by Pugh et al.[10]

More modern scores, used in the allocation of liver transplants but also in other contexts, are

the Model for End-Stage Liver Disease (MELD) score and its pediatric counterpart, the Pediatric

End-Stage Liver Disease (PELD) score.

The hepatic venous pressure gradient, the difference in venous pressure between afferent and

efferent blood to the liver, also determines severity of cirrhosis, although hard to measure. A

value of 16 mm or more means a greatly increased risk of dying.

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Complications (4,5,)

As the disease progresses, complications may develop. In some people, these may be the first

signs of the disease. Complications of cirrhosis are:

- Bruising and bleeding, due to decreased production of coagulation factors.

- Jaundice due to decreased, processing of bilirubin.

- Itching (pruritus), due to bile products deposited in the skin.

- Hepatic encephalopathy, the liver does not clear ammonia and related nitrogenous substances

from the blood, which are carried to the brain, affecting cerebral functioning: neglect of personal

appearance, unresponsiveness, forgetfulness, trouble concentrating, or changes in sleep habits.

Sensitivity to medication due to decreased metabolism of the active compounds.

- Hepatocellular carcinoma is primary liver cancer, a frequent complication of cirrhosis. It has a

high mortality rate.

- Portal hypertension, blood normally carried from the intestines and spleen through the hepatic

portal vein flows more slowly and the pressure increases. This leads to the following

complications:

a. Ascites, fluid leaks through the vasculature into the abdominal cavity. Fluid in the abdomen

(ascites) may become infected with bacteria normally present in the intestines (spontaneous

bacterial peritonitis).

b. Esophageal varices, collateral portal blood flow through vessels in the stomach and esophagus.

These blood vessels may become enlarged and are more likely to burst.

- Immune system dysfunction, leading to infection. Signs and symptoms of infection may be

aspecific are more difficult to recognize (e.g. worsening encephalopathy but no fever).

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Problems in other organs.

- Hepatorenal syndrome, insufficient blood supply to the kidneys, causing acute renal failure.

This complication has a very high mortality (over 50%).

- Hepatopulmonary syndrome, blood bypassing the normal lung circulation (shunting), leading

to cyanosis and dyspnea (shortness of breath), characteristically worse on sitting up.[6]

- Portopulmonary hypertension, increased blood pressure over the lungs as a consequence of

portal hypertension.

Laennec’s Cirrhosis (4,6,7)

Chronic alcoholism can cause cirrhosis, it’s called Laennec’s cirrhosis. This condition should be

renamed "alcoholic cirrhosis". Laennec's cirrhosis has three stages. The pathologic features of this form

of cirrhosis change with time. Therefore, it is helpful to break the disease down into three stages, the fatty

liver stage, the fibrotic liver stage and the nodular liver stage.

Alcoholic liver injury mechanism is still uncertain. Mechanism is estimated as follows:

1. Hypoxia centrilobular, metabolism Acetaldehyde ethanol increase the consumption of oxygen of

lobular, occurs hypoxemia on lobular and make cell injury in areas that far from the flow of blood.

2. Infiltration or neutrofile activity increased because of Acetaldehyde ethanol.

3. Formation of acetaldehyde-protein adducts role as a neoantigen and make limfocyte and specific

antibody actived. Both cells attack hepatosit that have that neoantigen.

4. The formation of free radicals by alternative routes and ethanol metabolism.

In early stages the liver is large and fatty. In this early stage, fat accumulates in the liver cells

around the central vein (fatty change). The liver becomes large, even huge (hepatomegaly). The

normal liver weighs about 1,200 grams. By comparison, fatty livers can weigh in at over 6,000

grams and may, in the living patient, fill the abdominal cavity (remember that the normal liver

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extends 2-3 finger below the right costal margin). At autopsy, the fatty liver is greasy and a cut

surface is yellow. As dramatic as these changes are, the fatty change is reversible.

In later stages, the liver becomes scarred (fibrotic). In this stage, the liver returns to a more

normal size, however, it does not return to normal in any other way. In fact, the changes that

develop during this stage are irreversible. The fatty change subsides and is replaced by fibrosis

(scarring) and some chronic inflammation. No doubt the retreat of fatty change and the shrinking

effect of scar tissue is responsible for the over-all decrease in liver size.

In the final stage, the liver becomes lumpy (nodular). In this stage, the liver shrink even

further. It may not extend below the costal margin at all. Liver cells attempt to regenerate in an

increasingly fibrotic setting. They find it difficult to do so and form "regenerative nodules" that

only partially carry out normal liver function. This shrunken, nodular texture has been dubbed

the "hob-nail" or "cobble stone" effect.

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