Alcoholic liver disease

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ALCOHOLIC LIVER DIASEASE

Dr [email protected]

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Incidence Prevalence of alcohol related disorders was 1.7 % worldwide and alcohol was

the 3rd leading cause of death in US.

Worldwide mortality is estimated to be 150,000 per year .

Among heavy drinkers 90-100% will develop hepatic steatosis in 10 years.

Only 10-35% develop steatohepatitis and 8-20% will develop cirrhosis in the same period.

Liver cirrhosis develops in 6-14 % of those who consume > 60-80g alcohol daily for men and > 20g daily in women .

Who drink >120g daily only 13.5 % will suffer serious alcohol related injury .

Despite cessation of alcohol use only 10% will have normalization of histology and LFTs .

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Progression in alcoholic liver disease

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Alcohol Content of Some Common Beverages

12oz of BEER contain 12g of alcohol .

5oz of WINE contain 12g of alcohol .

1.5oz of HARD LIQUAR contain 12g of alcohol .

One drink is equal to 8g in UK and 19.75g in Japan .

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Definations

The following categories are designated by NIAA criteria :

Moderate drinking: low risk for alcohol problems

Men: <3 drinks per day Women: <2 drinks per day People age ≥65: < 2 drinks per day

Heavy drinking: at risk for alcohol problems

Women: >7 drinks per week or 3 drinks per occasion Men: >14 drinks per week or 4 drinks per occasion

Binge drinking:

Women: 4 or more drinks in a row Men: 5 or more drinks in a row

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Pathogenesis

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Pathogenesis

Cofactors that potentiate the development of ALD . AGE

Early age alcohol use is associated with alcoholism later in life.

Highest rate of alcohol abuse morbidity occurs among individuals aged 45-64 years with a prevalence rate of 94.8 % per 100,000.

GENDER The overall prevalence of alcohol abuse and related liver disease is higher

among man than women .

Woman are more prone than man to alcohol related liver injury and fibrosis progression for the same amount of the alcohol consumption .

This may be due to different rates of alcohol metabolism lower body mass.

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Cofactors that potentiate the development of ALD .

Ethnicity Susceptibility to ALD is believed to vary among different ethnic groups in U.S :

Alcoholic cirrhosis related deaths are highest in Hispanic males.

Prevalence among female is highest in black non Hispanic.

Studies in U.K suggest that south asian men are more susceptible to alcohol related liver injury than European men .

Hepatitis C infection Between 14 and 36% of individuals with ALD also have Chronic hepatitis C.

Combination of HCV and ALD accelerate the progression and severity of liver disease .

Increase the risk of HCC .

Decrease the likelihood of virilogic response to interferon Alfa therapy.

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Cofactors that potentiate the development of ALD .

Hepatitis B (HBV) infection. Data suggest that chronic HBV infection and alcohol consumption

increase the risk for HCC .

Iron overload Both iron and alcohol generate reactive O2 species that promote lipid

peroxidation with subsequent damage to cellular integrity .

Excessive alcohol consumption (>60g/day) in patients with hemochromatosis is associated with :

accelerated fibogenesis Inc risk for HCC and lower long term survival .

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Cofactors that potentiate the development of ALD .

Medications Have increase risk of liver injury after ingestion of multiple or above

recommended dose of acetaminophen .

Due to rapid depletion of glutathione stores .

Diet and lifestyle

Have limited data. Coffee may be protective in ALD and related cirrhosis . Some studies suggest that obesity (BMI >25kg/m2 ) for >10yrs

accelerates progression of ALD . Pork products have been shown to be associated with alcoholic hepatitis

and cirrhosis .

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Pathophysiology of Alcohol-Induced Liver Injury

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PATHOGENESIS OF ALCOHOLIC LIVER INJURY

Centrilobular hypoxia   Alcohol ingestion have demonstrated susceptibility of the hepatic 

pericentral area to hypoxemia due to competitive O2 consumption by ethanol metabolism .

These changes mimic those induced by thyroid hormone.  These findings have led to clinical trials of PTU in patients with ongoing 

alcoholic liver injury .

Neutrophil infiltration and activation  One of the most characteristic pathologic hallmarks of alcoholic hepatitis 

is infiltration of neutrophils,  interleukin-8 (IL-8) and a lipid metabolite of arachidonic acid both acts as 

neutrophil chemoattractants . Inflammatory mediators from Kupffer cells (liver macrophages) may also 

have a role in ethanol-induced hepatic injury .

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PATHOGENESIS OF ALCOHOLIC LIVER INJURY

Antigenic adduct formation   Acetaldehyde and hydroxyethyl radicals bind covalently to proteins, 

thereby forming adducts that are antigenic .

Provoking both cell-mediated and humoral immune responses to attack cells bearing these compounds .

Action of injurious cytokines   Several studies have documented increased levels of the 

proinflammatory cytokines tumor necrosis factor and interleukin-6 .

In one study, mice lacking the TNF receptor 1 gene (but not the TNF receptor 2 gene) were protected from the development of liver disease following ethanol ingestion .

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Alcohol Metabolism

cytosol mitochondria

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Clinical findings

Abdominal wall collaterals (caput medusa) Ascites Cutaneous telangiectasias Digital clubbing Dupuytren's contractures Gynecomastia Jaundice Malnutrition Palmar erythema Peripheral neuropathy Splenomegaly Testicular atrophy

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Lab findings

Abnormality  Diagnostic characteristics* 

Serum AST>ALT (ratio usually >2.0, both usually <300 IU/L, and almost never >500 IU/L) IF >500 ??

Sensitivity and specificity have not been well studied, but may vary with the magnitude of the ratio 

Elevated serum AST Sensitivity 50 percentSpecificity 82 percent

Elevated serum ALT Sensitivity 35 percent Specificity 86 percent

Elevated serum GGT Sensitivity approximately 70 percentSpecificity approximately 60 to 80 percent

High MCV  Sensitivity approximately 30 to 50 percentSpecificity approximately 85 to 90 percent

Elevated carbohydrate-deficient transferrin Sensitivity approximately 60 to 70 percent (lower values have been reported)Specificity approximately 80 to 90 percent

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Histopathological findings

Fat droplet Neutophilic infiltration .Mallory bodies

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Imaging studies Imaging studies do not confirm the presence of alcoholic liver 

disease . Can be used to assess for hepatic parenchymal changes. 

Ultrasound, CT scan, and MRI can be used to diagnose fatty change, cirrhosis, or neoplastic diseases of the liver.

On MRI,  specific features that are suggestive of alcoholic cirrhosis 

versus cirrhosis from viral hepatitis include a higher volume index of the caudate lobe,  smaller size of regenerative nodules of the liver,  more frequent visualization of the right posterior hepatic notch .

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Imaging studies

Hepatic phosphorus 31 magnetic resonance spectroscopy.

Can calculate hepatic energy metabolism and phospholipid membrane metabolism . 

Patients with cirrhosis from alcohol have lower phosphodiesterase to ATP ratios than patients with cirrhosis from other causes 

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ROLE OF LIVER BIOPSY  Biopsy may be indicated in: 

Any patient with serum aminotransferases elevations that persist for >6 months, even if the patient is asymptomatic. 

Patients who have evidence of liver failure (eg, abnormal prothrombin time, hypoalbuminemia) in addition to elevated aminotransferases. If a coagulopathy is present, transjugular biopsy is usually safer than percutaneous biopsy.

Patients in whom the diagnosis of alcoholic hepatitis is uncertain based upon clinical and laboratory findings. 

Patients who may have more than one type of liver disease (such as alcohol and hepatitis C) in whom a liver biopsy may help determine the relative contribution of these factors .

Patients in whom a more detailed understanding of prognosis is desired. 

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Screening for alcohol abuse

Several screening tools exist to establish the diagnosis of alcoholism, including the 

CAGE, 

AUDIT (Alcohol Use Disorders Identification Test). 

MAST (Michigan Alcoholism Screening Test), 

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CAGE QUESTIONNAIRE  Have you ever felt the need to Cut down on drinking? Have you ever felt Annoyed by criticism of your drinking? Have you ever had Guilty feelings about your drinking? Do you ever take a morning Eye opener (a drink first thing in the

morning to steady your nerves or get rid of a hangover)?

One positive response to any CAGE question suggests the need for closer assessment .

A positive response to at least two questions is seen in the majority of patients with alcoholism and to all four questions in approximately 50 percent .

In comparison, over 80 percent of nonalcoholic subjects have a negative response to all four questions .

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Alcohol Use Disorder Identification Test (AUDIT)

AUDIT was designed to identify patients with recent heavy drinking in addition to alcohol dependence;

AUDIT focuses on identifying heavy drinkers and has a higher sensitivity and specificity than shorter screening instruments (sensitivity 51 to 97 percent; specificity 78 to 96 percent in primary care setting)

it performs better than the CAGE questionnaire for these purposes .

A major limitation to the AUDIT is its length !!

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Differential diagnosis Nonalcoholic steatohepatitis.

Patients history . ALT usually twice that of AST . And AST is rarely >500 in alcoholic hepatitis .

Hemochromatosis Patients History Genetic testing may reveal HFE gene. Pt: with ALD may have elevated transferrin saturation & ferritin levels

similar to those seen in hemochromatosis .

Acetaminophen toxicity History of drug ingestion AST >500 .

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Indices of prognosis The presence of liver failure manifested by coagulopathy, jaundice,

and/or encephalopathy is a poor prognostic indicator .

Several predictive models have been described

Maddrey's Discriminant function Model for End-Stage Liver Disease (MELD) score Glasgow alcoholic hepatitis score Lille model

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Indices of prognosis Maddrey's Discriminant function

Discriminant function = (4.6 x [prothrombin time - control PT]) + (serum bilirubin) Used for estimation of Disease severity and mortality risk .

A value greater than 32 is associated with a high short-term mortality, and has been used to determine the need for corticosteroids in patients with severe alcoholic hepatitis .

MDF > 32 associated with spontaneous survival of 50-65 % without steroids therapy .

MDF < 32 associated with spontaneous survival of 90 % .

In one report, the one-month mortality in patients with values above 32 who did not receive corticosteroids was 35 % In the absence of encephalopathy .

approximately 45 % if encephalopathy was present .

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Indices of prognosis Model for End-Stage Liver Disease (MELD) score

The score is based upon the serum bilirubin, creatinine and INR.

Used routinely for organ allocation in the United States.

May also predict mortality in patients hospitalized for alcoholic hepatitis .

In one study, the MELD score had similar predictive accuracy as the Discriminant function in predicting 30- and 90-day mortality .

MELD score >11 have 30 days mortality and >21 has 90 days mortality predictive accuracy .

A MELD score of 21 had a sensitivity and specificity of 75 percent for predicting 90-day mortality.

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Indices of prognosis

Glasgow alcoholic hepatitis score A multivariate model predicting mortality in alcoholic hepatitis .

Includes age, serum bilirubin (at day 1 and day 6 to 9), blood urea nitrogen, prothrombin time, and peripheral white blood cell count .

An initial validation study found it had better predictive accuracy for mortality at 28 days than the Discriminant function .

A benefit from corticosteroids was observed only in patients with a score ≥9.

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Indices of prognosis Lille model

Proposed for predicting mortality in patients with severe alcoholic hepatitis who have been treated with corticosteroids .

Combines six variables age Renal insufficiency (Cr >1.3 or creatinine clearance <40) Albumin Prothrombin time Bilirubin and evolution of bilirubin at day 7 .

Performed better than the Child-Pugh score, discriminant function, or Glasgow score in predicting survival at six months.

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TREATMENT Abstinence .

Nutrition .

Medical therapy .

Liver transplantation .

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Treatment Abstinence

Leads to reversal of liver disease and improvement in survival .

Less than 20 % of patients will demonstrate progression of liver disease after abstinence .

5 year survival improves from 34 % to 60 % for those with decompensated liver disease .

Patients with chronic HCV infection should abstain from any alcohol intake due to the risk for rapid acceleration of liver disease .

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Treatment

Nutrition

Alcoholism is associated with nutritional deficiencies .

Enteral as well as tube feeding found to be associated with decreased mortality .

Continued entral nutrition support after hospitalization also improves long term morbidity .

Cirrhotic patients usually have protein malnutrition with decrease BCCAs.

Dietary protein should not be restricted for fear of hepatic encephalopathy.

During hepatic encephalopathy BCAAs may be considered .

In patients with alcoholic hepatitis BCCAs has not been found to influence short term or long term survival .

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Treatment Corticosteroids

Only five studies have shown benefit in survival mostly in rural populations the remaining studies have been equivocal .

Corticosteroid therapy is beneficial in improving 30 and 60 days mortality only in patients with severe acute alcoholic hepatitis and an MDF >32 in the absence of acute GI bleeding, renal failure, acute infection or pancreatitis .

2 month survival is about 80 % but up to 40 % of patients still die in 6 months.

Significant improvement in LFTs is evident at 7 day after initiation of therapy and may be present up to 1 year .

Patients with a score >0.45 using lille model had a mortality rate of 76 % at 6 months.

Prednisolone given at a dose of 40mg daily for 4 wks followed by rapid 4 wks taper .

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Pentoxifylline

An inhibitor of TNF synthesis .

Shown to decrease the risk of HRS in pateints whose MDF >32 .

Survival benefit was related to a reduction in mortality associated with the HRS .

Recommended dose in 400mg thrice a day.

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Propylthiouracil

PTU is given in an attempt to reverse this hypermetabolic response, thereby reducing pericentral hypoxia and cell injury.

A Cochrane review of six trials including 710 patients with alcoholic liver disease treated with PTU versus placebo did not reveal a benefit to PTU treated patients on liver histology or overall mortality and liver-related mortality .

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Colchicine

Effects on hepatic fibrogenesis, including the inhibition of collagen production, enhancement of collagenase activity .

Meta-analysis of 15 randomized trials with 1714 patients with varying degrees of alcoholic liver disease, showed no benefit of colchicine on liver tests, histology, or overall mortality and liver-related mortal

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Silmyrin

Has been used for 2000 years in Europe for treatment of liver disease . Believed to enhance liver regeneration and protect hapetocytes from

toxicity . Clinical trails have yet to demonstrate a clear benefit .

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Liver Transplantation Liver transplantation is the only definitive therapy .

Alcoholic hepatitis has been considered an absolute contraindication to liver transplantation .

Survival after transplantation is similar for patients with ALD and non ALD .

Requirements for transplant listing are the same as those for other types of liver disease except :

For a 6 months of abstinence and psychiatric evaluation before a patient become eligible for transplantation .

Veldt et al. suggested that patients with liver failure resulting from alcoholic liver disease who do not recover within the first 3 months of abstinence are unlikely to survive.

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THANK YOU