Too Much Alcohol is Bad for Your Liver Alcohol and Your Liver Anna Lembke, MD Department of Psychiatry and Behavioral Sciences Stanford, University Medical Center Stanford, California

Your Healthy Liver

Healthy Hepatic Portal Triad

Your Liver on Alcohol

Cirrhosis close-up

This Lecture Reviews How a healthy liver metabolizes EtOH How a healthy liver metabolizes EtOH How too much EtOH damages the liver How too much EtOH damages the liver How much is too much How much is too much How to help How to help

This Lecture Reviews How a healthy liver metabolizes EtOH How a healthy liver metabolizes EtOH How too much EtOH damages the liver How too much EtOH damages the liver How much is too much How much is too much How to help How to help

Alcohol Metabolism ADH ALDH ADH ALDH CH3CH2OH  CH3CHO  CH3COOH Ethanol Acetaldehyde Acetic Acid Ethanol Acetaldehyde Acetic Acid

EtOH Metabolized Faster Male Male High body mass High body mass Heavy drinker Heavy drinker Fast metabolizer Fast metabolizer

ALDH 2*2, 2*2 Homozygotes (ALDH 2*2, 2*2) Homozygotes (ALDH 2*2, 2*2) Vomiting, diarrhea, etc. Vomiting, diarrhea, etc. No alcoholics No alcoholics Heterozygotes (ALDH2*2) Heterozygotes (ALDH2*2) Alcohol reaction but not ill Alcohol reaction but not ill Less alcoholism Less alcoholism

Alcohol Dehydrogenase (ADH) Mutations Faster ↓ EtOH Faster ↓ EtOH Faster ↑ acetaldehyde Faster ↑ acetaldehyde Slightly ↓ alcoholic risk Slightly ↓ alcoholic risk

This Lecture Reviews How a healthy liver metabolizes EtOH How a healthy liver metabolizes EtOH How too much EtOH damages the liver How too much EtOH damages the liver How much is too much How much is too much How to help How to help

Alcoholic Liver Disease (ALD) Damage to liver by alcohol Damage to liver by alcohol Typically occurs in progression Typically occurs in progression Fatty liver  Fatty liver  Alcoholic hepatitis  Alcoholic hepatitis  Cirrhosis  Cirrhosis 

Step 1: Fatty Liver ADH metabolizes EtOH ADH metabolizes EtOH ↑ Acetaldehyde and free radicals ↑ Acetaldehyde and free radicals Acetaldehyde more toxic than alcohol  Acetaldehyde more toxic than alcohol  Mild inflammation Mild inflammation Fat cell proliferation Fat cell proliferation

Fatty Liver Almost all heavy drinkers Almost all heavy drinkers Usually asymptomatic Usually asymptomatic Reversible Reversible

Healthy Liver vs Fatty Liver

Step 2: Hepatitis Alcohol  release of toxins from gut Alcohol  release of toxins from gut Liver Kuppfer cells release cytokines Liver Kuppfer cells release cytokines Decrease inflammation Decrease inflammation But also ↑ cell death But also ↑ cell death

Alcoholic Hepatitis Up to 35% of hazardous drinkers Up to 35% of hazardous drinkers Usually reversible Usually reversible

Step 3: Cirrhosis Liver cell death  Liver cell death  ↑ Stellate cells ↑ Stellate cells Specialized liver cell Specialized liver cell Normal healing Normal healing  Scarring  Scarring Disrupts architecture Disrupts architecture Impairs function Impairs function

Cirrhosis ~ 20% after 10 years hazardous use ~ 20% after 10 years hazardous use 12th leading cause of death in adults 12th leading cause of death in adults Damage irreversible Damage irreversible

Other ALD Risk Factors Genetic Genetic ALDH 2*2 protects ALDH 2*2 protects ADH 1C2 ↑ risk ADH 1C2 ↑ risk Diet ↑ ’s risk Diet ↑ ’s risk Drink without food Drink without food ↑ Polyunsaturated fats ↑ Polyunsaturated fats Obesity Obesity ↑ Iron ↑ Iron ↑ Blood sugar ↑ Blood sugar Gender: ↑ Risk in women (2x mortality) Gender: ↑ Risk in women (2x mortality)

This Lecture Reviews How a healthy liver metabolizes EtOH How a healthy liver metabolizes EtOH How too much EtOH damages the liver How too much EtOH damages the liver How much is too much How much is too much How to help How to help

ALD Dose Dependent More EtOH x more time  ↑ risk ALD More EtOH x more time  ↑ risk ALD >2 drinks/daily  ↑ risk ALD >2 drinks/daily  ↑ risk ALD AUDIT-C > 5  ↑ risk ALD AUDIT-C > 5  ↑ risk ALD Standard drink = Standard drink = 12 oz. beer 12 oz. beer 4 oz. wine 4 oz. wine 1.5 oz. whiskey 1.5 oz. whiskey

Screening Tests for Consumption Time-Line-Follow-Back (TLFB) Method Time-Line-Follow-Back (TLFB) Method Counting backwards from today Counting backwards from today Standard drinks per day Standard drinks per day Total standard drinks per week Total standard drinks per week Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) Alcohol Use Disorders Identification Test for Consumption (AUDIT-C)

AUDIT-C 3 Questions 3 Questions How often do you have an EtOH drink? How often do you have an EtOH drink? How many drinks per drinking day? How many drinks per drinking day? How often > 6 per occasion? How often > 6 per occasion? AUDIT-C Scores (0-12) AUDIT-C Scores (0-12) 0 = non-drinker 0 = non-drinker 1-4 = low level drinker 1-4 = low level drinker 5-8 moderate EtOH misuse 5-8 moderate EtOH misuse 9-12 severe EtOH misuse 9-12 severe EtOH misuse

Hazardous Alcohol Use  ↑ Risk ALD Men Men > 14 drinks/week or > 14 drinks/week or > 4 drinks on any occasion > 4 drinks on any occasion Women Women > 7 drinks/week or > 7 drinks/week or > 3 drinks on any occasion > 3 drinks on any occasion AUDIT-C score > 5 AUDIT-C score > drinks most days or 1-2 drinks most days or > 6 per occasion some days > 6 per occasion some days

EtOH in Moderation Healthy? Moderate drinkers vs. non-drinkers Moderate drinkers vs. non-drinkers ↓ Mortality ↓ Mortality ↓G.I. illnesses ↓G.I. illnesses ↓Gastritis, gallstones ↓Gastritis, gallstones ↓Cardiovascular disease ↓Cardiovascular disease ↓Dementia (vascular and Alzheimer’s) ↓Dementia (vascular and Alzheimer’s) Results may be misleading Results may be misleading

Abuse vs. Dependence Abuse ( ≥1) Role failure Role failure Risk of harm Risk of harm Run-ins with law Run-ins with law Relationship trouble Relationship trouble Dependence (≥3) Tolerance Tolerance Withdrawal Withdrawal Not sticking to limits Not sticking to limits Not able to cut down Not able to cut down Spending time EtOH Spending time EtOH Less time elsewhere Less time elsewhere Despite problems Despite problems

This Lecture Reviews How a healthy liver metabolizes EtOH How a healthy liver metabolizes EtOH How too much EtOH damages the liver How too much EtOH damages the liver How much is too much How much is too much How to help How to help

EtOH Misuse is Prevalent 77% Low-risk or abstention 77% Low-risk or abstention 16% Hazardous or at-risk use 16% Hazardous or at-risk use 7% Abuse or dependence 7% Abuse or dependence Almost 1 out of 4 is misusing EtOH Almost 1 out of 4 is misusing EtOH

Screen for EtOH Consumption Time Line Follow-Back (TLFB) Method Time Line Follow-Back (TLFB) Method Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) Single Question Screen: ”How many times in the past year have you had…?” Single Question Screen: ”How many times in the past year have you had…?” >4 drinks/day men >4 drinks/day men >3 drinks/day women >3 drinks/day women

Gamma-Glutamyl Transferase (GGT) ↑ Before damage to liver; GGT > 35 IU/L ↑ Before damage to liver; GGT > 35 IU/L If GGT >51, may signal liver damage If GGT >51, may signal liver damage ↑ in 75% of chronic heavy drinkers ↑ in 75% of chronic heavy drinkers Not specific to ALD (70% specificity) Not specific to ALD (70% specificity)

Carbohydrate Deficient Transferrin (CDT) Plasma protein carries iron to bone Plasma protein carries iron to bone > 2.6% suggestive of 5+ drinks/day > 2.6% suggestive of 5+ drinks/day Sensitivity/specificity slightly > GGT Sensitivity/specificity slightly > GGT

Liver function tests (ALT/AST) Alanine transaminase (ALT) Alanine transaminase (ALT) (9-60 IU/L normal range) (9-60 IU/L normal range) Aspartate transaminase (AST) Aspartate transaminase (AST) (10-40 IU/L normal range) (10-40 IU/L normal range) AST/ALT ratio > 2/1 AST/ALT ratio > 2/1  suggestive of ALD  suggestive of ALD

Intervene at Level of Need Drinking type Abuse/Dependence  Hazardous Use  Low risk/abstention  Intervention type Treatment Brief intervention No intervention

If Hazardous Use… Try “SBIRT” Try “SBIRT” Screening, brief intervention, referral to tx. Screening, brief intervention, referral to tx. SBIRT can ↓ avg. # drinks/week by ~25% SBIRT can ↓ avg. # drinks/week by ~25% Assess, Advise, Agree, Assist, Arrange Assess, Advise, Agree, Assist, Arrange

If Abuse or Dependence… Refer to 12-step mutual help groups Refer to 12-step mutual help groups Alcoholics Anonymous Alcoholics Anonymous Double Trouble in Recovery Double Trouble in Recovery Narcotics Anonymous Narcotics Anonymous Refer to higher level of AUD care Refer to higher level of AUD care Day treatment Day treatment Residential Residential Clean and sober living environment Clean and sober living environment Consider medications Consider medications

Medications for EtOH; Use with Care in ALD Naltrexone: mg/daily Naltrexone: mg/daily Acamprosate: ~ 2 g/daily Acamprosate: ~ 2 g/daily Disulfiram: 250 mg/daily Disulfiram: 250 mg/daily

Treating ALD Stop drinking Stop drinking Limit medications Limit medications Low sodium diet Low sodium diet

Reduce Ascites Diuretic Diuretic Paracentesis Paracentesis Antibiotics Antibiotics Transjugular intrahepatic portosystemic shunt (TIPS) Transjugular intrahepatic portosystemic shunt (TIPS)

Control Variceal Bleeding Vasoconstrictor medications Vasoconstrictor medications Shunts: redirect blood flow Shunts: redirect blood flow Endoscopic variceal banding Endoscopic variceal banding

Minimize Encephalopathy Lactulose Lactulose Powerful laxative Powerful laxative Prevents build-up of gut ammonia Prevents build-up of gut ammonia Dose = up to 60 mL/day Dose = up to 60 mL/day Low protein diet Low protein diet Avoid Sedatives Avoid Sedatives

Summary: How to Help Screen Screen TLFB/AUDIT-C TLFB/AUDIT-C One question One question Abuse or Dependence Abuse or Dependence Intervene Intervene Hazardous use  SBIRT, MM Hazardous use  SBIRT, MM Dependence  AA, day treatment, residential Dependence  AA, day treatment, residential Treat ALD Treat ALD Control ascites, varices, encephalopathy Control ascites, varices, encephalopathy Liver transplant Liver transplant

Take-Home Message Too much alcohol is bad for your liver Too much alcohol is bad for your liver Too much = Too much = Men > 14 drinks/wk, > 4 drinks/occ. Men > 14 drinks/wk, > 4 drinks/occ. Women > 7 drinks/wk, > 3 drinks/occ. Women > 7 drinks/wk, > 3 drinks/occ. AUDIT-C > 5 AUDIT-C > 5