Alcohol and the GIT.pdf

Alcohol and the GIT
Dr Onyekwere CA

outline
• Introduction; alcohol, public health perspective
• Types & Pattern of alcohol consumption, quantity
• Safe level and toxicity; effect on motility, mucosa
effects, acid secretion, bactericidal action on H
pylori and other enteropathogens, promotion of
malignancy, effect on the liver and pancreas
• Managing alcohol abuse disorder

Terminologies
• Alcohol use disorders;-EASL as a problematic pattern
of alcohol use leading to clinically significant impairment or
distress ‘
• WHO still uses the terms hazardous and harmful alcohol use and
alcohol dependence
• The term ‘risky drinker’ is commonly used to define people who
drink excessively

Alcohol use disorders:
DSM-V criteria
*Or a closely related substance, such as benzodiazepine
EASL CPG ALD. J Hepatol 2018;69:154–81
Manifested by ≥2 of the following, occurring within a 12-month period:
1 Alcohol is often taken in larger amounts or over a longer period than was intended
2 There is a persistent desire or unsuccessful efforts to cut down or control alcohol use
3
A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from
its effects
4 Craving, or a strong desire or urge to use alcohol
5 Recurrent alcohol use resulting in a failure to fulfil major role obligations at work, school, or home
6
Continued alcohol use despite having persistent or recurrent social or interpersonal problems
caused or exacerbated by the effects of alcohol
7
Important social, occupational, or recreational activities are given up or reduced because of
alcohol use
8 Recurrent alcohol use in situations in which it is physically hazardous
9
Alcohol use is continued despite knowledge of having a persistent or recurrent physical or
psychological problem that is likely to have been caused or exacerbated by alcohol
10
Tolerance, as defined by either of the following:
a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect
b. A markedly diminished effect with continued use of the same amount of alcohol
11
Withdrawal, as manifested by either of the following:
a. The characteristic withdrawal syndrome for alcohol
b. Alcohol* is taken to relieve or avoid withdrawal symptoms

Public health aspects:
Alcohol-related morbidity and mortality
1. WHO. Global status report on noncommunicable diseases 2014.
Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018;
• Worldwide, harmful use of alcohol is associated with:
– ~3.3 million deaths every year 1
• 5.9% of all deaths overall (7.6% in men, 4.0% in women)1
– ~139 million disability-adjusted life years
• 5.1% of the global burden of disease and injury
• Alcohol has an impact on over 200 diseases and types of injuries
• Most deaths attributable to alcohol consumption from:
– Cardiovascular diseases
– Injuries
– Gastrointestinal diseases
• Mainly cirrhosis
– Cancers
• Alcohol-attributable fraction is highest for liver diseases and foetal
alcohol syndrome

Public health issues:
Definitions of “drink” and “drinking”
• Quantification of alcohol consumption is not easy in clinical practice
• Grams of alcohol is more precise, but:
– Time consuming and frequently difficult to obtain
– Patients cannot recall the different amounts and types of drink
Term Definition
One standard drink 10 g of alcohol
Harmful drinking Where alcohol use is causing damage to either
physical or mental health
Heavy episodic drinking Consumption of more than 60 g of pure alcohol
on one occasion
Binge drinking Consumption within about 2 hours of four or
more drinks for women and five or more drinks
for men

Data are conflicting around a safe alcohol limit
• Light–moderate intake: reduced risk of coronary artery disease
• Heavy chronic alcohol intake: increased risk of cardiomyopathy,
hypertension, atrial arrhythmias and haemorrhagic stroke
• Alcohol is a recognized carcinogen
– No threshold level of consumption known for cancer risk
• Chronic use of alcohol is a risk factor for cirrhosis
• Unclear whether there is a continuous dose–response relationship
• Unclear whether there is a threshold at which the risk emerges
• Risks of binge drinking vs. daily drinking remain controversial
• Cessation of drinking at any point reduces risk of disease progression
and occurrence of complications
Recommendation
Limit daily intake to ≤2 standard drinks for women and ≤3 for men.
This amount is not associated with significant increase in cirrhosis mortality

Effect on motility including GERD
• In healthy volunteers, alcohol reduces the
pressure of the LES as well as the oesophageal
motility, thereby worsening the symptoms of
GERD
• However in chronic alcoholics, is said to increase
the tone of the LES but with frequent spontanous
relaxation of the LES.
• In the stomach, small quantity of alcohol is
thought to improve gastric emptying while large
percentage reduces it. Also it causes reduction in
small intestinal motility.

Effect on mucosa including mallory
Weiss tear
• It has direct toxic effect on the mucosa, the
injury ranges from mild erythema to
hemorrhagic gastritis.
• The mallory weiss is a linear tear in the cardia
following protracted retching after a bout of
alcohol.

Effect on gastric acid secretion
• In small quantity, alcohol stimulates gastric
acid secretion by action on gastrin release and
to lesser extent by direct effect on parietal
cells.
• This effect is thought to be due to presence of
maleic and succinic acid which is removed
during distillation, such that wine, champagne
has little of these property

Antibacterial effect
• Wine has long been known for its disinfecting and
cleansing properties, even from the biblical times.
Infact wine was used during the Prussian War to
prevent dysentery.
• It has been shown to have bactericidal effect on
salmonella, shigella and helicobacter species, action
thought to be related to the acid PH and acohol.

Alcohol and GI tumours
• Alcohol consumption has been linked to
increased risk of tumors in the pharynx,
esophagus, stomach and colon. Some of the
factors associated with alcohol consumption
that may favor the development of tumors
include: generation of free radicals (peroxide,
superoxide) and other oxidizing factors,
inorganic arsenic, preservatives

Alcohol and Pancreas
• Alcohol consumption is linked to the
development of recurrent acute pancreatitis

Alcoholic liver disease
• Alcohol is a major cause of chronic liver
disease in the west especially Europe and UK.
• The exact pathogenesis of alcoholic liver
injury is still not clear but immune
mediated and free radical hepatic injury
are thought to be important. Genetic
factors are thought to predispose to
hepatic injury in susceptible individuals.

Factors increasing susceptibility to ALD
• Lifetime intake of alcohol
• Female sex
• Genetic factors
• Drinking without food
• Binge drinking
• High concentration alcoholic drinks—for example,
spirits
• Drinking multiple different alcoholic beverages

Pathogenesis and spectrum of Alcohol
liver disease
• Alcohol metabolism takes place in the
mitochondria. Ethanol is oxidised to acetaldehyde
by alcohol dehydrogenase, which in turn is
oxidised to acetate by acetaldehyde
dehydrogenase.
• These oxidation reactions are associated with the
formation of NADH and NAD and alter the redox
state of the cell. This has harmful effects on lipid
and carbohydrate metabolism—for example,
steatosis.

Spectrum of alcohol liver disease &
pathology
• Major classiﬁcation of ALD: Alcoholic fatty liver
(steatosis),
• Acute alcoholic hepatitis,
• Alcoholic cirrhosis
• Histological features of ALD: Steatosis (fatty liver)
• Mallory’s hyaline bodies
• Cholestasis
• Liver ﬁbrosis
• Micronodular cirrhosis
•

Alcoholic liver disease contd.
• Diagnosis is based on accurate history, raised serum
markers such as γ-glutamyltransferase, mean
corpuscular volume, and IgA and liver histology when
obtainable.
• Abstinence is the most important aspect of treatment.
• Newer drugs such as acamprosate and naltrexone
are used to reduce alcohol craving.
• Vitamin supplements and nutrition are vital.
• corticosteroids have a role in acute alcoholic hepatitis
• Liver transplantation is beneficial in abstinent patients
with end stage liver disease

Screening to reduce ALD-related morbidity and mortality
• Early recognition and intervention are required
– Goal of abstinence or decreased alcohol consumption should be
implemented to reduce the risk of liver disease in harmful drinkers
• Screening for harmful drinking should be performed by GPs, and in
patients admitted to emergency facilities, with screening for ALD in
high-risk patients
• Suggested screening methods include:
– Blood markers
– Transient elastography
• Screening must be followed by an intervention with a multidisciplinary
team
– Specialist alcohol care teams are required to care for patients

Screening tools: AUDIT
WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018;
• Developed by the WHO in 1982 and remains the gold standard
• Good sensitivity and specificity in clinical settings across countries
Question
Score
0 1 2 3 4
1. How often do you have a drink containing alcohol? Never Monthly or
less
2 to 4 times a
month
2 to 3 times
a week
4 or more
times a week
2. How many drinks containing alcohol do you have on a typical
day when you are drinking?
1 or 2 3 or 4 5 or 6 7 to 9 10 or more
3. How often do you have five or more drinks on one occasion? Never Less than
monthly
Monthly Weekly Daily or
almost daily
4. How often during the last year have you found that you were not
able to stop drinking once you had started?
Never Less than
monthly
almost daily
5. How often during the last year have you failed to do what was
normally expected of you because of drinking?
Never Less than
monthly
almost daily
6. How often during the last year have you needed a first drink in
the morning to get yourself going after a heavy drinking session?
Never Less than
monthly
almost daily
7. How often during the last year have you had a feeling of guilt or
remorse after drinking?
Never Less than
monthly
almost daily
8. How often during the last year have you been unable to
remember what happened the night before because of your
drinking?
Never Less than
monthly
almost daily
9. Have you or someone else been injured because of your
drinking?
No – Yes, but not in
the last year
– Yes, during
the last year
10. Has a relative, friend, doctor or other healthcare worker been
concerned about your drinking or suggested you cut down?
No – Yes, but not in
the last year
– Yes, during
the last year

Alcohol audit-interpretation
• Question 1-3 explore consumption pattern
• Question 4-6 evaluate dependency
• Question 7-10 investigate alcohol related problems
• Total score of >8 indicate alcohol abuse disorder while
• > 20 indicate alcohol dependency

Screening
• Patients with AUD have a high prevalence of psychiatric co-morbidity
– Anxiety disorders
– Affective disorders
– Schizophrenia
• At higher risk of developing other addictions
– Special attention should be paid to coordination between hepatologists
and addiction specialists (psychiatrists, psychologists, and social workers)
Recommendations
• AUDIT or AUDIT-C should be used to screen patients for
AUD and dependence
A 1
• Patients with AUD should be screened for concurrent
psychiatric disorders and other addictions
A 1
Grade of recommendation Level of evidence

Management of alcohol withdrawal syndrome
• AWS is a severe medical condition affecting alcohol-dependent
patients who suddenly discontinue or decrease alcohol consumption
• Light or moderate AWS usually develops 6–24 hours after the
last drink
• Symptoms may include:
– Increased blood pressure and pulse rate
– Tremors
– Hyperreflexia
– Irritability
– Anxiety
– Headache
– Nausea and vomiting
• Symptoms may progress to more severe forms of AWS
– Characterized by delirium tremens, seizures, coma, cardiac arrest,
and death

Management of alcohol withdrawal syndrome
• Pharmacological treatment is recommended for both moderate and
severe AWS
– Symptom-triggered regimen rather than fixed-dose schedule in order to
prevent accumulation
• Benzodiazepines are considered the ‘gold standard’ treatment for AWS
– Efficacy for reducing both withdrawal symptoms and the risk of seizures
and/or delirium tremens
Recommendations
• Benzodiazepines should be used to treat AWS but
should not be prescribed beyond 10–14 days because of
the potential for abuse and/or encephalopathy
A 1

Medical management of AUD in patients with ALD
1. Lackner C, et al. J Hepatol. 2017;66:6108;
• Alcohol abstinence is a critical goal in patients with ALD
– Abstinence improves clinical outcomes at all stages of ALD
• Naltrexone, nalmefene, disulfiram and acamprosate are approved to
treat AUD
– Disulfiram should be avoided in patients with severe ALD
• Disulfiram, naltrexone and acamprosate are approved for abstinence
Effect of abstinence during follow-up on survival probability1
0
0.0
0.2
2
0.4
0.6
0.8
1.0
4 6 8 9 10
Time (years)
Survival
probability
1 3 5 7
Abstinence
No
Yes P=0.017
0
0.0
0.2
2
0.4
0.6
0.8
1.0
4 6 8 9 10
Time (years)
Survival
probability
1 3 5 7
Abstinence
No
Yes P=0.013
Early/compensated ALD Decompensated ALD

Diagnostic tests in the management of ALD:
Screening and clinical diagnosis
• Diagnosis of ALD is usually suspected with:
– Documentation of regular alcohol consumption of >20 g/d in females
and >30 g/d in males
AND
– Presence of clinical and/or biological abnormalities suggestive of
liver injury
• A high proportion of patients with histological features of ALD do not
show any clinical symptoms or laboratory abnormalities
– Asymptomatic patients consuming a critical amount of alcohol should
undergo appropriate screening investigations
• Consider ALD in patients presenting with extrahepatic manifestations
of AUD
– E.g. symmetric peripheral neuropathy, pancreatitis, cardiomyopathy

Screening investigations
*Platelets >150,000 and Fibroscan® <20
Rule out alternative or additional
causes of liver injury
• HBV and HCV serology
• Autoimmune markers
• Transferrin and transferrin saturation
• α1-antitrypsin
Suspected advanced fibrosis
or cirrhosis
Evaluate liver function and evidence of
portal hypertension:
• Serum albumin, prothrombin time or INR
• Serum bilirubin levels
• Platelet and WBC counts
Upper GI endoscopy for oesophageal
varices unless low risk based on Baveno
criteria*
Abnormalities on initial screening
Liver function tests (including GGT, ALT, AST)
+
Liver fibrosis (e.g. TE)
Ultrasound

Role of liver biopsy
• Liver biopsy generally not recommended except in the following
situations.
• Liver biopsy may be used to:
– Establish the definite diagnosis of ALD
– Assess the exact stage and prognosis of liver disease
– Exclude alternative or additional causes of liver injury

Histological features and diagnosis of ALD types
Images provided courtesy of Lackner C.
• Lesions predominate in
centrilobular regions (in
pre-cirrhotic stages)
– Alcoholic steatosis
o Macro and eventually variable
blend of macro- and microvesicles
– Alcoholic steatohepatitis (ASH)
o Variable degree of macrovesicular
steatosis
o Hepatocellular injury with
ballooning, potentially necrosis
o Lobular inflammation
– Alcoholic fibrosis/cirhosis
o Pericellular fibrosis (PCF) and/or
septal F in precirrhotic stage
o Micronodular cirrhosis ± PCF
• A single lesion or any combination
may be found in a given individual
Main histological diagnoses:
Steatosis
Steatohepatitis
Cirrhosis

Indirect markers of alcohol consumption
Biomarker
Biological
material
Detection
window
EtOH
amount Sens. Spec. Confounding factors
GGT Serum
Chronic
excessive
42–86% 40–84% Liver disease, BMI, sex, drugs
AST Serum
Chronic
excessive
43–68% 56–95%
Liver and muscle diseases,
BMI, drugs
ALT Serum
Chronic
excessive
30–50% 51–92% Liver disease, BMI, drugs
MCV Serum
Chronic
excessive
24–75% 56–96%
Vitamin B12,
folic acid deficiency,
haematological diseases
% CDT Serum 1–2 weeks
50–80 g/d for
>1–2 weeks
25–84% 70–98%
Liver cirrhosis/disease, nicotine,
transferrin level, weight, sex,
pregnancy, rare genetic
variations
Diagnostic performance of indirect markers is not adequate

Management of alcoholic hepatitis:
Evaluation of severity
*Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating
specific therapy
• Different prognostic models aim to identify patients at high risk of early death
– Often incorporate the same variables and have similar efficacy in predicting
short-term survival
• Lille model can predict pattern of response to corticosteroid treatment
– Based on pre-treatment data plus the response of serum bilirubin
Score Bilirubin PT/INR
Creatinine/
urea Leucocytes Age Albumin
Change in
bilirubin
(Day 0 to 7)
Maddrey
DF*
+ + – – – – –
MELD + + + – – – –
GAHS + + + + + – –
ABIC + + + – + + –
Lille + + + – + + +

General measures
• Alcohol abstinence is the cornerstone of therapy
– Early management of AUD is recommended in all patients with AH
• Considering the potential risk of Wernicke’s encephalopathy,
supplementation with B-complex vitamins is recommended
• Other general approaches include:
– Treatment of hepatic encephalopathy (lactulose, rifaximin)
– Treatment of ascites (salt restriction)
– Prevention of renal failure in patients with severe AH
• Avoidance of diuretics and nephrotoxic drugs
• Volume expansion if needed
• Use of beta-blockers may increase the risk of AKI

Nutrition
• Protein energy malnutrition is present in almost every patient with
severe AH, and is associated with poor prognosis
• Use of tube feeding is strongly recommended if patients are not able to
maintain adequate oral intake
• Insufficient evidence to support a recommendation for parenteral
nutrition, particularly given the high risk of line sepsis
Recommendations
A careful evaluation of nutritional status should be performed; patients
should aim to achieve a daily energy intake ≥35–40 kcal/kg BW and
1.2–1.5 g/kg protein, and to adopt oral route as first-line
intervention
A 2

Corticosteroids
*Prednisolone 40 mg/day or methylprednisolone 32 mg/day
• Use of corticosteroids is limited by concerns about heightened risks of sepsis and
gastrointestinal bleeding
• Early identification of non-responders to corticosteroids is important to define stopping
rules and limit unnecessary exposure
• At the end of the course of treatment corticosteroids can be stopped immediately or
the dose tapered over a period of 3 weeks
Recommendations
In the absence of active infection, corticosteroids* should be
considered in patients with severe AH to reduce short-term mortality
A 1
N-acetylcysteine (for 5 days, intravenously) may be combined with
corticosteroids in patients with severe AH
B 2
Early non-response (at Day 7) to corticosteroids should be identified
and strict rules for the cessation of therapy should be applied
A 1
In case of non-response to corticosteroids, highly selected patients
should be considered for early liver transplantation
A 1

Infection
• Infection is a frequent and severe complication in patients with severe AH, and
is one of the major causes of death
– Bacterial infections are responsible for 90% of infectious episodes
– Invasive aspergillosis has been reported as a complication associated with
poor outcome
– Sporadic cases of pneumocystis pneumonia have been described in patients with
severe AH and concomitant corticosteroid treatment, with a very high mortality rate
• Corticosteroids do not appear to increase the risk of infection or mortality from
infection, but may exacerbate infection
Recommendations
Systematic screening for infection should be performed before
initiating therapy, during corticosteroid treatment, and during
follow-up period
A 1

Alcohol-related fibrosis and cirrhosis
*Ascites, jaundice, variceal bleeding, infections, hepatorenal syndrome, hepatic encephalopathy, cachexia
• A range of environmental and host factors have been linked with risk of
progression to advanced ALD (extensive liver fibrosis and cirrhosis)
– Cigarette smoking, gender, ethnicity, comorbid conditions (e.g. diabetes
and obesity), microbial dysbiosis, chronic infection with HBV and HCV
and/or HIV, α-antitrypsin deficiency, iron overload
– Genetic risk factors
• Polymorphisms in the PNPLA3 gene
• Genetic variants on TM6SF2 and MBOAT7
– Type and pattern of alcohol use
• ALD cirrhosis may present as compensated or decompensated*
– May also be associated with extrahepatic alcohol-related organ damage
• Alcohol-related cardiomyopathy, acute and chronic pancreatitis, central and
peripheral nerve involvement, hepatic encephalopathy

Management of suspected alcoholic hepatitis:
Treatment algorithm
*Particularly in null responders (Lille score ≥0.56).
Stop treatment* and assessment
for early liver transplantation in
highly selected patients
Continue treatment for 28 days
Lille score ≥0.45
Lille score <0.45
mDF <32 and GAHS <9
Assess treatment response at
Day 7 (Lille score)
Prednisolone 40 mg/day ± NAC No specific therapy
mDF ≥32 or GAHS ≥9
Assessment of disease severity
(prognostic scores)
• Systematic evaluation of nutritional
status and energy intake
• Daily target 35–40 kcal/kg BW
• Prefer oral route as first-line intervention
• Supplementation with B-complex
vitamins
Consider liver biopsy if
diagnosis is uncertain
Perform systematic extensive
screening for infection
Treatment of alcohol
dependence
Clinical diagnosis of AH

Liver transplantation:
Trends in liver transplantation of ALD
1. Data from European Liver Transplant Registry; EASL CPG ALD. J Hepatol 2018;69:154–81
• LT is the most effective therapeutic option for patients with ESLD
– 1-year post-transplant patient and graft survival is ~80–85%
• Liver outcomes after LT in patients with AUD have improved
– Graft and patient survival now similar to after LT for other aetiologies
• Alcohol-related cirrhosis represents an increasing proportion of LTs in Europe1
ALD cirrhosis (24,452)
Autoimmune cirrhosis (2,992)
Cryptogenic (unknown) cirrhosis (5,750)
Other cirrhosis (2,880)
Primary biliary cirrhosis (8,130)
Secondary biliary cirrhosis (998)
Viral + cirrhosis due to alcohol (2,792)
Virus-related cirrhosis (28,043)
0
20
40
60
80
100
Percentage
Aetiology of cirrhosis leading to LT in Europe

Policies to reduce population risk for ALD
• Effective interventions include:
– Price based policies
• Taxation
• Minimum unit pricing
– Limitation of alcohol availability
– Restriction of marketing and advertising
• Policies based on age-related vulnerability
– Partial or total advertising bans
– Restrictions on access to alcohol through minimum ages at which it is legal
to purchase alcohol
– Laws to prevent any alcohol consumption by young people when
driving vehicles

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