Alcoholic liver disease

1. Alcoholic liver disease
Ian Ch’ng
23/6/23

2. Topics
1. Alcoholic hepatitis
2. Alcohol related fibrosis
3. Alcohol related cirrhosis

3. Incidence
• Harmful use of alcohol has been estimated to cause approximately
3.3 million deaths every year according to WHO in 2014
• 6% of all deaths globally
• 139 million disability-adjusted life years, or 5.1% of the global burden
of disease and injury were attributed to alcohol consumption

5. • Alcohol related morbidity and mortality- highest alcohol attributable
fractions reported in the WHO European region.
• Mean alcohol consumption in the world is 6.2 L of pure
alcohol/person/year
• Europe: 10.9 L/person/year
• OECD report 2017: 9L/person/year. 30% of men and 12% of women
binge-drink at least once per month
• In the EU, at least 41% of liver deaths are due to alcohol

7. Alcohol- health impact
• Alcohol has an impact on over 200 diseases and injuries. Most cases
are detrimental
• Most common: CV diseases, injuries, GI diseases (mainly liver
cirrhosis), and cancers.
• Lower consumption in lower economic wealth country, but morbidity
and mortality risks are higher per liter of pure alcohol consumed than
in the higher income countries.

8. How much is too much?
• Alcohol is a recognized carcinogen, and no threshold level of
consumption exists for the risk of cancer
• Cirrhosis- unsure whether there is a continuous dose response
relationship or a threshold of consumption at which the risk emerges
• 2010 meta analysis: increased risk of mortality from liver cirrhosis
among men and women drinking 12-24g of ethanol per day
• Good clinical evidence that cessation of drinking at any point in the
natural history of the disease reduces the risks of disease
progressions and occurrence of complications from cirrhosis

9. Screening for alcohol misuse
• Quantity frequency questionnaires and diaries (e.g Timeline
Followback)
• Apps (e.g Drinkaware)
• AUDIT (Alcohol Use Disorders Inventory Test)
• 1-3: consumption
• 4-6: dependence
• 7-10: alcohol related problems
• 2 cut off points, one for dependence and one for risky drinking
• Shorter version: AUDIT-C (reliable for the screening of risky drinking)

10. Alcohol use disorder
• Problematic pattern of alcohol use leading to clinically significant
impairment or distress, with graded levels of severity depending on
the number of diagnostic criteria met (DSM V)
• mild 2-3 criteria
• moderate 4-5 criteria
• severe 6 or more

12. Screening for other psychiatric disorder
• Patients with AUD have a high prevalence of psychiatric comorbidity.
• High prevalence of anxiety disorders, affective disorders, and
schizophrenia.
• They also have higher risk of developing other addictions (cigarette
smoking, illicit drug use)

13. Management of alcohol withdrawal syndrome
(AWS)
• Light or moderate AWS usually develops within 6-24 h after the last
drink
• Symptoms
• Increased BP, tachycardia
• Tremors
• Hyperreflexia
• Irritability, anxiety
• Headache
• Nausea, vomiting

14. • Severe forms of AWS
• Delirium tremens
• Seizures
• Coma
• Cardiac arrest, death
• CIWA-Ar score >8 indicates moderate and ≥15 indicates severe AWS.
• Benzodiazepine is the gold standard
• Short and intermediate acting (e.g lorazepam, oxazepam) are safer in elderly
and in those with hepatic dysfunction
• Long acting (e.g diazepam, chlordiazepoxide) provides more protection
against seizures and delirium.

15. • Alcohol abstinence
• Disulfiram- effective alcohol pharmacotherapy, but should be avoided
in severe ALD because of possible hepatotoxicity
• Naltrexone (opioid antagonist) and acamprosate (glutamatergic
receptor modulator)- approved for abstinence
• Nalmefene (opioid modulator)- approved for the reduction of heavy
drinking
• Topiramate (anticonvulsant)- demonstrated safety and efficacy in
reducing heavy drinking
• Baclofen- only drug studied in promoting alcohol abstinence in
patients with ALD and cirrhosis. Mixed results.

16. Alcoholic liver disease
• Alcoholic hepatitis (AH)
• Alcoholic liver fibrosis
• Alcoholic liver cirrhosis

17. Alcoholic liver disease
• Early recognition is essential
• Screening for harmful alcohol consumption should be done
systematically by GP and ED
• Screening for ALD should be undertaken in patients with
• clinical signs of suggestive of harmful alcohol consumption or liver cirrhosis
• High risk populations- those in alcohol rehabilitations clinic, or harmful
drinkers identified by GP

18. Alcoholic hepatitis- Diagnosis
• Suspected upon regular consumption of >20g/d in females and 30g/d
in males
+
• Presence of clinical/biological abnormalities suggestive of liver injury

19. • Asymptomatic patients consuming a critical amount of alcohol should
be screened as they may not express any clinical symptoms or
laboratory abnormalities
• Consider alcoholic liver disease in patients presenting with
extrahepatic manifestations of AUD
• Symmetrical peripheral neuropathy
• pancreatitis
• cardiomyopathy, etc

20. Investigations
• Full LFT including ALT, AST, and GGT
• TE for liver fibrosis
• Ultrasound
• Exclude alternate cause of liver injury: HBV, HCV, AIH, transferrin/tsat,
a1-antitrypsin, in some case caeruloplasmin
• Non-invasive model: ALD/NAFLD index
• MCV
• AST/ALT ratio
• BMI
• Gender

21. • In advanced cirrhosis/fibrosis:
• albumin
• PT/INR
• serum bilirubin level
• platelet/ WCC
• OGDS (base on Baveno criteria - plt > 150,000 and fibroscan <20)

22. Markers to differentiate ALD vs other liver disease
• No single or combination of markers can differentiate between
different causes of liver disease.
• GGT is usually higher in patients with ALD compared to other liver
disease.
• AST levels are elevated in ALD (50% sensitivity and 80& specificity)
• AST/ALT ratio typically > 1 (not specific/sensitive particularly in
cirrhosis)
• Carbohydrate deficient transferrin (CDT) can indicate heavy alcohol
consumption (50-80g daily intake over past 1-2 weeks)

23. Direct markers for alcohol consumption
• Ethyl glucoronide (EtG): urine EtG is wide applied in many European countries
for proving recent alcohol abstinence in forensic settings/ regular monitoring
for alcohol addicted patients prior to listing for liver transplantation
• Scalp hair (hEtG): can monitor long term abstinence from alcohol over a
period of up to 6 months. 1cm hair reflects consumption over approximately 1
month
• ethyl sulfate
• phosphatidylethanol
• fatty acid ehtyl esters
Advantage: much longer detection window

24. Liver biopsy
Indication
• establish definite diagnosis of ALD
• assess exact stage and prognosis
• exclude alternative or additional causes of liver injury
Potential complications
• intrahepatic bleeding
• pneumothorax
• biopsy is not generally recommended for all patients with suspected ALD,
risk should be carefully weighed against the clinical benefits and
therapeutic consequences

25. Biopsy findings
• macrovesicular steatosis, eventually a variable blend of macro and
micro-vesicles (mixed type steatosis);
• hepatocellular injury with ballooning (swelling, rounding, and pale
staining of the cytoplasm), potentially necrosis;
• lobular inflammation;
• fibrosis or cirrhosis
*morphological lesion of ALD and NAFLD show broad overlap.
(hepatocellular injury and fibrosis are often more severe in ALD,
though)

26. Morphological lesions more specific in ALD
• sclerosing hyaline necrosis
• alcoholic foaming degeneration
• fibro-obliterative changes in hepatic veins
• portal acute inflammation
• cholestasis
All these features are very rare or have not been described in patients
with pure NAFLD

27. Non invasive test
• Risk of liver biopsy is well recognised, hence it has fostered efforts to
develop non-invasive test.
• Serum levels of caspasecleaved keratin 18 (K18) epitopes M30 and
M65 (by ELISA) – predict histological diagnosis of AH with modest
diagnostic accuracy
• Also predictor of non-HCC liver related mortality in patients with
alcoholic cirrhosis
• Liver stiffness measurement by TE is useful for assessing hepatic
fibrosis in ALD

28. • Alcoholic hepatitis markedly increases LSM in patients with ALD
independent of fibrosis stage, hence patients with AST > 100 with ALD
should have their stiffness values interpreted with caution. (May have
falsely elevated liver stiffness as a result of superimposed alcoholic
hepatitis)
• Other factors affecting fibroscan result
• Inflammation
• Cholestasis
• Liver congestion

29. • LSM by TE and 2-D elastography -> equally suited to rule out rathe
than rule in advanced fibrosis and cirrhosis (high negative predictive
values)
• Other imaging techniques (USG/MRI/CT)
• Allow quantification of steatosis
• Help exclude other causes of CLD such as PSC
• Assesssment of advanced liver disease and tis complications independently of
the aetiology

30. Alcoholic Hepatitis
• Def: recent onset of jaundice with or without other signs of liver
decompensation in patients with ongoing alcohol abuse
• Possible to have onset of symptoms days or weeks after ceasing
alcohol consumption.
• Cardinal sign: progressive jaundice, often associated with fever (even
in the abscence of infection)
• malaise
• weight loss
• malnutrition

31. ix
• neutrophilia
• hyperbilirubinemia
• serum AST > 2x ULN
• AST > 50 (rarely > 300)
• AST/ALT ratio typically > 1.5 - 2.0
• liver biopsy can be useful to confirm the diagnosis, rule out other
diagnosis, and for prognostification.
Severe:
- prolonged PT, hypoalbuminemia, thrombocytopenia

32. Evaluation of severity
1) Maddrey discrimination function = (4.6 x [PT - control PT] + serum
bilirubin)
• DF ≥32 in the presence of HE predicts > 50% mortality at 28 days, 1
month survival > 90% if DF <32
2) MELD score for short term pregonisis of alcoholic hepatitis (above20-
high risk of 90 day mortality)
3) Glasgow alcoholic hepatitis score (GAHS)- derived from 5 variables
(age, bilirubin, urea, PT, WCC) and identifies patients at greatest risk of
death in the absence of treatment

33. Treatment
• ALD should be considered a dual pathology including both a liver and
an addiction disease.
• Alcohol abstinence is the cornerstone of therapy regardless of
severity (main determinant of long term prognosis)
• Vitamin B complex (Wernicke’s encephalopathy)
• Lactulose, rifaximin (hepatic encephalopathy)
• Salt restriction (ascites)
• Beta blocker (varices prevention – may cause AKI)
• Risk of development of AKI- poor prognosis

34. Nutrition
• Protein energy malnutrition is present in almost every patient with
severe AH -> poor prognosis
• Daily energy intake of 35-40 kcal/kg of BW and daily protein intake of
1.2- 1.5g/kg of BW
• For example- 60kg patients- 2100 kcal intake + 72g protein intake per
day
• Use of tube feeding recommended if unable to achieve

35. • Use of corticosteroid is controversial -> effect modest, increase risk of
sepsis and GI bleed
• Prednisolone 40mg OD or methylpred 32mg OD x 28/7. Can be stopped all
at once or taper gradually. Use lille score to predict poor response to
steroid at 7 days of therapy.
• New multicentre French trial showed combination of NAC with
prednisolone significantly reduced the incidence of hepatorenal syndrome
and infections, and prognosis of patients with severe AH.
• G-CSF: contrasting studies
• Pentoxifylline, anti TNF agents (e.g infliximab, etanercept)- not
recommended

36. • Extracorporeal liver support procedures can remove some potentially
damaging circulating molecules
• To date, no clear benefit has been demonstrated

37. Infection in alcoholic hepatitis
• One of the major causes of death in severe AH.
• Use of corticosteroid is controversial- may increase infection.
However having baseline infection who received prednisolone, there
was a significant reduction in 90-day mortality associated with
continued antibiotic therapy when compared with those patients in
whom antibiotic therapy was stopped before initiating prednisolone.
• More commonly bacterial infections – SBP (44%), UTI (32%)
• Pneumonia 40% if given corticosteroid. PCP were also reported.
• Invasive aspergillosis has been reported to complicated severe AH
(investigate with serum galactomannan)

39. Alcohol related fibrosis
• Excessive alcohol consumption may induce -> pure alcoholic steatosis,
steatohepatitis, progressive liver fibrosis, and HCC
• Above a daily consumption of 30g/day, or a weekly consumption above 7
units in women and 14 units in men, risk of developing ALD is increased.
• Pure hepatic steasosis, oten symptomatic and overlooked, is almost
constant in individuals consuming alcohol in excess (> 100g/day) and
may fully reverse following severeal weeks of abstinence.
• In excessive drinkers in whom liver biopsy was repeated after four years
of follow-up, both steatosis and lesions of AH were independently
associated with progression of fibrosis.

40. Other factors
• amount, type and pattern of alcohol consumption
• cigarette smoking- smoking at least 1 pack a day triped the risk of ALD
• Coffee drinking- 2 cups of coffee/day decreased nearly half the risk of
alcoholic cirrhosis.
• Gender, ethnicity
• Comorbids (DM, obesity)
• Chronic infections (HBV, HCV, HIV) etc

41. Management
• Challenging- most patients are asymptomatic in the early phase.
• Complete and sustained alcohol abstinence- cornerstone of
management of ALD
• Fibrosis potentially reversible.
• Treating comorbid conditions such as obesity/metabolic syndrome
• Interventions targeting alcohol misuse
• Future development of molecules targeting extracellular matrix and
liver fibrosis may open novel therapeutic perspectives in chronic liver
diseases including ALD
• Monitoring changes in fibrosis can be done by Fibroscan.

42. Alcoholic cirrhosis
• Liver fibrosis can progress to cirrhosis, as defined by a marked
distortion of hepatic architecture by extensive fibrosis
• chicken wire pattern
• formation of regenerating nodules
• abnormal sinusoidal blood flow
• Patients who reach durable abstinence have no or mild steatosis, and
minor parenchymal lymphomonocytic infiltrate, if any.
• Persistence of steatosis may suggest NAFLD as a comorbid condition,
or result from ongoing alcohol intake.

43. Screening for liver cirrhosis
• Southampton traffic light test
• Transient elastography techniques (excellent diagnostic value for liver
fibrosis in ALD)
• Must be followed by an intervention with a multidisciplinary team

44. Compensated vs decompensation
• Compensated- aysmptomatic
• Decompensated- jaundice, ascites, variceal bleed, infections,
hepatorenal syndrome, hepatic encephalopathy, cachexia.
• Increased risk of HCC/ bacterial infection/ sepsis
• Alcoholic cardimyopathy, alcoholic pancreatitis, igA induced
nephropathy, central and peripheral nerve involvement
• CNS: Wernicke’s encephalopathy, withdrawal syndrome
• Prognosis: child pugh or MELD

45. Liver transplant
• Most effective therapeutic option for patients with end-stage liver
disease
• Post transplant patient and graft survival at 80-85% at 1 year.
• Only a minority of patients with AUD meet the rigorous criteria
required for transplant candidates (numbers have increased for the
past 2 decades)

47. • Self inflicted disease?
• Degree of priority for transplant?
• Personal moral judgment vs ethical exercise of medicine?

48. • survival benefit restricted to patients with advanced decompensation
• MELD accurately estimates the survival benefit following transplant,
recommended to prioritise organ allocation.

49. Pre-transplant workup
• Psychosocial assessment to establish the likelihood of long-term abstinence after
transplant
• Psychiatric evaluation
• Risk factors for relapse: duration of sobirety before transplant, poor social
support, family history of alcoholism.
• 6-month period of abstinence
• allow the liver disease to recover
• Identify subsets of patients likely to maintain abstinence after transplant
• pancreatic function, renal function, nutritional status
• Detecting neuropathy, myopathy, cardiomyopathy
• Rule out IHD (since tobacco use is common), neoplastic/pre-neoplastic disease

50. END

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