Alcoholic liver disease Management .pptx

Alcoholic liver disease

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

2. Topics Alcoholic hepatitis Alcohol related fibrosis 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

4. 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

5. 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.

6. 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

7. 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)

8. 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

9. 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)

10. 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

11. 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.

12. 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.

13. Alcoholic liver disease Alcoholic hepatitis (AH) Alcoholic liver fibrosis Alcoholic liver cirrhosis

14. 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

15. 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

16. 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

17. 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

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

19. 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)

20. 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

21. 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

22. 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)

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

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

34. 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)

35. 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.

36. 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

37. 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.

38. 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.

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

40. 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

41. 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)

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

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

44. 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

45. END

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