Case Presentation: Alcoholic Liver Disease (ALD) Prince Firm

1. Case Presentation: Alcoholic Liver Disease (ALD)Prince Firm AichaRais, Amos Meir, AneelaNawaz, Anoop Jose, Catherine Taylor, Eleanor Jones-Snape, Iain Murphy, ShwetaRamkumar

2. Patient History: PC F, 46 presented one week ago with diffuse pain and bloating of the abdomen Pain in her abdomen began four days before admission Pain and abdominal distension were getting worse

3. Patient History: HPC The pain was intermittent and worse on movement, radiating to her lower back The pain was stabbing in nature and was associated with shortness of breath and loss of appetite Paracetamol and codeine did not relieve her pain Pain score is 7

4. Patient History: PMH, SH, FH • Was admitted to hospital 5 weeks ago with a similar episode of abdominal swelling and fluid overload • She was diagnosed 4 years ago with Alcoholic Liver Disease (ALD) • She has Hepatitis C • Used to drink 126 units of alcohol per week for 18 years • Stopped drinking alcohol 6 months ago • Smokes 2-3 rolls of tobacco per day and has done so for the past 32 years • Ex-IVDU • No significant family history

5. Patient History: DH • Paracetamol – 1 g, PO/IV, 6 hourly PRN • Codeine – 30-60 mg, PO, 6 hourly PRN • Oramorph – 2.5-5 mg, PO, 4 hourly PRN • Amoxicillin – 500 mg, PO, TDS • Dalteparin sodium – 2500 units, SC, OD • Lansoprazole – 15 mg, PO, OD • Bumetanide – 2 g, PO, OD • Spironolactone – 100 mg, PO, OD • Quinine sulphate – 300 mg, PO, OD • Thiamine – 50 mg, PO, QDS • Vitamin B Co Strong – PO, BD • Lactulose – 20 ml, PO, TDS • Anusol – Cream, PR, PRN • Bonjela – Gel, Topical, QDS • Corsodyl mouthwash – 10 ml, QDS • Fortisip – 200 ml, PO, QDS

6. Patient History: On Examination • Bilateral palmarerythema • Bilateral track marks • Bilateral yellowing of the sclera (jaundice) • Spider naevi on the upper chest and abdomen • Area of redness around umbilicus (cellulitis) • Distended abdomen with shifting dullness • Lower abdominal tenderness and tenderness along left flank • Bilateral pitting oedema extending up to thighs • Gained 12 kg over the past 2 weeks • Bibasal fine crackles on lung auscultation

7. Patient History: Blood test results

8. Patient History: Ddx Hepatitis C virus (HCV) infection Hepatic vein thrombosis Acute liver failure Decompensated alcoholic liver disease (ALD) Drug or toxin induced hepatitis Autoimmune hepatitis

9. Patient History: Treatment • Tap +/- ascitic drain • Continue diuretic therapy for fluid overload and perform CXR to monitor pulmonary oedema • Assessment to be added to the liver transplant list

10. Epidemiology • 4.4% of all male deaths and 2.0% of all female deaths in England attributed to alcohol (in 2005) • Death rates linked to alcoholic liver disease have risen by 69% in the past 30 years. • 90-100% of heavy drinkers have alcoholic fatty liver disease • One in four drinkers with fatty liver disease will develop alcoholic hepatitis • One in five drinkers with fatty liver disease will develop cirrhosis

11. Aetiology Chronic, heavy alcohol intake- a threshold of around 40-80g/day in men and around 20-40mg/day in women for 10-12 years can cause alcoholic hepatitis/cirrhosis. There is no set amount of alcohol intake that can predict the onset of ALD.The presence of co-existent liver diseases such as hepatitis C can lead to alcohol-related damage occurring at much lower levels of alcohol intake Obesity (vs a normal BMI) doubles the risk of developing alcohol-related liver damage

12. Aetiology (cont) The progression to fibrosis is faster in those patients who smoke Studies into the predisposition to cirrhosis (through enzymes involved in alcohol/acetaldehyde metabolism, or those involved in pro-inflammatory and anti-inflammatory mechanisms) are currently inconsistent

13. Risk Factors Key risk factors for the development of ALD are continued alcohol ingestion, the female gender, and co-existent Hepatitis C The co-existence of ALD and hepatitis C synergistically enhances disease progression of both fibrosis and hepatocellular carcinoma (HCC). Fibrosis will occur at an earlier time point, and its progression is accelerated.

14. Risk Factors (cont) Various studies have been conducted, looking at the progression to HCC. Alcohol consumption of >80g/day increases the risk of HCC 5-fold, whilst presence of HCV increases the risk 20-fold. However, if both excessive alcohol consumption and HCV are present concurrently, the risk of HCC increases over 100-fold A number of mechanisms have been proposed for this synergy including increased oxidative stress (via CYP2E1) and hepatic iron accumulation.

15. Pathophysiology: Alcohol and the Liver • Excess alcohol consumption – 3 key Results: • -Steatosis (Fatty Liver)-Hepatitis-Cirrhosis

16. Pathophysiology: Metabolism of Ethanol in the Liver There are 3 enzyme systems in the Liver for the catabolism of ethanol but the main process is that: Alcohol is primarily metabolised in the liver (can also be metabolised in gastric mucosa) It diffuses in to hepatocytes and is oxidisedto acetaldehyde by alcohol dehydrogenase enzyme. Acetaldehydeis inactivated by undergoing further oxidation in the mitochondria by the enzyme aldehydedehydrogenase, generating acetyl co-enzyme A (acetyl –CoA) Acetyl–CoAconverted into energy or stored as fat. The NAD+:NADH Co-factor ratio is important. *Disfuliram (Antabuse) – aldehydedehydrogenaseinhibitor. * Aldehydedehydrogenase enzyme may be congentially deficient.

17. Pathophysiology: Steatosis (fatty liver) Lipid accumulates even with moderate alcohol Chronic intake – large clear macrovesicular globules of fat develop Fatty Liver: -Large 4-6Kg (normal around 1.5 Kg) -Soft, Yellow and greasy. Late development of Fibrosis. Biochemistry: Catabolism of fat by peripheral tissues is increased = Increased delivery of fatty acids to the liver. The excess of NADH and lowered numbers of NAD+ results in oxidation of the fatty acids by mitochondria being decreased. Reversible!

18. Pathophysiology: Alcoholic Hepatitis • Inflammation of the liver • Acetaldehyde is directly toxic to liver cells and causes free radical formation • Autoimmune response is triggered by acetaldehyde binding with cell membranes • Fat-filled hepatocytes rupture, leading to inflammation • Cytokines including TNF alpha induce apoptosis

19. Pathophysiology: Cirrhosis • End stage liver damage – fibrosis • Activated stellate cells produce excess collagen • Liver has a nodular appearance • Collagen deposition and contraction restrict blood flow through the liver

20. Signs and symptoms • RUQ discomfort/pain, nausea, jaundice • Palmarerythema, spider angioma, asterixis • Hepatosplenomegaly • Ascites, variceal bleeding

21. Diagnosis • Blood tests - liver function tests detect enzymes only present after liver damage • ALT (Alaninetransaminase) • ALP (Alkaline phosphatase) • Total protein (albumin + globulin) • Bilirubin (uncongugated) • CRP • Albumin

22. Recap: Blood test results

23. Diagnosis (cont) Blood tests Alcohol consumption US, CT, MRI Liver biopsy Endoscopy

24. Treatment • Aim: reduce symptoms and treat complications • Pharmacotherapy • No therapy for ALD • Treat symptoms and complications • Ascites requires diuretics (spironolactone, furosemide) & sodium restricted diet • Abstinence • Alcohol withdrawal syndrome (counseling, naltrexone/acamprosate) • Weight Loss • In obese patients likely to reduce steatosis, steatohepatitis, and cirrhosis.

25. Treatment (cont) • Nutrition • Malnutrition is extremely high in ALD patients • Nutritional supplements to improve Nitrogen balance • Vitamins and Thiamine • Re-feeding syndrome (hypokalaemia, hypophosphataemia, hypomagneasia • Liver transplantation • End stage liver disease • Requires 6-months alcohol abstinence

26. Prognosis • Those with transplant have a 58% chance of surviving 15 years • Failure of the new liver occurs in 10% to 15% of all cases. • However, these statistics are obviously not specific for any individual and depend on a variety of factors such as: • Age • Co-morbidities • Life-style choices • Adherence to treatment regime • Personal coping abilities.