Alcoholic Liver Disease Strategies for Seamless Care or An Clinical Approach to the Jaundiced Alcoholic Patient

Transcription

1 Alcoholic Liver Disease Strategies for Seamless Care or An Clinical Approach to the Jaundiced Alcoholic Patient Liver Disease for the General Physician Royal College of Physicians July 2017 Dr Ewan Forrest Glasgow Royal Infirmary

2 Increasing Burden of Alcoholic Liver Disease >60% increase in discharges with alcoholic liver disease 2000/1 to 2009/ % increase in alcohol-related deaths 1980 to 2010.

3 The start of another medical receiving ward round year old woman history of alcohol excess; flu-like symptoms for 5 days increasingly unwell; yellow eyes Bilirubin 126; AST 3241; ALT 1194; ALP 234; PTr 3.9 Jaundiced; no ascites evident What is this likely to be? A. Alcoholic Hepatitis B. Acute Liver Injury C. Portal Vein Thrombosis D. Decompensated Alcoholic Cirrhosis E. Ascending Cholangitis

4 Biochemical Patterns of Alcoholic Liver Disease De Ritis Ratio Decision Limit Condition < to < to < Healthy Women (up to 1.7) Men (up to 1.3) Children Neonate Acute Viral Hepatitis Resolving Worsening Fulminant Alcoholic Liver Disease Resolving Alcohol Abuse Acute Hepatitis Chronic Liver Disease Stable Fibrosis risk Other Causes Muscle Disease Chronic Resolving Acute Raised AST : ALT ratio (De Ritis Ratio) AST not >500 (ALT usually <300)

5 The Jaundiced Alcoholic: Scenario 1 Acute Liver Injury In context of either no background fibrotic liver disease or established cirrhosis Atypical biochemistry; clinical context Possible Causes Drug induced: even therapeutic paracetamol Acute viral infection (HAV; HBV; HEV) Ischaemic/ Hypoxic hepatitis Co-incident primary liver disease: AIH

6 Another ward round in an alternate universe year old woman >80g alcohol per day; abdominal and ankle swelling increasingly unwell for 6 months; yellow eyes for 4 months Bilirubin 105; AST 93; ALT 32; ALP 234; PT 22 seconds (PTr 1.9); Urea 6.5; WCC 3.4 Jaundiced; drowsy; moderate abdominal distension; hepatic flap present. What is this likely to be? A. Alcoholic Hepatitis B. Acute Liver Failure C. Acute Portal Vein Thrombosis D. Decompensated Alcoholic Cirrhosis E. Ascending Cholangitis

7 The Jaundiced Alcoholic: Scenario 2 Chronic Decompensation of Chronic Disease In context of established cirrhosis Typical biochemistry; SIRS not florid Clinical Context Progressive deterioration over weeks/ months Jaundice evident >2 months Ascites and encephalopathy often predominant Represents progressive disease with continued drinking but may herald development of hepatoma

8 In the next bed, just arrived year old woman >80g alcohol per day; flu-like symptoms for 5 days increasingly unwell; yellow eyes for 2 weeks Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds (PTr 2.4); Urea 6.5; WCC 17.4 Jaundiced; pyrexial; drowsy; abdominal distension Abdominal US showed large ascites and hepato-splenomegaly. What should we do next? A. Percutaneous liver biopsy B. MRCP C. Transjugular liver biopsy D. CT Head E. Diagnostic Ascitic Aspiration

9 Sepsis in Alcoholic Liver Disease Ascitic Fluid Analysis SBP diagnosed in 20% cirrhotics admitted to hospital, and 2-3% attending for outpatient paracentesis >250 neutrophils/cm 3 (>500 WBC/ cm 3 ) and suggest spontaneous bacterial peritonitis (SBP) Samples to be sent in blood culture bottles Early antibiotics (see local guidelines) and Albumin (20% HAS: 1.5g/kg Day 1; 1g/kg Day 3 for high risk patients: Bilirubin >68 and/or Urea>11)

10 The Jaundiced Alcoholic: Scenario 3 Acute Decompensation of Chronic Disease Precipitant: often GI bleeding/ Sepsis/ Portal Vein Thrombosis Typical biochemistry; SIRS usually evident Clinical Context Can be difficult to differentiate from Alcoholic Hepatitis (and may co-exist) Full sepsis screen: blood cultures; urinalysis and culture; diagnostic ascitic tap; CXR Low threshold for antibiotics (but be wary of gentamicin)

11 BSG/BASL Clinical Bundle for Decompensated Liver Disease: the First 24 hours Stuart McPherson et al. Frontline Gastroenterology

12 Curiously an hour later there arrives year old woman Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds (PTr 2.4); Urea 6.5; WCC 17.4 Jaundiced; pyrexial; drowsy; moderate abdominal distension Abdominal US showed moderate ascites and hepatosplenomegaly. Sepsis screen negative What is this likely to be? A. Alcoholic Hepatitis B. Acute Liver Failure C. Portal Vein Thrombosis D. Decompensated Alcoholic Cirrhosis E. Ascending Cholangitis

13 The Jaundiced Alcoholic: Scenario 4 Clinically relevant Alcoholic Hepatitis Essential Features excess alcohol within 8 weeks < 2 month onset of Bilirubin > 80 mol/l Exclusion/ treatment of sepsis AST < 500 (AST: ALT ratio >1.5) Characteristic Features hepatomegaly fever leucocytosis hepatic bruit NIAAA 2016: Probable Alcoholic Hepatitis Inclusion Criteria Onset of jaundice within prior 8 weeks Ongoing consumption of > 40 (female) or 60 (males) g alcohol/day for 6 months with <60 days of abstinence before the onset of jaundice Aspartate aminotransferase > 50, aspartate aminotransferase/alanine aminotransferase > 1.5, and both values < 400 IU/L Serum bilirubin (total) > 3.0 mg/dl (50µmol/l) Liver biopsy confirmation in patients with confounding factors

14 Back to our patient year old woman Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds (PTr 2.4); Urea 6.5; WCC 17.4 Jaundiced; pyrexial; drowsy; moderate abdominal distension Abdominal US showed moderate ascites and hepatosplenomegaly. What is her short-term (28 day)prognosis? A. Excellent (>95% survival) B. Reasonable (~80% survival) C. Moderate (~60% survival) D. Poor (~50% survival) E. Terrible (<40% survival)

15 We Need to Talk About Maddrey... DF: the usual means of identifying severe alcoholic hepatitis DF = 4.6 (PT PATIENT PT CONTROL ) + Serum Bilirubin ( mol/l) / 17 BUT Concerns regarding accuracy (50%) Kulkarni et al, patients C-statistic: Wide variation in the measurement of prothrombin time

16 Sensitivity The Glasgow Alcoholic Hepatitis Score Specificity DF GAHS DF GAHS AUC: GAHS = ( ) DF = ( ) (p=0.014) Day 1 Data Day 28 Outcome (Accuracy) Score Given Age < WCC (10 9 /l) < Urea (mmol/l) < PT ratio/ INR < > 2.0 Bilirubin ( mol/l) < > 250 Day 84 Outcome (Accuracy) GAHS</ 9 81% 75% DF</ 32 49% 53% AUC: GAHS = ( ) DF = ( ) (p=0.014) Day 6-9 Data GAHS</ 9 81% 78% DF</ 32 52% 57%

17 Alternatives to GAHS: MELD=3.8 x log e (bilirubin, mg/dl) x log e (INR)+ 9.6 x log e (creatinine,mg/dl) ABIC=(age*0.1)+(bilirubin*0.08)+(creatinine*0.3)+(INR*0.8) < % survival % survival >9.0 22% survival Lille Score: R = (0.101*age in years) + (0.147*albumin day 0 in g/l) + (0.0165*evolution in bilirubin level in M) - (0.206*renal insufficiency) # - (0.0065*bilirubin day 0 in M) - (0.0096*INR) # creatinine>115 M Score = EXP(-R) / [1+EXP(-R)]

18 Back to our patient year old woman Bilirubin 326; AST 241; ALT 94; ALP 234; PT 27seconds (PTr 2.4); Urea 6.5; WCC 17.4; Alb 26 Jaundiced; pyrexial; drowsy; moderate abdominal distension US showed moderate ascites and hepato-splenomegaly. Sepsis screen negative What treatment should be considered? A. Terlipressin and Albumin infusions B. Pentoxifylline orally C. Prednisolone orally D. Rifaximin E. Broad spectrum antibiotics

19 STeroids Or Pentoxifylline for Alcoholic Hepatitis Pentoxifylline 400mg tds; Prednisolone 40mg: each for 4 weeks Primary End-point: 28 Day mortality Pentoxifylline No Yes Total No 16.7% (45/269) 19.4% (50/258) 18.0% (95/527) Prednisolone Yes 14.3% (38/266) 13.5% (35/260) 13.9% (73/526) Total 15.5% (83/535) 16.4% (85/518) 16.0% (168/1053)

20 Prednisolone vs No Prednislone STOPAH: Mortality Pentoxifylline vs No Pentoxifylline OR = 0.72 ( ) p = OR = 1.02 ( ) p = OR = 1.07 ( ) p = OR = 0.97 ( ) p = OR = 1.01 ( ) p = OR = 0.99 ( ) p = 0.972

21 Determinants of 28 Day Outcome Multivariate and Meta- Analysis Multivariate Analysis Variable Odds ratio (95% CI) p-value Prednisolone vs no prednisolone ( ) Prothrombin ratio ( ) Bilirubin ( ) Age ( ) <0.001 White Blood Cells ( ) Urea ( ) Creatinine ( ) Hepatic Encephalopathy ( ) <0.001

22 Risks of Prednisolone in Alcoholic Hepatitis: Infection Placebo/ Placebo (n=272) Pred/ Placebo (n=274) Placebo/ PTX (n=273) Pred/ PTX (n=273) Infection developed in 13% of those who received prednisolone (cf 7%; p=0.002) Total (n=1092) Infections and infestations 27 (20%) 44 (24%) 16 (11%) 30 (19%) 117 (19%) Lung infection 11 (8%) 20 (11%) 6 (4%) 18 (11%) 55 (9%) Vergis et al, 2017: for patients who present with infection If not receiving prednisolone, continuation of antibiotics does not impact upon mortality If receiving prednisolone concurrent antibiotic therapy significantly reduces mortality

23 Corticosteroid Responsiveness: baseline disease severity *p<0.05 cf no treatment #p<0.005 cf no treatment

24 Corticosteroid Responsiveness : Day 7 Progress Mathurin et al, patients: DF 32, biopsy-proven AH. ECBL response. Louvet et al, patients: DF 32, biopsy-proven; 118 in validation set. Lille model

25 Intensive Enteral Nutrition in Alcoholic Moreno et al 2016 Hepatitis Conventional nutrition or intensive EN: 14 days NG tube 48.5% premature NG tube removal: 3 cases of aspiration No increased risk of upper GI bleeding 6 month mortality: 44.4% with EN; 52.1% without (p=0.406) Improved survival if 1692kcal/day or 21.5kcal/kg/day irrespective of treatment group

26 GAHS EASL Guidelines 2012?

27 Just then in the next bed... Patient with known alcohol related cirrhosis Admitted 36 hours earlier with jaundice Increasing confusion with agitation Now shouting and threatening staff and other patients How should her agitation be managed? A. Regular Diazepam B. Symptom-triggered Diazepam C. Symptom-triggered Lorazepam D. Intravenous Chlormethiazole E. 5-10mg Haloperidol

28 Confusion and Agitation in the Jaundiced Alcoholic: a Broad Differential Withdrawal State Alcohol; benzodiazepine; (SSRI) Wernicke s Encephalopathy Undernourished; dextrose load; low Mg Hepatic Encephalopathy Acute; Chronic (porto-systemic) Brain Injury Traumatic: subdural (history of falls); chronic ARBD Seizure Disorder Post-ictal: unwitnessed seizure; Non-convulsive Status Delerium/ Metabolic Hyponatraemia; Possible sepsis Intoxication Prolonged effect (unknown street drugs); illicit use (Psychiatric)

29 Alcohol Withdrawal in the Liver Patient NICE Clinical Guidelines 100, 2010: In older adults and people with compromised liver function, long-acting agents are known to accumulate. In the absence of clinical evidence supporting one agent over another, the GDG agreed on consensus that a shorter-acting agent (e.g. oxazepam or lorazepam) could be offered to the elderly or if there was evidence of encephalopathy. Consider Symptom Triggered Treatment (STT) rather than Fixed Dose Treatment (FDT): Lorazepam 1-2mg Haloperidol for severe agitation (note QT interval) Anaesthetic involvement in extreme cases

30 Glasgow Modified Alcohol Withdrawal Score (GMAWS) Tremor 0) No tremor 1) On movement 2) At rest Sweating 0) No sweat visible 1) Moist 2) Drenching sweats Hallucination 0) Not present 1) Dissuadable 2) Not dissuadable Orientation 0) Orientated 1) Vague, detached 2) Disorientated, no contact Agitation 0) Calm 1) Anxious 2) Panicky BSG 2016 Score: (Do not use scoring tool if patient intoxicated; must be at least 8 hours since last drink.) 0: Repeat Score in 2 hours (Discontinue after scoring on 4 consecutive occasions, except if less than 48hrs after last drink) 1 3: Give 10mg Diazepam: Repeat Score in 2 hours 4 8: Give 20mg Diazepam: Repeat Score in 1 hour 9-10: Give 20mg Diazepam : Repeat Score in 1 hour; discuss with medical staff Derived from Foy et al, 2006 and Swift et al, Preferred by nursing staff in acute medical units compared with CIWA-Ar (McPherson et al, 2012).

31 Importance of abstinence... Alcohol Consumption at Day 90 n Odds ratio 1 year mortality 95% CI p- value Not reduced (still drinking as much or more than when presented) vs Abstinent <0.001 Reduced drinking but above safety limits vs Abstinent Reduced drinking to below safety limits vs Abstinent

32 Pharmacotherapy Options in ALD Little evidence with significant alcohol-related liver injury. Acamprosate has the best safety profile. No hepatic metabolism and no reported hepatotoxicity. Acamprosate does not adversely affect neuropsychiatric status in patients with Child's Grade A and B cirrhosis. Naltrexone not associated with hepatotoxicity Disulfiram related to hepatotoxicity: 28% mortality Baclofen: Addolorata et al, 2007 alcoholic cirrhosis; Baclofen 10mg tds for 12 weeks 71% abstinent (cf 29%): OR 6.3 (2.4, 16.1), p= excluded people with diabetes, encephalopathy, psychiatric comorbidity and comorbid drug misuse

33 The Jaundiced Alcoholic: an approach Is it Alcohol? Look for other precipitants; atypical biochemical pattern Is it chronic decompensation or a more acute change? >2 month history; relative lack of SIRS; typical biochemistry If acute, is there sepsis or other trigger? Full sepsis screen; Abdo US; early treatment If acute and no sepsis, likely alcoholic hepatitis Assess severity: Prednisolone 40mg for 4 weeks if GAHS>8 and improvement after 7 days; continue antibiotics if sepsis For ALL patients: Address general nutrition and specific deficits (Folate; B1; Mg) Manage AWS safely Engage with alcohol services