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Home , Alcoholic hepatitis, Alcoholic liver disease

Alcoholic 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 Increasing Burden of Alcoholic

• >60% increase in discharges with 2000/1 to 2009/10. • 222% increase in -related 1980 to 2010. The start of another medical receiving ward round.....

• 35 year old woman – history of alcohol excess; flu-like symptoms for 5 days – increasingly unwell; yellow eyes • 126; AST 3241; ALT 1194; ALP 234; PTr 3.9 • Jaundiced; no evident

• What is this likely to be? A. Alcoholic B. Acute Liver Injury C. Portal Vein Thrombosis D. Decompensated Alcoholic E. Biochemical Patterns of Alcoholic Liver Disease De Ritis Ratio Decision Limit

Condition <1.0 1.0 to <1.5 1.5 to <2.0 ≥ 2.0 Women (up to 1.7) Healthy Children Neonate Men (up to 1.3) Acute Resolving Worsening Fulminant

Alcoholic Liver Disease Resolving Acute Hepatitis

Chronic Liver Disease Stable risk Other Causes

Muscle Disease Chronic Resolving Acute

• Raised AST : ALT ratio (De Ritis Ratio) • AST not >500 (ALT usually <300) 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 Another ward round in an alternate universe..... • 35 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. B. Acute C. Acute Portal Vein Thrombosis D. Decompensated Alcoholic Cirrhosis E. Ascending Cholangitis 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 • evident >2 months • Ascites and encephalopathy often predominant – Represents progressive disease with continued drinking but may herald development of hepatoma In the next bed, just arrived..... • 35 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 B. MRCP C. Transjugular liver biopsy D. CT Head E. Diagnostic Ascitic Aspiration Sepsis in Alcoholic Liver Disease • Ascitic Fluid Analysis – SBP diagnosed in 20% cirrhotics admitted to hospital, and 2-3% attending for outpatient paracentesis – >250 /cm3 (>500 WBC/ cm3) and suggest spontaneous bacterial (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)

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) BSG/BASL Clinical Bundle for Decompensated Liver Disease: the First 24 hours

Stuart McPherson et al. Frontline Curiously an hour later there arrives...... • 35 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 hepato- splenomegaly. • Sepsis screen negative

• What is this likely to be? A. Alcoholic Hepatitis B. C. Portal Vein Thrombosis D. Decompensated Alcoholic Cirrhosis E. Ascending Cholangitis 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 •  fever  leucocytosis  hepatic

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 Back to our patient...... • 35 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 hepato- splenomegaly.

• 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) We Need to Talk About Maddrey......

• DF: the usual means of identifying ‘severe’ alcoholic hepatitis

DF = 4.6 (PTPATIENT – PTCONTROL) + Serum Bilirubin (mol/l) / 17

• Kulkarni et al, 2004 – 89 patients • BUT – C-statistic: 0.666 – Concerns regarding accuracy (50%) – Wide variation in the measurement of prothrombin time

The Glasgow Alcoholic Hepatitis Score

100 Score Given 1 2 3 80 Age < 50  50 - 9 WCC (10 /l) < 15  15 - 60 Urea (mmol/l) < 5  5 - DF DF PT ratioGAHS/ INR < 1.5 1.5 – 2.0 > 2.0 Sensitivity 40 GAHS Bilirubin (mol/l) < 125 125 - 250 > 250

AUC: GAHS = 0.783 20 (0.736 – 0.825) DF = 0.721 Day 28 Outcome Day 84 Outcome (0.671 – 0.767) (Accuracy) (Accuracy) 0 (p=0.014)Day 1 GAHS

DF = 0.721 (0.671 – 0.767)

(p=0.014) Alternatives to GAHS:

– MELD=3.8 x loge(bilirubin, mg/dl)+ 11.2 x loge(INR)+ 9.6 x loge(creatinine,mg/dl)

– ABIC=(age*0.1)+(bilirubin*0.08)+(creatinine*0.3)+(INR*0.8) <6.71 100% survival 6.71 – 9.0 70% survival >9.0 22% survival – Lille Score: R = 3.19 - (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)]

Back to our patient...... • 35 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. orally C. orally D. Rifaximin E. Broad spectrum antibiotics 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

16.7% 19.4% 18.0% No (45/269) (50/258) (95/527) Prednisolone 14.3% 13.5% 13.9% Yes (38/266) (35/260) (73/526)

15.5% 16.4% 16.0% Total (83/535) (85/518) (168/1053) STOPAH: Mortality Prednisolone vs No Prednislone Pentoxifylline vs No Pentoxifylline

OR = 0.72 (0.52 - 1.01) p = 0.056 OR = 1.07 (0.77 - 1.49) p = 0.686 OR = 1.02 (0.77 - 1.35) p = 0.875 OR = 0.97 (0.73 - 1.28) p = 0.807

OR = 1.01 (0.76 - 1.35) p = 0.937 OR = 0.99 (0.74 - 1.33) p = 0.972 Determinants of 28 Day Outcome Multivariate and Meta- Analysis

Multivariate Analysis Variable Odds ratio (95% CI) p-value Prednisolone vs no prednisolone 0.609 (0.409 – 0.090) 0.015

Prothrombin ratio 1.381 (1.129 – 1.691) 0.002 Bilirubin 1.002 (1.001 – 1.003) 0.003 Age 1.050 (1.029 – 1.071) <0.001 White Blood Cells 1.030 (1.002 – 1.060) 0.037 Urea 1.065 (1.015 – 1.118) 0.037 Creatinine 1.564 (1.048 – 2.332) 0.028 3.073 (2.050 – 4.605) <0.001 Risks of Prednisolone in Alcoholic Hepatitis: Infection Placebo/ Pred/ Placebo/ Pred/ Total Placebo Placebo PTX PTX (n=1092) (n=272) (n=274) (n=273) (n=273) 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%) • Infection developed in 13% of those who received prednisolone (cf 7%; p=0.002) • 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 Responsiveness: baseline disease severity

*p<0.05 cf no treatment #p<0.005 cf no treatment Corticosteroid ‘Responsiveness’: Day 7 Progress

• Mathurin et al, 2003 • Louvet et al, 2007 – 238 patients: DF32, – 320 patients: DF 32, biopsy-proven AH. biopsy-proven; 118 in validation set. – ECBL response. – ‘Lille model’ Intensive Enteral Nutrition in Alcoholic Hepatitis

• Moreno et al 2016 – ‘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

GAHS

EASL Guidelines 2012

? 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

Confusion and Agitation in the Jaundiced Alcoholic: a Broad Differential • Withdrawal State – Alcohol; ; (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) 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 Glasgow Modified Alcohol Withdrawal Score (GMAWS) Tremor 0) No tremor 1) On movement 2) At rest • Derived from Foy Sweating et al, 2006 and 0) No sweat visible Score: (Do not use scoring tool if Swift et al, 2010. 1) Moist patient intoxicated; must be at least 8 hours since last drink.) 2) Drenching 0: Repeat Score in 2 hours • Preferred by sweats (Discontinue after scoring on 4 Hallucination consecutive occasions, except if less nursing staff in 0) Not present than 48hrs after last drink) acute medical 1) Dissuadable 1 – 3: Give 10mg Diazepam: 2) Not dissuadable Repeat Score in 2 hours units compared 4 – 8: Give 20mg Diazepam: Orientation Repeat Score in 1 hour with CIWA-Ar 0) Orientated 9 - 10: Give 20mg Diazepam : (McPherson et al, 1) Vague, detached Repeat Score in 1 hour; 2) Disorientated, discuss with medical staff 2012). no contact Agitation 0) Calm 1) Anxious 2) PanickyBSG 2016 Importance of abstinence... 1 year mortality Odds p- Alcohol Consumption at Day 90 n 95% CI ratio value Not reduced (still drinking as much or more than when presented) vs Abstinent 478 2.99 1.47 - 6.05 <0.001

Reduced drinking but above safety limits vs Abstinent 478 2.28 1.07 - 4.86 0.032 Reduced drinking to below safety limits vs Abstinent 478 2.17 1.07 - 4.39 0.031 Pharmacotherapy Options in ALD

• Little evidence with significant alcohol-related liver injury. • 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 • 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=0.0001 – excluded people with diabetes, encephalopathy, psychiatric comorbidity and comorbid drug misuse

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 (; B1; Mg) – Manage AWS safely – Engage with alcohol services