4/12/2017

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Alcoholism and Liver Disease

Christopher Chang, MD, PhDDivision of Gastroenterology/Hepatology

University of New Mexico School of Medicine

And

New Mexico VA Health Care System

April 21, 2017

National Conference for Nurse Practitioners

Nashville, TN

Overview

• Burden of alcoholism and alcoholic liver disease

• Natural history of ALD and pathogenesis

• Alcoholic hepatitis (AH)

– Clinical features and diagnosis

– Assessing severity and prognosis

– Treatment: what does the evidence show?

– Ineffective and pipeline therapies

– Summary and approach to the AH patient

• Major complications of cirrhosis and portal hypertension: Cliff

Notes version

– Variceal bleeding

– Ascites and SBP

– Hepatorenal syndrome

– Hepatic encephalopathy

– Hepatopulmonary syndrome

– Hepatocellular carcinoma

Burden of Alcoholic Liver Disease

• Nearly 6% of all deaths globally were attributable to

alcohol (WHO data, 2012)

• Alcoholic cirrhosis is the 8th most common cause of

all mortality in U.S.

• In-hospital mortality rate of 6.8% for alcoholic

hepatitis in U.S.

• The “good news”: Only minority of heavy drinkers

develop AH and/or cirrhosis.

• The Bad News: Rising prevalence of 12-month

and lifetime Alcohol Use Disorder (13.9% and

29.1%), classified in DSM-V

Asrani 2010, Hepatology 52:408

Grant 2015, JAMA Psychiatry 72: 757

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Adult per capita alcohol consumption: 2010

Liangpunsakul '16, Gastroenterology 150: 1786

Alcohol-attributable deaths by cirrhosis

• 493,300 deaths in 2010.

• 0.9% of all global deaths

What is a standard drink?

Answer: drink containing ~14 gm pure alcohol

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Risk Factors for ALD

• Female: Lower alcohol threshold for ALD

• Young age daily drinking > Binge/episodic drinking

• PNPLA3 allele GG vs. CC (Odds ratio 4.30)

• Obesity, NASH, or malnutrition

• Chronic liver disease: HCV, HBV, iron overload

• Tobacco

Long-term health risks of alcoholism

• Neurologic: dementia, stroke, neuropathy

• Cardiovascular: cardiomyopathy, a fib, Htn, MI

• Cancer: mouth, throat, esophageal, liver,

colon, breast

• GI: Alcoholic hepatitis, cirrhosis, pancreatitis,

gastritis

• Psychiatric: depression, anxiety, suicide

• Social: unemployment, lost productivity, family

problems, violence

Medications to treat alcoholism

• Pharmacotherapy with brief medical-management counseling

can reduce heavy drinking in persons with alcohol dependence

Good reference: Friedmann'13, Alcohol use in adults, NEJM 368:365

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WHO global strategy to reduce harmful use of

alcohol

Natural History of Alcoholic Liver Disease

• Alcoholic hepatitis pathology: steatosis, ballooned hepatocytes,

inflammatory infiltrates, Mallory-Denk bodies, mega-

mitochondria, and pericellular and perivenular fibrosis (“chicken

wire” fibrosis)

Gut immune system and microbiome in

homeostasis with normal liver

Szabo'15, Gastroenterology 148:30

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Gut-liver axis in ALD

New understanding new Rx targets

Singal'14, Clinical Gastro and Hep 12:555

Case Presentation

• 35 year old women brought to clinic by fiancée

• Complains that he exaggerates and she only

drinks when she parties

• She noticed some “yellow skin and eyes”

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Case Presentation

• Initial eval: anxious young woman

• Has very slight tremor notable in her upper

extremities

• Mild scleral icterus

• Vitals: 160/85, HR 85, 37.5 degrees C

• She has hepatomegaly, no palpable

splenomegaly, and no notable ascites

• Lungs are clear. Skin icteric

Clinical Features of Alcholic Hepatitis

• History

– Alcohol intake: Current; usually binge; or recently

discontinued.

– New onset jaundice

– Weight loss, malnutrition

• Exam

– Toxic-appearing, fever, tachycardia

– Tender hepatomegaly +/- bruit

– Signs of chronic liver dz (ascites, spider

angiomata, muscle loss, hepatic encephalopathy)

• Similar to decompensated alcoholic cirrhosis,

aside from recent alcohol intake

Lab Features of AH

• AST, ALT elevation rarely >400

• AST/ALT ratio >2 (AST increase from

mitochondrial damage)

• T. Bili >5 mg/dl

• WBC > 10K (DDx infection)

• Decreased platelets BM suppression vs

portal HTN

• Increased INR

• Decreased Hgb nutritional deficieny vs

bleeding

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Making the diagnosis of AH

• Clinical suspicion and history

• Labs

• Rule out other etiologies

• Consider liver biopsy, when in doubt

– Not routinely done in US despite gold standard

– Thrombocytopenia and coagulopathy in many pts

– Transjugular route most common and safest

– Perform for diagnostic uncertainty that would

impact clinical managment

Assessing AH severity and prognosis

• Spontaneous encephalopathy: grave prognosis

• Steatohepatitis score

• Multi-organ Failure and Systemic Inflammation

Syndrome

• Various prediction models or scoring systems:

– Maddrey’s modified discriminant function (DF):

Bilirubin + PT

– MELD score: Bilirubin + INR + Cr

– ABIC: Age + bilirubin + INR +Cr

– Glasgow alcoholic hepatitis score: ABIC + WBC

– Lille score: Dynamic model. Assess response to

steroids at day 7. Establish threshold for steroid

treatment futility (Age, albumin, bilirubin, Cr, PT)

Discriminant function

• Most widely used prediction model.

• >32 predicts survival benefit if treated with prednisolone

• Specificity suboptimal. Static variable, calculated on adm

• Key inclusion criteria for prospective treatment trials

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Glasgow AH Score

• a

MELD: model for end-stage liver disease

• 3.8 x loge(bilirubin in mg/dL) + 11.2x loge(INR) + 9.6 x

loge(Cr mg/dL) + 6.4 USE THE APP!!• http://www.mayoclinic.org/medical-professionals/model-end-stage-liver-

disease/meld-score-90-day-mortality-rate-alcoholic-hepatitis

• Commonly used and dynamic model

• No clear threshold to define poor prognosis

• >21 or 20 and rising portends poor prognosis, high

30-day mortality risk. Should be treated.

Lille Score

• Incorporates age, bilirubin day 0 and 7, day 0 Cr,

albumin, and PT

• Response at day 7 predictor of outcome

• No change in bilirubin day 7 stop therapy

• Establishes threshold for steroid treatment futility

• Day 7 score <0.45 vs

> 0.45, 6 month

survival 83% vs 23%

• http://www.lillemodel.

com/score.asp

6 month survival based on early response to steroids:

Improved bilirubin at day 7

Unchanged bilirubin at day 7

Louvet'07, Hepatology 45: 1348

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Back to the case

• Labs:

– WBC 12K

– Plts 90K

– Hgb 12.8

– Electrolytes, BUN, Cr are normal

– TBili 7.5, Dbili 4, AST 175, ALT 55

– INR 2.0

• Ultrasound:

– Hepatomegaly and steatosis

– Spleen is upper limit of normal

– No masses, no ascites

Assessment of this patient

• Severity by MELD and discriminant function is

high:

– MELD = 22

– DF = 35

• What do you do next?

Initial treatment for AH

• Resuscitation: Sick! 6.8% in-hospital mortality

• Rule out infection—resembles AH

– Ascites paracentesis to r/o SBP

– Low threshold for antibiotics

• Liver biopsy (transjugular route) if needed

• Renal fxn: replete fluids, no NSAIDS; albumin;

caution with diuretics, contrast dyes

• Encephalopathy: lactulose, rifaximin

• Withdrawl: benzodiazepine protocols

• Nutrition: Vit B complex (Wernicke’s), protein.

• Abstinence: critical to recovery

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Enteral nutrition vs prednisone

Cabre '00 Hepatology 32:36

71 pts randomized:

Prednisone 40 mg x 30d

Vs

Total enteral nutrition

2000 kcal/d x 30d

Surv

ival

Intention to treat analysis

• Similar 30 day mortality (9/36 vs 11/35)

• 1 year mortality higher with steroids

– 10/27 vs 2/24 p = 0.025

– 9 of 10 steroid group deaths due to infection

• Nutrition comparable to steroids

Intensive vs conventional nutrition

Moreno'16, Gastroenterology 150: 903

Multicenter RCT:

136 patients

Methylprednisolone +

Conventional EN

Vs

Intensive EN

14 days via NGT

6 month survival as primary

end point

• Per protocol analysis: 6m survival 69.8% (intensive) vs 46.8%

(conventional); p = 0.015

• Intention to treat analysis: No statistical difference ( p = 0.406)

• 48.5% withdrew feeding tube prematurely

• Low daily calories (< 21.5 kcal/kg/day) associated with death

Meta analysis of nutrition studies

• 9 enteral feeding trials; 4 parenteral trials

• 20% drop in mortality with feeding

• Nutrition associated with less HE and infections

• Better trials needed.

• Recommend 1600-2000 kcal/d; 60-100 gm protein

Fialla’15 Liver Int 35:2072

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What about abstinence?

• Very few long term studies on impact of abstinence in

recovery

• Most clinical improvement in first 6-12 months

• 5 yr mortality: 45% in persisting drinkers vs. 13% in

abstainers.

• STOPAH trial:

– Abstinence rate only 37% at 1 year

– Any alcohol use at day 90 2-3 fold increase in mortality

• Slips or relapses do not cause immediate liver failure

Markel '96, Hepatology 24:820.

STOPAH trial'15, NEJM 372: 1619

Corticosteroids for AH

• >15 clinical trials. Lots of pt heterogeneity.

• Conflicting meta-analyses

– Mortality benefit at 1 month if DF >32 or hep enceph

– RR 0.37

• “Gold standard” meta of 5 recent RCTs

– N = 418. Prednisone 40 mg/d x 30 d

– 28 day survival 80% vs 66% (controls)

– NNT = 5 with 30% RRR

– Exclusion: Active GIB, renal failure, coma, ?infxn

Mathurin '11, Gut 60:255

28 day survival benefit with steroids: meta-analysis

• 28 day survival base

on Lille score at day7

of treatment.

• Significant survival

benefit in

– Complete responders

– Partial responders

• No benefit in non-

responders.

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Recommendations for steroid use

• AASLD: Prednisolone 40 mg/d (usually oral) for 4

weeks. Rapid taper. Prednisone also OK

• DF score >32

• Compare Lille score day 0 vs day 7. Score > 0.56

STOP (no response and increased infection risk)

• On admission: culture blood, urine, ascites; x-rays

– Start steroids if no infection

– If infection, start steroids after 48 hours of antibiotics

– Response to steroids is better predictor of survival than

presence of infection

• Discontinue steroids:

– Active, uncontrolled infection (urine > ascites > pulmonary)

– Acute kidney injury

– GIB

– Acute pancreatitis

Pentoxifylline

Akriviadis 2000, Gastroenterology 119:1637

• Inhibitor of TNFa

• 400 mg po TID

• 4 weeks

• N = 101; DF > 32

• 6 month mortality:

– 25% vs 46% (PBO)

• Marked reduction

in HRS (p = 0.0015)

• Well tolerated

P = 0.037

RR = 0.59

• Subsequent trials have not reproduced this efficacy

Prednisolone +/- Pentoxifylline

Mathurin’13, JAMA 310: 1033

• Different mechanisms combo better?

• N = 270; DF > 32; bx-proven AH

• Standard dosing for 4 weeks. 6m survival endpoint

• No improvement in 6 month survival (70% vs 69%)

• Cumulative incidence HRS (8.4 % vs 15.3%, p = 0.07)

• Lille score at day 7 predicted survival again

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STOPAH Trial

Thursz'15, NEJM 372:1619

• Multicenter RCT in UK. N=1092. DF>32, bili>4. No GIB, infxn.

• Pred vs PTX vs Pred/PTX vs double placebo for 28 days

• Borderline reduction in mortality in prednisolone group at 28d

– Mortality at 28d OR (1.07 PTX vs 0.72 Pred, p = 0.06)

• No benefit at 90 days or 1 yr for prednisolone, PTX or combo

• Serious infxns: 13% prednisone vs 7% no pred, p = 0.002

STOPAH: 1 year survival curve

Take away messages of STOPAH:

• PTX no effective for AH

• Steroids not effective beyond 1 month to improve survival

• Abstinence is key

N-acetylcysteine

• French study; 180/430 randomized

• DF >32; bx-confirmed AH

• Prednisolone 40 mg/d +/- NAC

• NAC bolus day 1; 5 days IV total

• Primary endpoint = 6 month survival

Nguyen-Khac'11, NEJM 356:1781

• 6m survival not significantly improved (27% vs 38%)

• 1m mortality significantly lower (8% vs 24%)

• Decreased HRS and infection rates

• Overall safe. No harm to add NAC to steroid?

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Granulocyte Colony-Stimulating Factor

• G-CSF stimulates bone marrow to

produce and release neutrophils and

stem cells (CD34+)

• May stimulate liver regeneration

• Pilot RCT in India. N = 46

• “standard medical therapy” of PTX +

nutrition +/- G-CSF

• G-CSF given 5 mcg/kg SQ q12 hrs

for 5 days, then q3 days through d30

Singh'14, Am J Gastro 109:1417

• Marked improvement survival at day 90 in G-CSF arm

(78.3% vs 30.4%, p=0.001)

• Significant reduction in MELD, DF and Child-Pugh scores

• Significant increase in peripheral blood CD34+ cells

When all else fails….Liver transplant?

OLT for AH: French experience

Mathurin'11. NEJM 365: 1790

• US and most countries require 6 month abstinence

• Non-responding AH patients: >50% die within first 3 months

• Only 3% of livers transplanted into AH patients

• Many ethical issues

• Prospective study. N=26

steroid non-responders. Lille

score >0.45. Received OLT

• Matched controls w/o OLT

• 6 month survival 77% vs 23%

• 2 year survival 71%

• 3 recipients returned to drinking

Similar outcomes between AH and alcoholic cirrhosis

liver transplantation: U.S. experience

• 55 post-OLT for AH followed. Matched with 165 post-OLT for alc cirrhosis

• 5 year survival 80% vs 78%

• Causes of graft loss and pt mortality were similar in both groups. Not

alcohol-related.

Singal'12, Hepatology 55:1398

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AH Treatment

Ineffective therapy for AH

Thursz and Morgan'16, Ibid

Anti-TNFa therapy (infliximab, entanercept)

Therapeutic strategies undergoing trials

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Approach to acute AH patient

1. Resuscitate and stage

2. Nutrition

3. Treat complications of cirrhosis and infection

4. Establish diagnosis if uncertain. Biopsy?

5. Treatment options:

MELD > 20 or DF > 32

Steroids: Survival benefit only to 1 month

PTX: No proven benefit

NAC: Little harm. Need more data

G-CSF: promising. Need more data

6. Assess at day 0 and 7 with Lille model

Response Continue treatment

Refer to abstinence program

No/Slow response Clinical trials; OLT if

available; palliative care

Use steroids to get severe AH patient through

the first month so that they can abstain.

Reach out to expert and/or transplant centers

Abstinence is the key intervention

Approach to acute AH patient

Major complications of cirrhosis

and portal hypertension

• Variceal hemorrhage

• Ascites

• Spontaneous bacterial peritonitis

• Hepatic encephalopathy

• Hepatorenal syndrome

• Hepatopulmonary syndrome

• Hepatocellular carcinoma

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2.8 (1.0-7.5)

8.7 (3.3-22.6)

10.7 (2.5-45.6)

10.1 (0.6-181.4)

6.6 (2.0-22.3)

2.7 (0.2-30.2)

9.9 (3.2-30.0)

11.3 (6.3-20.1)

7.3 (4.8-11.1)

OR

0.1 0.5 1 10 50

Protective Effect Increased Risk

OR (95% Cl) Study (year/bacteria)

Ji (2005/Shigella)

Mearin (2005/Salmonella)

Wang (2004/Unspecified)

Okhuysen (2004/Unspecified)

Cumberland (2003/Unspecified)

llnyckyj (2003/Unspecified)

Parry (2003/Bacterial NOS)

Rodriguez (1999/Bacterial NOS)

Pooled estimate

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Control of acute variceal bleeding

• Resuscitate and assess severity

– Intubate massive bleeder or agitated. MICU care.

– IVF, blood products

• Endoscopic therapy

– Variceal band ligation in majority; gastric varices less success

– Sclerotherapy—injection of sclerosant directly into varices

• Splanchnic vasoconstriction: Octreotide 50-100 mcg/hr

• Balloon tamponade: Usually if endoscopy and

octreotide fail and awaiting TIPS or urgent

transplantation. Many potential complications.

• Transjugular intrahepatic portosystemic shunt (TIPS)

– Bridge to transplant

– HE in 20-30%

– Stenosis or occlusion in 30-60%

• 30 day mortality remains high at 15-20%

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Prevention of variceal bleeding

• Variceal band ligation repeat until obliterated

• Propranolol or nadolol: Non-selective beta-blocker to decrease portal hypertension.

• TIPS: Bridge to transplant

• Portosystemic shunt: Infrequent since TIPS available

• Primary prophylaxis: Band ligation vs beta-blockers

Largely replaced by more objective MELD score,

but need to know

Ascites: accumulation of fluid in peritoneum

Most common complication

of cirrhosis

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Ascites in cirrhosis

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Think diagnostic paracentesis….

Inoculate fluid directly into blood culture bottles.

Diagnose SBP with cell count and culture.

Calculate SAAG to confirm diagnosis

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Treatment of cirrhotic ascites

• Rigid salt restriction: < 2 gm Na/day

• Diuretics: titrate to effect or complication (HE, HRS)

– spironolactone 100-200 mg/d (max 400mg) and

– furosemide 40-80 mg/d (max 160 mg)

• Monitor wt, urine Na and K, serum lytes, and Cr

• Refractory ascites: diuretic failure

– Repeated large volume paracentesis (5-10 L) with IV

albumin infusion (10 g/liter removed)

– TIPS: associated with HE; does not improve survival

• Consider OLT evaluation

Ascites prognosis poor without definitive therapy

Spontaneous bacterial peritonitis

No evidence of intra-abdominal secondary source

of infection

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Keep high index of suspicion for SBP

SBP Treatment

• Ascites fluid PNM count > 250/ul. Confirm by positive

culture

• E. coli, Klebsiella, other gut microbes most common.

Gram positive also found

• Cefotxime 2 gm IV q 8hrs for 5 days.

• Avoid aminoglycosides (nephrotoxic)

• Recommend prophylaxis abx in patients with variceal

bleeding

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Hepatorenal Syndrome

Arterial vasodilation in splanchnic circulation triggered

by P-HTN reduction in renal perfusion

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Poor prognosis

• Unless hepatic fxn improves or OLT

• Primarily diagnosis of exclusion

• Very low Na excretion

• Oliguria

HRS management

• Identify other causes

• Establish circulatory volume

• IV midodrine, octreotide, and albumin

• Restrict Na and water

• Avoid nephrotoxic agents

• Hemodiaysis if needed

• OLT evaluation: prognosis poor without

definitive treatment

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Alteration in mental status and cognitive function

Acute/reversible vs chronic/progressive

Gut-derived neurotoxins no longer removed by

cirrhotic liver now reach the brain

Clinical features of HE

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Testing for HE

Normal < 30 sec

Add rifaximin

2-3 soft stools/d

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Hepatopulmonary Syndrome

• Clinical triad:

– Liver disease

– Increased alveolar-arterial gradient while breathing room air

– Intrapulmonary vascular dilations

• Pathophysiology:

– Increased vasodilators (nitric oxide?) due to increased liver

production or decreased clearance

– Microscopic intrapulmonary A-V dilations

– Overperfusion V/Q mismatch increased alveolar-arterial

gradient

• Diagnosis:

– Dyspnea and hypoxemia, worse when standing

– Pulse ox and ABG

– Contrast echocardiography. Rapid transit of venous contrast

through lungs to left atrium

• Treatment: Liver transplantation, supplemental O2,

Hepatocellular Carcinoma

• Marked increase risk in cirrhotics, esp from HBV, HCV, NASH, and

hemochromatosis

• Frequently asymptomatic until late. Suspect in decompensated

previously doing well.

• Pain, early satiety, obstructive jaundice, and palpable mass

• Diagnosis:

– Elevated alpha fetoprotein; not specific

– Ultrasound. Recommend q 6 month surveillance

– Triple phase CT

• Treatment: OLT most definitive

– Surgical resection. Recurrence common

– Transcatheter arterial chemoembolization (TACE). High dose chemo to

feeding artery of tumor.

– Systemic chemotherapy. HCC poorly responsive. Sorafenib promising

– Brachytherapy