4/12/2017. Alcoholism and Liver Disease. Burden of Alcoholic Liver Disease. Overview

Transcription

1 Alcoholism and Liver Disease Christopher Chang, MD, PhD Division 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 8 th 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 1

2 Adult per capita alcohol consumption: 2010 Liangpunsakul '16, Gastroenterology 150: 1786 Alcohol-attributable deaths by cirrhosis 493,300 deaths in % of all global deaths What is a standard drink? Answer: drink containing ~14 gm pure alcohol 2

3 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 3

4 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, megamitochondria, and pericellular and perivenular fibrosis ( chicken wire fibrosis) Gut immune system and microbiome in homeostasis with normal liver Szabo'15, Gastroenterology 148:30 4

5 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 5

6 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 6

7 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 7

8 Glasgow AH Score a MELD: model for end-stage liver disease 3.8 x log e (bilirubin in mg/dl) x log e (INR) x log e (Cr mg/dl) USE THE APP!! 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 6 month survival based on early response to steroids: Improved bilirubin at day 7 Day 7 score <0.45 vs > 0.45, 6 month survival 83% vs 23% Unchanged bilirubin at day 7 com/score.asp Louvet'07, Hepatology 45: 1348 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 8

9 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 9

10 Survival 4/12/2017 Enteral nutrition vs prednisone Intention to treat analysis 71 pts randomized: Prednisone 40 mg x 30d Vs Total enteral nutrition 2000 kcal/d x 30d Similar 30 day mortality (9/36 vs 11/35) 1 year mortality higher with steroids 10/27 vs 2/24 p = of 10 steroid group deaths due to infection Nutrition comparable to steroids Cabre '00 Hepatology 32:36 Intensive vs conventional nutrition 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 = 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 Moreno'16, Gastroenterology 150: 903 Meta analysis of nutrition studies Fialla 15 Liver Int 35: enteral feeding trials; 4 parenteral trials 20% drop in mortality with feeding Nutrition associated with less HE and infections Better trials needed. Recommend kcal/d; gm protein 10

11 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 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 28 day survival benefit with steroids: meta-analysis Mathurin '11, Gut 60: day survival base on Lille score at day7 of treatment. Significant survival benefit in Complete responders Partial responders No benefit in nonresponders. 11

12 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 P = RR = 0.59 Inhibitor of TNF a 400 mg po TID 4 weeks N = 101; DF > 32 6 month mortality: 25% vs 46% (PBO) Marked reduction in HRS (p = ) Well tolerated Subsequent trials have not reproduced this efficacy Akriviadis 2000, Gastroenterology 119:1637 Prednisolone +/- Pentoxifylline 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 Mathurin 13, JAMA 310:

13 STOPAH Trial 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 = Thursz'15, NEJM 372:1619 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? 13

14 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 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 Singh'14, Am J Gastro 109:1417 When all else fails.liver transplant? OLT for AH: French experience 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 Mathurin'11. NEJM 365: 1790 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:

15 AH Treatment Ineffective therapy for AH Anti-TNFa therapy (infliximab, entanercept) Thursz and Morgan'16, Ibid Therapeutic strategies undergoing trials 15

16 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 Approach to acute AH patient 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 Major complications of cirrhosis and portal hypertension Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Hepatorenal syndrome Hepatopulmonary syndrome Hepatocellular carcinoma 16

17 Protective Effect Increased Risk 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 OR (95% Cl) 2.8 ( ) 8.7 ( ) 10.7 ( ) 10.1 ( ) 6.6 ( ) 2.7 ( ) 9.9 ( ) 11.3 ( ) 7.3 ( ) OR 17

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19 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 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% 19

20 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 20

21 Ascites in cirrhosis 21

22 Think diagnostic paracentesis. Inoculate fluid directly into blood culture bottles. Diagnose SBP with cell count and culture. Calculate SAAG to confirm diagnosis 22

23 Treatment of cirrhotic ascites Rigid salt restriction: < 2 gm Na/day Diuretics: titrate to effect or complication (HE, HRS) spironolactone mg/d (max 400mg) and furosemide 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 23

24 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 24

25 Hepatorenal Syndrome Arterial vasodilation in splanchnic circulation triggered by P-HTN reduction in renal perfusion 25

26 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 26

27 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 27

28 Testing for HE Normal < 30 sec 2-3 soft stools/d Add rifaximin 28

29 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 O 2, 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 29