5/8/2018. Update on Liver Disease. Learning Objectives. Abnormal Liver Tests

Transcription

1 Update on Liver Disease Heather Patton, MD, AGAF, FAASLD Transplant Hepatology San Diego Learning Objectives Categorize liver test abnormality as hepatocellular, cholestatic, or mixed and based on pattern, severity, and duration of abnormality & pursue appropriate diagnostic evaluation Understand the spectrum of nonalcoholic fatty liver disease (NAFLD), population at risk for NAFLD and nonalcoholic steatohepatitis (NASH). Review diagnosis of NAFLD and current therapies for this condition Review chronic viral hepatitis (B and C): who to screen, how to make sense of the serologies, who needs therapy and what are the current treatment options Understand definition of cirrhosis and review common complications of cirrhosis and how to recognize these complications Abnormal Liver Tests Review components of liver function test panel: markers of injury versus markers of function What is a normal ALT/AST and when is alkaline phosphatase indicative of liver abnormality Recognize pattern of liver test abnormality: hepatocellular injury, cholestatic injury, mixed pattern, and isolated hyperbilirubinemia Applying abnormal liver test pattern to build a differential diagnosis Clinical assessment of abnormal liver tests: history, physical, and targeted specific testing 1

2 Approach to Abnormal Liver Tests PATTERN DURATION Hepatocellular Cholestatic Acute Mixed Chronic SEVERITY SEVERE mild Liver Function Tests- Semantics ALT, AST, Alkaline Phosphatase, Bilirubin, GGT Liver chemistries including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin are markers of liver injury, not liver function, and should be referred to as liver chemistries, or liver tests. Albumin, bilirubin, and prothrombin time are markers of liver function that can also be influenced by extrahepatic factors. An elevated alkaline phosphatase level of hepatic origin may be confirmed by elevation of gamma-glutamyl transferase (GGT) or fractionation of alkaline phosphatase. Liver Labs: Where do they come from? ALT: LIVER (hepatocytes) AST: Hepatocytes, cardiac muscle, skeletal muscle, kidney, brain Alkaline Phosphatase: Hepatocytes, bone, placenta, intestine, kidney Bilirubin: RBC breakdown, predominantly circulates as unconjugated form bound to albumin (not excreted in urine). Conjugation (in the liver) makes bilirubin water soluble (excreted in stool and urine) Albumin: synthesized by the liver, circulating ½ life 3 weeks Prothrombin time: measures clotting function related to factors 1/2/5/7/9/10; influenced by cholestasis (vit K depletion) hepatocellular dysfunction, vitamin K antagonists (warfarin) 2

3 Liver Tests: What s Normal? Normal reference range for local lab determined by healthy control population Prospective data from truly healthy individuals support the following ULN for ALT: Men: IU/l Women: IU/l Approach to Abnormal Liver Tests Pattern Hepatocellular: ALT/AST Cholestatic: Alk Phos Mixed: ALT/AST + Alk Phos Timeline Acute (days-weeks) Chronic (months-years) Severity Mild: Up to 2 x ULN Moderate: 2-5 x ULN Severe: 5-15 x ULN History: alcohol, medications, risks for viral hepatitis, risks for NAFLD, family history Physical: Stigmata of chronic liver disease Imaging: biliary obstruction, fat, cirrhotic morphology, vascular thrombosis, mass lesions Labs: serological work-up based on differential diagnosis Hepatocellular Liver Test Abnormality (ALT/AST) Alcohol Viral Hepatitis NAFLD Drug Induced Liver Injury (DILI) Autoimmune Hepatitis Iron overload/hemochromatosis Copper overload/wilson Disease Alpha-1 antitrypsin deficiency Vascular (Budd Chiari, SOS) Ischemic Celiac Disease Sepsis Pregnancy: AFLP, HELLP Syndrome Most common etiologies 3

4 Drug Induced Liver Injury (DILI) Remember to ask about OTC/herbal/supplemental Remember to consider previous antibiotic exposures Livertox.nih.gov Severe or Massive Hepatocellular Injury Drugs: Acetaminophen Acute viral hepatitis Autoimmune hepatitis Toxins: Aminta phalloides Ischemic Hepatitis/Shock Liver Acute Liver Failure (ALF): Rapid development of acute livery injury with severe impairment of synthetic function (INR>1.5) and hepatic encephalopathy (any grade) in a patient without evidence of underlying chronic liver disease Cholestatic Abnormality Bile duct obstruction: stone, cancer Large duct disease: PSC, ischemia, AIDS, IgG4 Small duct disease: PBC, autoimmune cholangiopathy Infiltrative: TB, sarcoid, amyloid, lymphoma Drug induced liver injury (DILI) ICU, post-op, TPN, sepsis Benign recurrent intrahepatic cholestasis (BRIC) Intrahepatic cholestasis of pregnancy (ICP) 4

5 Hyperbilirubinemia: Fractionation is the key Unconjugated Bilirubin: IT S PROBABLY NOT THE LIVER Gilbert s syndrome Crigler-Najjar syndrome Hemolysis Ineffective erythropoiesis Resorption of large hematomas Neonatal jaundice Hyperthyroidism Medications Post-blood transfusion Conjugated Bilirubin: IT S PROBABLY THE LIVER Bile duct stricture/disease/obstruction Acute or chronic liver disease, cirrhosis Sepsis/Post-op/ICU TPN Infiltrative disease (cancer) Congestive hepatopathy Benign recurrent cholestasis (BRIC) Dubin-Johnson Syndrome Rotor Syndrome Nonalcoholic Fatty Liver Disease (NAFLD) Definitions: nonalcoholic fatty liver, isolated fatty liver/simple steatosis, nonalcoholic steatohepatitis, NASH cirrhosis Estimated prevalence of NAFLD, NASH in the US Risk factors for NAFLD Clinical assessment of NAFLD: diagnosis an staging Medical management of NAFLD: lifestyle modification and medications Fatty Liver Alcohol (men 3+ daily drink equivalents, women 2+ daily drink equivalents) Nonalcoholic Medications (amiodarone, methotrexate, tamoxifen, corticosteroids) Hepatitis C genotype 3 Wilson Disease Starvation TPN Acute fatty liver of pregnancy 5

6 NAFLD Histology NAFL = Simple Steatosis = Isolated steatosis ( 5%), NO cellular injury NASH = steatosis + inflammation + ballooned hepatocytes +/- fibrosis NASH Cirrhosis = stage 4 fibrosis +/- residual histology from NASH NAFLD Breakdown Nonalcoholic Fatty Liver (NAFL) 80% of NAFLD Nonalcoholic Steatohepatitis (NASH) 20% of NAFLD NASH Cirrhosis 20% of NASH 35 studies from N America, total of 8,016,928 people NAFLD prevalence is 12.89% (95% CI: ) by laboratory testing and 24.3% (95% CI: ) by imaging Estimated overall prevalence of NASH % 6

7 NAFLD/NASH Risk Factors Obesity (entire spectrum from overweight-severe obesity) Type 2 DM (30-60% diabetics with NAFLD) Dyslipidemia (high triglycerides and low HDL cholesterol) Metabolic syndrome Prevalence and severity increase with age Prevalence in men 2x prevalence in women Polycystic ovarian syndrome NAFLD Diagnosis/Staging NAFLD Diagnosis: (1) hepatic steatosis by imaging or histology, (2) no significant alcohol consumption, (3) there are no competing etiologies for steatosis, and (4) there are no coexisting causes of chronic liver disease Recommend to assess for common comorbidities Steatosis imaging: US, CT, MRI NASH Diagnosis: Liver Biopsy Staging: Noninvasive versus Liver Biopsy The ability to distinguish IFL from NASH in a way that is non-invasive and accurate is key to being able to allocate resources to patients at highest risk for morbidity and mortality 7

8 Liver Fibrosis Normal Cirrhosis Noninvasive Assessment Tools Fibrosis Scoring systems NAFLD Fibrosis Score (NFS) FIB-4 APRI US Elastography (FibroScan) MR Elastography 8

9 Exercise and NAFLD Meta-analysis of 28 randomized trials of exercise-based lifestyle interventions Physical activity, independent of diet change, was associated with a significant reduction in intrahepatic lipid content and reduction in ALT and AST Orci Clinical Gastroenterology and Hepatology 2016;14: BOTH aerobic and resistance training are effective at reducing liver fat minutes, 3 x a week appears sufficient Hashida Journal of Hepatology 2017 vol. 66 j Weight loss is needed to treat NAFLD Reduces liver fat 3-5% Reduces liver cell injury, inflammation >5% Can resolve fat and associated inflammation Reduce fibrosis (scar tissue) >7% 10% Liver International 2017; 37 (Suppl. 1):

10 Healthy Balance Viral Hepatitis Hepatitis B Who to screen Basics of Hep B serologies: surface antigen/ab, core IgM/IgG, Hep B DNA Natural history of HBV infection: immune tolerant, chronic active hepatitis, inactive carrier Who to consider for antiviral therapy Special circumstances: pregnancy and immunosuppression Hepatitis C Who to screen How to screen: overview of Hepatitis C serologies Update on therapies for Chronic HCV Hepatitis B 10

11 Globally ~240 million people chronically infected with HBV US estimates 704,000-2,200,000 Who to Screen for HBV Individuals born in areas with high (Western Africa, South Sudan) or intermediate prevalence rates (Mediterranean countries, Japan, Central Asia, Middle East, and parts of South America) for HBV including immigrants and adopted children US-born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity ( 8 percent) Household and sexual contacts of HBsAg-positive persons Persons who have ever injected drugs Persons with multiple sexual partners or history of sexually transmitted disease Men who have sex with men Inmates of correctional facilities Individuals with chronically elevated ALT or AST Individuals infected with HCV or HIV Patients undergoing renal dialysis All pregnant women Persons needing immunosuppressive therapy How to interpret the tests Surface Antigen/Antibody, Core Antibody (IgM, IgG), DNA 11

12 HBV DNA >1 million IU/mL 20,000 IU/m < 2,000 IU/mL 2,000 IU/mL Initial Evaluation of HBV Signs/Symptoms of cirrhosis Alcohol & metabolic risk factors (accelerate risk for fibrosis) Family history of HCC Vaccination status Labs: LFTs, CBC, INR, HBV DNA, HBeAg/eAb, HIV, HCV, HAV Imaging/Staging: US +/- fibrosis assessment (FibroScan, APRI/FIB-4, biopsy) Education: Vaccination of sexual partner(s), testing of first degree relatives 12

13 Hepatitis C 13

14 HCV Testing HCV Antibody, HCV RNA, HCV Genotype Hepatitis C Prevalence in the United States Estimated population prevalence of chronic HCV ~1% *NHANES data excludes the following: incarcerated, homeless, nursing home residents, persons on active military duty, and immigrants Denniston MM et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to Ann Intern Med. 2014;160: HCV Prevalence is Highest Among Those Born Between This graphic shows prevalence studies performed during two separate time periods: (blue line) and (purple line) Armstrong GL et al. The prevalence of hepatitis C virus infection in the United States, 1999 through Ann Intern Med. 2006;144:

15 Birth Cohort ( ) Testing In 2012 CDC recommendation for 1 time testing without prior ascertainment of risk factors HCV Ab prevalence in this cohort is 3.5%, accounts for 75% of HCV Ab+ persons in the US May identify an additional 808,580 infections, $2874 per case identified With new drugs, estimated 121,000 fewer deaths would occur at a cost of $35,700 per quality-adjusted life year saved In 2013 the United States Preventive Services Task Force (USPSTF) recommended offering one-time screening for HCV infection to adults born between 1945 and Which Drug? Genotype (1a/1b, 2, 3, 4, 5, 6) Treatment history (Naïve/Experienced, IFN or DAA) Cirrhosis (Yes/No, Compensated/Decompensated) Formulary Kidney function 15

16 Patients who have undetectable HCV RNA in the serum, as assessed by a sensitive polymerase chain reaction (PCR) assay, 12 weeks after treatment completion are deemed to have achieved SVR Cirrhosis How is cirrhosis defined What are the common versus uncommon etiologies of cirrhosis How to recognize cirrhosis clinically and options for invasive versus noninvasive diagnosis Overview of cirrhotic complications Portal Hypertension Hepatocellular dysfunction When liver transplant should be considered 16

17 Cirrhosis Severe fibrosis of the liver, the end result of chronic liver injury/inflammation 8 th leading cause of death in the US Etiologies of Cirrhosis Common: Alcohol, Viral Hepatitis (B and C), Nonalcoholic Fatty Liver Uncommon: Autoimmune liver disease (AIH, PBC), Primary Sclerosing Cholangitis, Hereditary Hemochromatosis, Wilson Disease, alpha-1 Antitrypsin Deficiency, Cardiac Cirrhosis, Budd Chiari Syndrome Many patients have more than 1 cause (HCV + ETOH, HBV + NAFLD, etc) Identification of Cirrhosis Physical Exam findings Labs: Platelets <150 Low albumin, high bilirubin (indirect), high INR AST>ALT Imaging: Nodular liver contour, coarse echotexture Splenomegaly Enlarged portal vein diameter Ascites Elastography, Scoring systems (NFS, APRI) Liver Biopsy 17

18 Natural History of Cirrhosis Compensated Cirrhosis Portal Hypertension Decompensated Cirrhosis Life Expectancy years Risk of death 4.7 x general population Life Expectancy 2 years Risk of death 9.7 x general population 10 Year Risk in Compensated Cirrhosis Ascites 47% Encephalopathy 28% GI Bleeding 25% Major Complications of Cirrhosis Ascites Spontaneous bacterial peritonitis (SBP) Hepatorenal syndrome (HRS) Variceal hemorrhage Portal Hypertensive gastropathy (PHG) Hepatopulmonary Syndrome (HPS) Hepatic hydrothorax Hepatic Encephalopathy (HE) Portopulmonary HTN Malnutrition/sarcopenia, frailty Hepatocellular carcinoma (HCC) Portal Hypertension Pressure = Flow x Resistance PHTN: Increased pressure in the PV and increased gradient between the PV and the HV Complications: Ascites, Varices, splenomegaly, thrombocytopenia 18

19 Varices Variceal Hemorrhage Hematemesis and/or melena Initial medical management: IV Octreotide + IV PPI + IV Antibiotics, DO NOT OVER-TRANSFUSE (Hgb 7-8) Endoscopic Management: urgent EGD with band ligation and/or sclerotherapy If endoscopy fails: Blakemore tube or esophageal stent followed by TIPS Secondary prophylaxis: Repeat EGD with band ligation to complete scarring and non-selective beta blocker (propranolol, nadolol) Carvedilol only for primary PPx When NSBBs used for primary PPx no EGD needed When NSBBs added to EVL as secondary PPx then repeat EGD is needed HEPATOLOGY, VOL. 65, NO. 1,

20 Ascites Fluid leaks off of the surface of the liver Management: 2,000mg sodium restriction daily Diuretics= Furosemide 40mg : Spironolactone 100mg ratio Large volume paracentesis (IV Albumin for >5-6 L) TIPS Spontaneous bacterial peritonitis: Diagnosed with ascites PMN 250 IV Abx 3-5 days + IV Albumin days 1 and 3 Prophylaxis with Cipro or Septra/Bactrim daily N Engl J Med 2016;375: TIPS: Transjugular Intrahepatic Portosystemic Shunt Indications: Diuretic refractory ascites Recurrent variceal bleeding (or unable to treat endoscopically) Risks: Worsening liver failure (MELD) Hepatic Encephalopathy Right-sided heart failure Work-Up: Imaging Echocardiogram MELD Score Assessment for HE 20

21 Hepatic Encephalopathy Measuring Serum Ammonia Level in Patients with Altered Mental Status Clinical impression is the main guide to diagnosing hepatic encephalopathy (HE) A normal or modestly elevated blood ammonia level does not rule out a diagnosis of HE Blood ammonia testing is not recommended to initiate or guide therapy Asterixis is easy to check for on examination: Elgouhari HM, O Shea R. Cleve Clin J Med 2009;76: HE Therapy Evaluation for triggers of overt HE: Infection GI bleeding Dehydration Electrolyte disorders Constipation/nonadherence to therapy Medications (benzos, opiates) Drug Name Lactulose Rifaximin Drug Class Poorly absorbed disaccharide Non-aminoglycoside semi-synthetic, nonsystemic antibiotic Mechanism of Action Decreases blood ammonia concentration - Promotes elimination of NH 3 - Fermentation by bacteria acidify colon and prevent absorption - Reduces urease-producing bacteria Decreases blood ammonia concentration - Broad spectrum antibiotic; results in a change in bowel flora - May cause downregulation of intestinal glutaminase activity 21

22 Malnutrition in cirrhosis: 50-90% Decreased Intake Low sodium diet Decreased appetite Ascites Encephalopathy Increased Losses Frequent paracentesis Decreased Absorption Portal Hypertension Cholestasis Bacterial overgrowth Altered Metabolism Overnight fast ~72 hour fasting (decreased glycogen stores in the liver) How does malnutrition impact health in cirrhosis? Lowered immune function Poor wound healing Sarcopenia/frailty Associated with ascites, variceal bleeding Increased risk for surgical complications and mortality Longer hospitalizations Clin Liver Dis 18 (2014) Sarcopenia Loss of skeletal muscle mass Present in 30-70% of individuals with cirrhosis Associated with a number of outcomes Reduced quality of life Increased likelihood to develop other complications of cirrhosis Increased risk for infections Reduced survival Reduced survival following liver transplant Journal of Hepatology 2016 vol. 65 j

23 Prognostic Models MELD: Model for End Stage Liver Disease MELD/MELD-NA utilized for organ allocation for liver transplant Prediction of outcome after TIPS Alcoholic Hepatitis 3 month survival CPT Score/Class Combines liver synthetic function and decompensation events Child-Pugh Score 23

24 Hepatocellular Carcinoma (HCC) At risk population: Advanced fibrosis/cirrhosis Chronic viral hepatitis B Screening: US +/- AFP q 6 months Diagnosis: Multiphasic contrast imaging (CT/MRI) >>> Biopsy Therapy: Surgical resection, IR therapies (ablation, transarterial therapies), Liver Transplant, radiation (SBRT), Systemic chemotherapy (palliative) HCC Diagnosis Multiphase contrast-enhanced imaging has nearly 100% specificity Sensitivity lower and more variable Tumors are arterial whereas surrounding parenchyma is mixed arterial/venous During arterial phase tumors are brighter than surrounding parenchyma During venous/washout phase, tumors are darker than surrounding parenchyma LIVER TRANSPLANTATION 12:S1-S7, 2006 Transarterial Therapy for HCC Normal liver parenchyma derives 75% of blood supply from the portal vein HCC are fed entirely by the hepatic artery and result in hypertrophy of HA Selective catheterization of HA can be utilized for delivery of therapy (chemo, radiation) to the tumor 24

25 Liver Transplant Evaluation: A Team Sport 3 aspects of candidacy addressed in the evaluation process 1. Patient needs a transplant (meets minimal listing criteria) 2. Patient has no medical comorbidities that would make transplant surgery too risky (such as cardiovascular or pulmonary disease) or that would significantly impact life expectancy after liver transplant (such as non-liver cancers) 3. Patient has all of the resources to successfully manage transplanted organ Caregiver, transportation Documented compliance with care Financially able to manage expenses of care (co-pays) No uncontrolled psychiatric or substance abuse issues that would impair their long-term success Transplant Hepatology Social work Addiction Medicine Psychiatry Supply and Demand As of 12/31/2015 there were 14,046 candidates listed for LT in the United States The total number of adult liver transplants performed in 2015 was 7,127 (6768 deceased donor and 358 live donor transplants) Consequences of the gap in supply and demand Need a system to determine organ allocation Objective Easily measured Equitable Transplant specialists have responsibility for good stewardship of this precious resource Don t waste an organ on someone who is not going to take care of it 25

26 MELD Score for Organ Allocation Geographic Variation in Average MELD for LT We are in one of the most challenging places in the US for liver transplant: - High average MELD at transplant - Long wait times Since we don t do the transplant within KP, we have the opportunity to send members to lower-meld regions for liver transplant 26

27 Thank you References Global epidemiology of nonalcoholic fatty liver disease-metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology Jul;64(1): AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology Jan;63(1): HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. The AASLD and IDSA in partnership with the panel have created an updated web experience to facilitate easier and faster access to this important resource. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries The American Journal of GASTROENTEROLOGY VOLUME 112 JANUARY Treatment of Patients with Cirrhosis. Phillip S. Ge, M.D., and Bruce A. Runyon, M.D. N Engl J Med 2016; 375: