Liver Disease in the US. Liver Disease in the US. Liver Function Testing. Liver Anatomy Question 1

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1 Liver Disease in the US NAVIGATING LIVER FUNCTION TESTING AND CHRONIC HEPATITIS Elizabeth Verna, MD, MSc Assistant Professor of Medicine Center for Liver Disease and Transplantation Division of Digestive and Liver Diseases Columbia University, College of Physicians and Surgeons 1 in 12 persons worldwide is living with viral hepatitis Viral hepatitis is the leading infectious cause of death in Americans Liver disease was the 12 th leading cause of death in 2007 in the US Likely underestimated, perhaps as high as 8 th overall As high as 4 th in certain populations 40-60% due to HCV, 10-15% due to HBV Liver Disease in the US Cost of liver disease in the US: In 2004, NIH estimated the annual costs in US of chronic liver disease and cirrhosis is $1.6 billion Based upon an estimate of 5.5 million people with liver disease More recent estimates of the population with liver disease in the US ranges from 15 to 30 million indicating annual cost may range from $5 to $10 billion Most of the 3-6 million Americans with viral hepatitis don t know they are infected Liver Function Testing 1. Definitions of individual liver tests 2. Measures of synthetic function 3. Patterns of disease Hepatocellular v. cholestasis Common chronic liver diseases 4. Common causes of chronic hepatitis 5. Initial diagnostic testing in patients with elevated liver tests Liver Anatomy Question 1 A 46 year old man presents with RUQ abdominal pain and jaundice following a 10 day cruise with his friends. On initial evaluation, he is hemodynamically stable, has icteric sclera and no other stigmata of chronic liver disease. His laboratory assessment includes total bilirubin 3.6, direct bilirubin 1.9, AST 291, and ALT 115, platelets 64,000. Which of the following statements about this man s liver disease is false? 1.This pattern of liver test elevation is most consistent with alcohol-related liver disease 2.Given his abdominal pain and acute jaundice, biliary obstruction from choledocholithiasis must be considered 3.The AST is higher than the ALT in this case because the patient likely has concomitant vitamin B12 deficiency 4.AST may come from sources other than the liver while ALT is liver-specific

2 Question 1 A 46 year old man presents with RUQ abdominal pain and jaundice following a 10 day cruise with his friends. On initial evaluation, he is hemodynamically stable, has icteric sclera and no other stigmata of chronic liver disease. His laboratory assessment includes total bilirubin 3.6, direct bilirubin 1.9, AST 291, and ALT 115, platelets 64,000. Which of the following statements about this man s liver disease is false? 1.This pattern of liver test elevation is most consistent with alcohol-related liver disease 2.Given his abdominal pain and acute jaundice, biliary obstruction from choledocholithiasis must be considered 3.The AST is higher than the ALT in this case because the patient likely has concomitant vitamin B12 deficiency 4.AST may come from sources other than the liver while ALT is liver-specific Aminotransferases Aspartate aminotransferase (AST, formerly SGOT) Alanine aminotransferase (ALT, formerly SGPT) Enzymes that participate in gluconeogenesis Catalyze the transfer of amino groups from aspartic acid or alanine to ketoglutaric acid in order to produce oxaloacetic acid and pyruvic acid, respectively Serum elevation results from leakage from damaged cells Associated with diseases that involve significant hepatic inflammation and necrosis Aminotransferases ALT Liver specific Located in the cytosol AST Found in liver, skeletal and cardiac muscle, kidney, brain, pancreas, and blood cells Present in both cytosol and mitochondria AST/ALT Ratio In most liver injury (including NASH), the ratio is 1 In alcoholic hepatitis, ratio may be > 2 Vitamin B6 (pyridoxine) deficiency Mitochondrial AST release Aminotransferases Degree of elevation may be a diagnostic clue Modest elevation (<500 mg/dl) Alcoholic hepatitis or biliary obstruction Large elevation (>1000 mg/dl) Submassive necrosis (viral or acetaminophen overdose) Extreme elevation (>2000 mg/dl) Ischemia Degree of elevation does not correlate with prognosis Abnormal ALT 19,877 Air Force Recruits, 99 (.5%) with elevated ALT, 12% of these with identifiable cause What is a normal ALT? Levels may not rise with cirrhosis or in the absence of significant ongoing liver injury Levels may fluctuate in normal people 4% of the general population have abnormal liver function tests 10-20% will develop cirrhosis ~15% of patients with chronic liver disease (HCV, NAFLD) have normal tests despite abnormal histology New cutoff recommendations Men-30 IU/ml Women-19 IU/ml Kundrotas et al. Dig Dis Sci, 1993

3 Lactate Dehydrogenase Distributed widely outside the liver Skeletal or cardiac muscle injury, hemolysis, stroke, renal infarction, liver disease Rarely useful in differentiating forms of liver disease Massive, transient rise suggests ischemia Sustained LDH rise along with rise in alkaline phosphatase might indicate malignant infiltration of the liver Alkaline Phosphatase A family of isoenzymes that catalyze the hydrolysis of phosphate esters Found in liver, bone, intestine, kidney, placenta, leukocytes, neoplasia Present on the canalicular domain of the hepatocyte plasma membrane and the luminal domain of the bile duct epithelium Alkaline Phosphatase Elevation results from increased synthesis and release into serum rather than from impaired biliary secretion May not become elevated for a day or two following acute biliary obstruction Half life is one week May remain elevated for several days after resolution of biliary obstruction Levels up to three times normal are nonspecific Striking elevations can be seen with infiltrative disease or with biliary obstruction With focal intrahepatic duct obstruction, AP may be elevated while bilirubin remains normal Gamma Glutamyl Transpeptidase Catalyzes the transfer of glutamyl groups of peptides such as glutathione to other amino acids Derived from hepatocytes and biliary epithelia Not found in bone Can confirm hepatic origin of elevated AP Induced by alcohol GGT/AP ratio > 2.5 has been reported to be suggestive of alcohol abuse Question 2 A 42 year old female with no significant past medical history presents to her primary care physician with mild scleral icterus after a recent knee surgery. Her total bilirubin is found to be elevated with the indirect fraction predominating. The remainder of her liver chemistries are normal. Viral hepatitis serologies are negative. Which of the following is the most likely diagnosis? 1.Crigler-Najjar syndrome 2.Gilbert Syndrome 3.Acute hepatitis 4.Cholelithiasis Question 2: Answer A 42 year old female with no significant past medical history presents to her primary care physician with mild scleral icterus after a recent knee surgery. Her total bilirubin is found to be elevated with the indirect fraction predominating. The remainder of her liver chemistries are normal. Viral hepatitis serologies are negative. Which of the following is the most likely diagnosis? 1.Crigler-Najjar syndrome 2.Gilbert Syndrome 3.Acute hepatitis 4.Cholelithiasis

4 Bilirubin Organic anion from the catabolism of hemoglobin Direct: Conjugated, water soluble Indirect: Unconjugated, lipid soluble Unconjugated Hyperbilirubinemia Indirect bilirubin fraction>85% Increased production Hemolysis (transfusions, medications, ineffective erythropoiesis), resorption of a hematoma, or muscle injury Disorders of conjugation from mutations in bilirubin uridine diphosphate glucuronyl transfersase (UGT) Crigler-Najjar syndrome Gilbert s syndrome Acquired defects in uptake or conjugation Preer G L, Philipp B L Arch Dis Child Fetal Neonatal Ed 2010 by BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health Conjugated Bilirubinemia Direct bilirubin fraction >50% Non-excreted bilirubin is regurgitated from the hepatocyte into the serum Delta fraction = circulating conjugated bilirubin bound to albumin and not excreted in the setting of prolonged cholestasis Hyperbilirubinemia may resolve more slowly than other liver functions after liver injury Urobilinogen (bilirubin in the urine) is always in a conjugated form and thus always indicative of hepatobiliary disease Conjugated Bilirubinemia Impaired biliary excretion Choledocholithiasis Malignancy Primary biliary cirrhosis, primary sclerosing cholangitis Infiltrative Disease End stage liver disease Disorders of canalicular bile transport Dubin-Johnson syndrome Rotor syndrome Sepsis Liver Function Testing 1. Definitions of individual liver tests 2. Measures of synthetic function 3. Patterns of disease Hepatocellular v. cholestasis Common chronic liver diseases 4. Common causes of chronic hepatitis 5. Initial diagnostic testing in patients with elevated liver tests Question 3 A 58 year old woman presents with nausea, vomiting and abdominal pain. On physical exam, she has diffuse mild abdominal tenderness and no stigmata of chronic liver disease. On initial laboratory evaluation, her WBC is 10.9, platelets 257, albumin 2.7, AST 4670, ALT 6957, total bilirubin 3.2, alkaline phosphatase 170, INR 2.8, LDH 425. Which laboratory value is most indicative of worrisome liver dysfunction and can be monitored in real time to predict prognosis? 1.INR ALT Albumin LDH 425

5 Question 3: Answer A 58 year old woman presents with nausea, vomiting and abdominal pain. On physical exam, she has diffuse mild abdominal tenderness and no stigmata of chronic liver disease. On initial laboratory evaluation, her WBC is 10.9, platelets 257, albumin 2.7, AST 4670, ALT 6957, total bilirubin 3.2, alkaline phosphatase 170, INR 2.8, LDH 425. Which laboratory value is most indicative of worrisome liver dysfunction and can be monitored in real time to predict prognosis? 1.INR ALT Albumin LDH 425 Liver Synthetic Function Liver function test is a misnomer Liver function is measured by synthetic ability: Protein Synthesis: Albumin, prothrombin time/inr Nutrient Metabolism Gluconeogenesis, ammonia Biotransformation Bilirubin (glucoronidation) Immune Defense Bile Acid Synthesis Prothrombin Time PT measures rate of conversion of prothrombin into thrombin Requires factors II, V,VII, X Prolonged PT may occur in patients with acute or chronic liver disease secondary to hepatocellular dysfunction or chronic cholestasis All major coagulation factors (except factor VIII) are synthesized in the liver Factors in PT have a short half-life (6 hrs) Useful in monitoring synthetic capacity in patients with acute liver failure in real time Prothrombin Time Vitamin K deficiency: Cholestasis causes fat and fat-soluble vitamin (A, D, E, K) deficiency Required for factors II, VII, IX, X In the setting of deficiency, vitamin K should reduce PT by 30% within 24 hours Route of administration may be important May give intravenously if concerned about oral absorption Albumin 10g of albumin is synthesized and excreted by the liver daily Low albumin is not specific for liver disease Dependent on extrahepatic factors: nutrition, volume status, vascular integrity, catabolism, loss in urine or stool, hormonal factors Long half-life (20 days) Less useful than PT in assessing hepatic synthetic function in the acute setting Can take weeks to normalize after resolution of an acute illness Model for End Stage Liver Disease MELD was originally derived to describe mortality in patients undergoing TIPS 3.8 x log (e) (bilirubin mg/dl) x log (e) (INR) log (e) (creatinine mg/dl) Predictive of 3 month mortality: 40: 71.3% mortality 30 39: 52.6% 20 29: 19.6% 10 19: 6.0% <9: 1.9% Used to prioritize patients for liver transplantation Malinchoc M, et al. Hepatology, 2000

6 Liver Function Testing 1. Definitions of individual liver tests 2. Measures of synthetic function 3. Patterns of disease Hepatocellular v. cholestasis Cirrhosis and decompensated end-stage liver disease 4. Common causes of chronic hepatitis 5. Initial diagnostic testing in patients with elevated liver tests Hepatitis vs. Cholestasis Hepatitis Cholestasis Aminotransferases 2-100x 1-5x Alkaline Phosphatase 1-3x 2-20x Bilirubin 1-30x 1-30x PT response to vitamin K None Decrease in prolongation Albumin Decreased Normal or decreased (chronic) Acute v. Chronic Acute Chronic Duration of elevation < 6 months > 6 months Prognosis Can be self-limiting Spontaneous recovery rare Regeneration Can result in normal Results in fibrosis liver Presentation Can have severe increases in liver tests Liver tests less elevated Transplantation For fulminant liver failure patients Decompensated cirrhosis Chronic Liver Disease and Cirrhosis Cirrhosis is end stage scarring of the liver 12th leading cause of death in US in % of all deaths Age-adjusted death rate of 9.6 per 100,000 population Probably underestimated 10 year mortality 34-66% depending on cause Rosen H. NEJM, 2011 Chronic Liver Disease and Cirrhosis Etiology Hepatocellular Viral: HBV, HCV Alcohol NAFLD Medications Autoimmune Vascular Metabolic Cholestatic PBC, PSC Secondary biliary cirrhosis Medications Neoplastic Liver Function Testing 1. Definitions of individual liver tests 2. Measures of synthetic function 3. Patterns of disease Hepatocellular v. cholestasis Cirrhosis and decompensated end-stage liver disease 4. Common causes of chronic hepatitis 5. Initial diagnostic testing in patients with elevated liver tests

7 HCV: Global Burden of Disease HCV is the most common chronic infection in the US > 5 % % % <1 % 170 million worldwide (3% of the world population) million in the US (75% unaware of diagnosis) Most common indication for liver transplantation Hepatitis C Virus Virus: Single stranded RNA virus Flaviviridae family Diagnositic Tests: HCV antibody detection: EIA, RIBA Quantitative or qualitative RNA, HCV genotype (1-6) Prognosis: Usually presents in asymptomatic chronic phase of infection ~80% will develop chronic infection ~20% of those with chronic infection will develop cirrhosis and/or hepatocellular carcinoma in their lifetimes HCV Infection: Natural Disease Progression Exposure (Acute Phase) 15% 85% Resolved Chronic 20% Time (years) Cirrhosis (20-year progression rate accelerated with HIV, HBV, etoh) 6% 4% HCC (5-year ESLD survival <5%) 3-4% Transplant/Death Di Bisceglie A et al. Hepatology. 2000;31: Genotypes 2/3: SVR > 80% Peg-IFN + ribavirin for 24 weeks All others (until 2011): SVR 40% Peg-IFN + ribavirin for 48 weeks Regimen Side Effects Constitutional symptoms such as fever, malaise, decreased appetite, weight loss Hematologic toxicities Thyroid disease, exacerbation/presentation of autoimmune diseases Depression Exacerbation of cardiopulmonary disease Vision changes Rash Hepatitis and decompensation Annals of Int Med, 2004

8 Directly Acting Antivirals (DAAs) Goals of new drug development: safer, shorter, more effective New drugs in development that target multiple different steps in the lifecycle Directly Acting Antivirals (DAAs) 2 newly approved agents are both NS3/4A serine protease inhibitors: Boceprevir (Victrelis) 750 mg po TID Telaprevir (Incivek) 800 mg po TID SVR rates ~80% for treatment naïve patients Approved only for: Patients with genotype 1 infection Use in combination with P-IFN and ribavirin No yet approved for: HIV, ESRD, post-lt, decompensated ESLD There are significant drug-drug interactions Comparing Regimens HBV: Global Burden of Disease Treatment naïve patients > 8% 2-8% < 2% CDC Worldwide: -350 million people are infected with chronic HBV -Responsible for 50-80% of HCC -Causes 600,000 annual deaths Hepatitis B Virus Virus: DNA virus in the Hepadnaviridae family Diagnostic Testing: HBsAg, HBsAb, HBcAb (IgG/IgM) Quantitative and Qualitative DNA, genotype (A-H) HBeAg, HBeAb Prognosis: Can present in acute or chronic phases of infection Children are less likely than adults to clear the infection > 95% of people infected as adults will clear ~30% for younger children and ~5% of newborns clear 40% lifetime risk of death from cirrhosis or hepatocellular carcinoma US HBV Incidence by Year HBsAg Screening of Pregnant Women Recommended Vaccine Licensed Infant Immunization Recommended Decline Among MSM & HCWs OSHA Rule Enacted Decline Among IDUs Adolescent Immunization Recommended Wasley A, et al. MMWR Surveill Summ. 2007;56(3):1-24.

9 HBV Treatment HBV Treatment Lok AS, et al. Hepatology, Lok AS, et al. Hepatology, Alcohol-related Liver Disease Spectrum including steatosis, steatohepatitis, fibrosis/cirrhosis and acute alcoholic hepatitis No known limit for safe amount of alcohol Risk factors: Amount, pattern of ingestion Gender and genetic factors Malnutrition Diagnosis: History AST/ALT ratio, GGT Liver biopsy Prognosis: 10-15% develop cirrhosis Am J Clin Path, Non-alcoholic Fatty Liver Disease Definition: Liver biopsy findings identical to those with ARLD with convincing evidence of negligible alcohol consumption (< 20g/wk) and negative for HBV and HCV Spectrum of disease including non-alcoholic steatohepatitis (NASH) and cirrhosis Epidemiology: Prevalence now well described; may be about 20-40% of adults in industrialized countries Statistically associated with obesity, DM, hypertension, hyperlipidemia, metabolic syndrome Diagnosis: Clinical diagnosis; cannot be differentiated from alcohol-related liver disease on liver biopsy alone Hepatic Steatosis Macrovesicular: Alcohol HCV (especially genotype 3) Wilson s disease Lipodystrophy Starvation Parenteral nutrition Abetalipoproteinemia Medications Amiodarone, methotrexate, tamoxifen, steroids Microvesicular: Reye s syndrome Medications Valproate, anti-retrovirals Acute fatty liver of pregnancy HELLP syndrome Inborn errors of metabolism NAFLD Treatment Gradual and sustained weight loss, through decreased caloric intake and/or increased exercise Loss of at least 3-5% of body weight appears to be necessary to improve steatosis Up to 10% may be needed to improve necroinflammation Tight control of metabolic syndrome Pharmacologic Intervetions: Metformin, insulin sensitizing, but in randomized controlled trials had no impact on liver histology and is not currently recommended Thiazolidinediones (such as pioglitazone and rosiglitazone) in randomized controlled trials and meta-analysis decreases steatosis and inflammation, but may not improve fibrosis Long term safety is not established

10 NAFLD Treatment Vitamin E: 800 IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH and is first-line pharmacotherapy Data do not yet support use in NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis History Duration of symptoms Type of symptoms: pain, pruritis, B symptoms Risk factors: transfusion, alcohol, intravenous drugs Medications Comorbidities: HIV, diabetes/metabolic syndrome, cardiac disease, autoimmune diseases Family History: HBV, autoimmune diseases, hemochromatosis Surgical history: Cholecystectomy, gastric bypass Sanyal AJ, et al. NEJM, Physical Exam Serologies Stigmata of portal hypertension Splenomegaly, ascites, spider angiomata, caput Liver size and shape Jaundice, xanthelasma, hyperpigmentation Petechiae, hematomas Kaiser-Fleischer rings Asterixis Signs of comorbid illnesses (e.g. obesity) Acute Liver Disease Hepatitis A IgM HBsAg, HBc IgM HCV RNA Acetaminophen, tox screen Pregnancy test ANA, ASMA, quant IgGs Ceruloplasmin if appropriate age Chronic Liver Disease HCV Ab HBsAg, HBc IgG Ferritin, iron studies A1c, FG, lipids ANA, ASMA, quant IgGs, AMA Ceruloplasmin, AT Imaging Ultrasound Test of choice for gallstones, dilated ducts, ascites Can also image vessels with doppler Not optimum for CBD, pancreas, mass lesions <2 cm Limitations dependent on body composition CT scan Mass lesions, CBD, pancreas, extrahepatic structures Better for obese patients, differentiating intra and extrahepatic obstruction, small mass lesions Can usually diagnose Budd-Chiari Limited in patients with renal disease, need IV contrast Imaging MRI Little advantage over CT except regarding vessels, vascular tumors Good for determining if cancer is resectable No longer used for patients with significant renal failure HIDA Can evaluate cholecystitis and CBD obstruction Need functioning liver and gallbladder, not helpful in the setting of significant cholestasis EUS/ERCP Excellent delineation of biliary anatomy and may have therapeutic applications Best for pathology near papilla (stones, strictures, malignancies)

11 Liver Biopsy Indications: Diagnosis: uncertain diagnosis, multiple diseases, FUO, abnormal focal or diffuse imaging finding Prognosis: stage of disease Treatment strategy Techniques Contraindications: Absolute: uncooperative patient, severe coagulopathy, hepatic infection, extrahepatic biliary obstruction Relative: ascites, morbid obesity, possible vascular lesion, amyloidosis, hydatid cysts Complications: Pain, bleeding (mild 1/500; severe in 1/ ,000), death (< 1 in 10,000), infection/sepsis, injury of other organs Rockey DC, et al. Hepatology, When to refer? When diagnosis uncertain Work-up negative, multiple positive tests, biopsy needed Prior to therapy for hepatitis Treatable biliary tract disease Indications for liver transplantation: Hepatic synthetic dysfunction due to acute liver failure, decompensated cirrhosis Very high transaminases or concern for the development of liver failure Hepatocellular carcinoma or other malignancies Summary Evaluation of LFT abnormalities involves differentiating Acute vs. chronic diseases Hepatitic vs. cholestatic diseases Compensated vs. decompensated liver function Knowing possible etiologies allows a more accurate and cost-effective evaluation A well planned laboratory and radiologic evaluation can often make diagnosis without liver biopsy Most of the evaluation can be done prior to referral to a hepatologist