ABNORMAL LIVER TESTS
Transcript of ABNORMAL LIVER TESTS
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ABNORMAL LIVER TESTS
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Antonio J. Sanchez, M.D.
Transplant HepatologistAssociate Professor of Medicine
Division of Gastroenterology and HepatologyUniversity of Iowa Hospitals and Clinics
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I , Antonio Sanchez, MD, disclose the following financial relationships with manufacturers of health care products:
Grant/Research Support: Merck, Shire, Ocera, Gilead
I, Antonio Sanchez, MD will not discuss medical devices during my presentation.
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OBJECTIVES
Define risk factors of acute and chronic liver disease
Discuss the diagnostic approach of patients with abnormal liver enzymes
Discuss indications for referral to Hepatology
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Clinical Scenario
53 y/ Caucasian man
Annual physical exam - Elevated liver enzymes
ALT - 130 ( 15-30) AST - 90 (15-30) Alkaline phosphatase - 105 ( 60-120)Total bilirubin - 0.8 mg/dl ( 0.5 - 1 mg/dl)Gamma GT - 40 u/L ( 35-60)
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Clinical Scenario
Unaware of liver enzyme elevationIncidental finding on annual examAsymptomatic
PAST MEDICAL HISTORYHyperlipidemia
FAMILY HISTORY:No liver disorders
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Clinical Scenario
SOCIAL HISTORYLawyerETOH: 1-2 beers/weekNo smoking, no illicit drugs, no tattoes, no blood transfusions, no herbals or natural products
REVIEW OF SYSTEMSFatigue20-pound weight gain – over past 12 monthsNo abdominal pain
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Clinical Scenario
PHYSICAL EXAM230 pounds – BMI 33No palmar erythemaAbdomen- Palpable right liver lobe. No ascitesNo stigmata of chronic liver disease on exam
LABSHB 15, Platelet count is 220,000Glucose 110 mg/dlTotal cholesterol 250 LDL 150 HDL 30Tryglicerides – 350
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Clinical Scenario
DIAGNOSTIC APPROACH
What is the etiology of his liver enzyme elevation?
What is the extent of liver disease ?
What are effective management interventions ?
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LIVER ENZYMES
ASTALTALKALINE PHOPHATASEGGTTOTAL BILIRUBIN5 NUCLEOTIDASE
LIVER ‘ FUNCTION TESTS’PT/INR, SERUM ALBUMIN, FACTOR V
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Aminotransferases
Released with hepatocellular injury
Aspartate aminotransferase (AST) Alanine aminotransferase (ALT)
AST/ALT ratio Normal is 0.8 In alcoholic liver disease, is usually > 2
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Alkaline PhosphataseIn liver, play an active role in down-regulating the secretory activities of the intrahepatic biliary epithelium
Found in:LiverBoneIntestineFirst trimester placentaKidney
Gamma-glutamyl transpeptidase (GGT): Liver origin: Elevated GGTBone origin: Normal GGT
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What causes ↑ bilirubin ?
- Overproduction by reticuloendothelial system
- Failure of hepatocyte uptake
- Failure to conjugate or excrete
- Obstruction of biliary excretion into intestine
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Bilirubin
Used to determine liver’s ability to clear endogenous and exogenous substances from the circulation
- Indirect (unconjugated) bilirubin Elevated with hemolysis, hepatic disease
- Direct (conjugated) bilirubin Elevated with biliary obstruction and hepatocellular disease.
Jaundice usually develops with a bilirubin ≥ 3 mg/dL
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Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000 Apr 27;342(17):1266-71.
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KEY ELEMENTS OF THE CLINICAL DIAGNOSTIC REASONING PROCESS
Bowen JL. Educational strategies to promote clinical diagnostic reasoning. N Engl J Med. 2006 Nov 23;355(21):2217-25
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How do we approach a patient with
abnormal liver enzymes ?
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Evaluation & Diagnosis
History! History! History!
Sexual contactsMetabolic
Risk FactorsPregnancy Illicit drug use
Medications Travel Hx ETOH use
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COMPLETE MEDICAL HISTORY
- History and physical exam-
Most important part of the evaluation in a patient with abnormal liver enzymes
- Acute vs. chronic liver disease
- Duration, pattern & progression - enzyme abnormalities
- Recheck liver profile/ previous liver profiles
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ETOH USE & EXPOSURE TO MEDICATIONS
- Amount /type of ETOH– alcoholic equivalents
- Medications ?
(prescription, over-the-counter and herbal therapies)
RX: statins, antibiotics, methotrexate, etc.
OTC’s : acetaminophen/NSAIDS
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Acetaminophen toxicity
N-acetylparabenzoquinoneimine
OH
NH C
O
CH3
NH C
O
CH3
O SO3-
NCO
CH3
O
NCO
CH3
OHSG
Acetaminophen
Acetaminophen sulfate
NH C
O
CH3
O C6H8O6-
UDP-glucuronosyl-transferase
<5%
Acetaminophen glutathione conjugate
CytoP450
Urine
Binding to cellular proteinsleading to hepatic and renal
injury
NAPQI
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Acetaminophen toxicity
Decreased hepatic gluthatione stores
ETOH useMalnutrition Anorexia nervosaBulimiaCystic fibrosis
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Risk factors - Acetaminophen toxicity
Max daily dose –patients chronic alcohol use: 2 g
Zimmerman et al: 67 pts with hepatic injury after APAP for therapeutic purposes, all alcoholics 60% < 6 g/day 40% < 4 g/day AST peaks: 3000 to 48,000 20% mortality
Hepatology. 1995 Sep;22(3):767-73.
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RISK FACTORS FOR VIRAL HEPATITIS TRANSMISSION
Illicit substances ( IV drug use)
Tatto placement/Blood Transfusions
Travel History (Endemic areas for hepatitis A - E )
Sexual History ( High risk sexual behavior)
Exposure to people with jaundice, contaminated foods
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ASSOCIATED MEDICAL PROBLEMS
- Metabolic Disorders ( DM, hyperlidemia, obesity) is a risk factor for non alcoholic fatty liver disease
- Autoimmune disorders ( SLE, RA, hypothyroidism)
- CHF/Congestive hepatopathy
- Hx of chronic pancreatitis in alcoholics
- Celiac disease/ Inflammatory bowel disease
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FAMILY HISTORY
History of liver disorders in family ( Hemochromatosis/ AA1AA deficiency)
Viral hepatitis in family (Hepatitis B in Asia)
Autoimmune disorders (hypothyroidism, Lupus, RA)
History of liver cancer (higher risk in hepatitis B)
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PHYSICAL EXAM
Presence/absence -pre-existing liver disease
Stigmata of portal hypertension
Evidence of hepatic decompensation
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PHYSICAL EXAM
STIGMATA OF CHRONIC LIVER DISEASE
Spider nevi Palmar erythema Gynecomastia Caput medusae Dupuytren's contractures Parotid gland enlargement Testicular atrophyTemporal/proximal muscle wasting
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LABORATORY TESTING
PATTERNS OF LIVER ENZYME ELEVATION
Hepatocellular
Cholestatic
Mixed
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Hepatocellular Injury
Hepatitis A: Acute infectionHistory: travel, recent outbreak, nausea, vomiting, jaundiceLabs: Profound ALT/AST. Hepatitis A IgM, elevated bilirubin
Hepatitis B:Can be acute or chronicHistory: Patient from Asia, Subsaharan Africa; sexual history, drug useLabs: ALT/AST, Hepatitis B surface antigen, Hb core antibody
Hepatitis C:History: IV drug abuse, blood transfusion prior to 1992, sexual history, tattoosLabs: Hepatitis C antibody (HCV viral load if immunocompromised)
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Hepatocellular Injury
Autoimmune HepatitisHistory: Young to middle-aged femalePersonal or family history of autoimmune disorders
Labs:AST/ALT elevationAnti-nuclear antibody: PositiveAnti-smooth-muscle antibody (SMA)Serum protein electrophoresis (SPEP) – increase in gamma globulin Liver biopsy (lymphocytic infiltrate/plasma cells)
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Hepatocellular Injury
Non-alcoholic steatohepatitis (NASH)Increase in AST/ALT are usually less than 4-fold.Ratio of AST/ALT is usually < 1History: metabolic syndrome, obesity, diabetes
Labs: Rule out other causes of liver diseaseAbdominal Ultrasound: increased liver echogenicity
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Cholestatic Pattern
Medications: Anabolic steroids, contraceptives, antibiotics
Total parenteral nutrition (TPN)
Cirrhosis:Viral hepatitis (Hepatitis B, C)Alcohol hepatitis
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Cholestatic Pattern Primary Biliary Cirrhosis
Autoimmune diseasePredominately in women, usually ages 35-65History of other autoimmune disordersSymptoms: Prurutis, fatigue, hyperpigmentation, musculoskeletal complaints
Labs:Elevated alkaline phosphatase and GGTAnti-mitochondrial antibodyLiver biopsy to verify diagnosis and/or overlap syndrome
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Cholestatic Pattern
Primary Sclerosing Cholangitis
Chronic progressive disorder - inflammation, fibrosis, and stricturing of medium size /large bile ducts in the intrahepatic and extrahepatic biliary tree ~ 90% have inflammatory bowel disease - ulcerative colitis (UC)Symptoms: Pruritus, fatigue, RUQ pain, UC symptoms
Diagnosis:UltrasoundERCP Cholangiogram: multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts
Prognosis:10-15% risk of developing cholangiocarcinomaLiver transplant is ultimate only treatment
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Cholangiogram Primary Sclerosing Cholangitis
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BACK TO OUR PATIENT
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53 y/o man
ALT 130 AST 90 - Normal Alk phos and T Bili
PLT count, PT/INR is normal
Asymptomatic
No baseline liver enzymes, remain high upon recheck
Hyperlipidemia/weight gain
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ADDITIONAL TESTING
Liver enzymes remain elevated, upon recheck
Viral hepatitis serologies for B and C are negativeIron Studies and Ferritin are normal
LIVER ULTRASOUND: Shows an enlarged liver with with diffuse increase echogenicity. No masses, no ductal dilatation or ascites
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What is the presumed etiology for his liver enzyme elevation ?
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NON ALCOHOLIC STEATOHEPATITIS
(NASH)
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NAFLD - Spectrum of Disease
Steatosis
Steatohepatitis (NASH)
Cirrhosis
NAFLD
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Epidemiology
Global distribution - Prevalence of NAFLD 13-18%
NAFLD is a leading cause of cryptogenic cirrhosis
Present in all ethnicities, and age groups
NHNAS III USA 23 % with abnormal liver enzymes
63 % in people with diabetes mellitus96 % in obese people
Clark J.M., Brancati F.L., Diehl A.M.: The prevalence and etiology of elevated aminotransferase levels in the united states. Am J Gastroenterol 98. (5): 960-967.2003Suzuki , A, Angulo P., Lymp J., et al: Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology 41. (1): 64-71.2005;
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Risk Factors for Fatty Liver Disease
0 10 20 30 40 50 60 70
Prevalence (%)
Obesity
High TG
Diabetes
Yu et al.. Nonalcoholic Fatty Liver Disease. Reviews in Gastroenterological Disorders. 2002; 2 (1):11-19
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Studies on Non-Alcoholic Steatohepatitis in Asia
Source: Asia Pacific Working Party on NASH
Country of Origin N Advanced hepatic fibrosis Author
AustraliaWestern Sydney 66 Cirrhosis 20% Chitturi
Brisbane 42 Cirrhosis 6% Powell
New Zealand (Auckland) 41 Cirrhosis 2% Samarsinghe
North Asia
China (Hong Kong) 30 Reported Advanced disease Leung
Japan 15 Reported Advanced disease Ueno
South AsiaIndia ( New Delhi) 52 Bridging Cirrhosis 12% Agarwal
India (Mumbai) 168 Cirrhosis 7% Amarapurkar
South Korea (seoul) 39 Reported Advanced disease Park
Sri Lanka (Kelaniya) 34 Cirrhosis 10% Janaki
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NAFLD Increased overall mortality compared to matched control populations.
Most common cause of death in patients with NAFLD and NASH is cardiovascular disease.
Increased liver-related mortality rate – increasingly common indication for liver transplantation (15-20%).
Kawamura Y et al (2011). Large scale long term follow up study of Japanese patients with NAFLD for the onset of HCC. American Journal of Gastroenterology doi:10.1038/ajg.2011.327
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Diagnosis of NAFLD - Ultrasound
Kawamura Y et al (2011). Large scale long term follow up study of Japanese patients with NAFLD for the onset of HCC. American Journal of Gastroenterology doi:10.1038/ajg.2011.327
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Clinical PredictorsNAFLD FIBROSIS SCORE
Multivariate model Presence or absence of advanced fibrosis
Age HyperglycemiaBody mass index Platelet count Albumin AST/ALT ratio
Independent indicators of advanced liver fibrosisAngulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007
Apr;45(4):846-54.
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Diagnosis of NAFLD- Fibroscan
Angulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007 Apr;45(4):846-54.
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Fibroscan
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Liver Biopsy Stage the severity of injury - Exclude other etiologies
Liver biopsy valuable diagnostic test for NASH.
Angulo et al. Age > 45 yearsObesity Type 2 diabetes mellitusAST/ALT ratio >1
Angulo P Hepatology 30(6):1356–1362, 1999
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Diferential Diagnosis
Exclude other etiologies of elevated liver enzymes
Viral
Autoimmune
Metabolic
Genetic
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Steatosis - Macrovacuolae
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Steatosis + lobular inflammation
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Fibrosis Extension
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Cirrhosis
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Insulin resistance
↑ Fatty acids
SteatosisLipid peroxidation
NASH
CytoprotectantsInsulin SensitizersAntihyperlipidemics
First Hit Second Hit
Weight Loss
Diet/Exercise
Antioxidants
NASH - How to Treat?
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Weight LossExplain diagnosis and set realistic target weightNutritional counseling – refer to dieticianExercise – 3-4 times per week, expend 400 kcal per session
Promrat et al 2010: Intensive lifestyle intervention (diet, exercise, behavior modification) vs structured education alone.
Weight loss 9.3% vs 0.2% (p = 0.003)Decrease in NAS 72% vs 30% (p=0.03)
Younossi ZM (2008). Review article: current management of NAFLD and NASH. Alimentary Pharmacology and Therapeutics 28: 2-12. Dowman JK, Armstrong MJ, Tomlinsomn JW, Newsome PN (2011). Current therapeutic strategies in NAFLD. Diabetes, Obesity and Metabolism 13: 692-702
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Antioxidants
Sanyal et al. NEJM 2010
247 adults – NASH, non diabetic
Pioglitazone Vitamin E Placebo
For 96 weeks
Primary outcome - improvement in liver histology
Vitamin E
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Antioxidants
Sanyal et al. NEJM 2010
Vitamin E vs. Placebo improvement in NASH 43 % vs. 19 %
Pioglitazone vs. Placebo not significant (34% and 19%)
Vitamin E and Pioglitazone reduced aminotransferasesreduced hepatic steatosis
No improvement in fibrosis scores
Pioglitazone group gained more weight
Vitamin E
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Farsenoid Nuclear Receptor Activators
Neuschwander-Tetri, et al Lancet 2015
141 patients with NASH Obeticholic acid 142 patients with NASH Placebo
45% in Obeticholic acid group improved liver histology
21% in placebo group improved liver histology
Obeticholic Acid
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33/70
Key NASH Therapies: Improvement in Fibrosis
Results from separate studies, not head to head– Time points and populations may differ among studies
1020
P = .0235
19
P = .00441
31
P = .2444
31
P = .12
3720
P = NS
No data 15/144
21/57
2/10
36/102
19/98
33/80
31/70
29/145
22/72
22/72
33/80
Active drug
Placebo
*
Cenicriviroc150 mg/day[4]
Obeticholic Acid
25 mg/day[2
]
Elafibranor 120
mg/day[3]
Vitamin E 800
IU/day[1]
Pioglitazone 30 mg/day[1]
Selonsertib 6 or 18
mg/day*[5]
100806040200
n/N =
Pts
(%)
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Clinical Trials in HepatologyPhase II Double-blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerabilityand Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi) inAdults With Nonalcoholic Steatohepatitis (NASH)
Volixibat increases bile acid excretion
Regulation Hepatic bile acid concentrations Fatty acid metabolism in the liver
Potential anti-fibrotic effect
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Referral to Hepatology
Persistent elevation of aminotransferases
Work up is abnormal
Evidence of portal hypertension
Decision for liver biopsy/perform Fibroscan
Access to clinical trials
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Summary
Recheck liver profile/ previous labs for progression
Complete history and physical exam
Define patient risk factors for liver disease
Behavior modification/changes
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Summary
Fatty liver disease is the hallmark of insulin resistance and reflects the metabolic syndrome affecting the liver
NASH is a progressive liver disease, associated with a risk of developing cirrhosis and hepatocellular carcinoma
Liver elastography is a reliable non-invasive method for the diagnosis of NAFLD
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Summary
No FDA approved pharmacologic interventions forNASH - Clinical Trials
Dietary changes associated with gradual weight losslead to biochemical/histologic improvement in NASH
Early identification of patients at risk for NAFLDessential to prevent complications
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