Hepatocytes produce. Proteins Clotting factors Hormones. Bile Flow

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1 R.J.Bailey MD

2 Hepatocytes produce Proteins Clotting factors Hormones Bile Flow

3 Trouble.. for the liver!

4 Trouble for the Liver Liver Gall Bladder Common Alcohol Hep C Fatty Liver Cancer Drugs Viruses Uncommon Iron hemochromatosis Copper Wilson s disease Alpha-1-Antitrypsin Auto Immune Chronic Active Hepatitis Bile Duct

5 Hepatocellular Disease Liver cells inflamed, infected, dying Patients feel unwell Lab tests: AST and ALT elevated Bilirubin not flowing through the sick cell - jaundice possible Bile salts not produced: no itch

6 Hepatocellular Disease NO NO NO Bilirubin Metabolism Albumin Clotting factors Hormones Filter Gut proteins Jaundice bilirubin Ascites, edema albumin Bruise, bleed INR Male- breasts Female- menses Fluids - edema Confusion EEG testes

7 Liver Biochemical Tests Test Pathophysiology Disease ALT Leak from damaged liver Mild to moderate Many liver problems Extra Hepatic Liver Origin Liver AST Leak from damaged liver Severe Hepatitis: viral, toxic, autoimmune, ischemic Muscle kidney RBC s, heart Clinical Clue AST/ALT > 2 Suggests alcohol or cirrhosis-any etiology.

8 Test Pathophysiology Liver disease Extra Hepatic Mild/moderate Many Liver Diseases Bilirubin Decreased clearance Marked: Obstruction Hepatitis Hereditary RBC breakdown Prothrombin time Decreased synthetic capacity Acute/chronic liver failure Obstruction (Vit K corrects) Albumin Decreased synthesis Chronic liver failure Vit K deficiency malabsorption malnutrition Nephrotic syndrome, enteropathy malignancy, malnutrition, inflammation

9 Elevated Aminotranferase History and Physical Ultrasound Drugs Prescribed Over the counter Viral Hep B Hep C Metabolic: Ferritin Fe TIBc Copper Caeruloplasmin Alpha-1- antitrypsin Fatty Liver Alcohol Diabetes Obesity Dyslipemia Autoimmune IgG Anti-actin Anti-nuclear Anti-TTG

10 And now comes trouble.. for the bile ducts!

11 Cholestasis Liver Gall Bladder Bile Duct

12 Cholestasis The bile is not flowing Bile is backing up Liver cells are not sick So patients are not sick Alkaline phosphatase, GGT elevated

13 Trouble for the Bile Duct Liver Gall Bladder Pancreas Common Gallstones Cancer of pancreas Uncommon Sclerosing Cholangitis Cholangio carcinoma Primary Biliary Cirrhosis Bile Duct

14 Test Pathophysiology Liver Disease Extra Hepatic Alkaline Phosphates Mild to moderate: Many Diseases Bone Placenta Gamma Glutamyl Transpeptidase (GGT) Overproduction and leakage into serum Marked: -Cholestasis obstruction -Infiltration: Tumour Granular Alcoholic hepatitis Kidney Spleen Heart Lung Pancreas Clinical Clue GGT/AP > 2.5 suggests alcohol

15 Elevated Alkaline Phosphatase History and Physical and Ultrasound Obstruction or Mass Pancreas Gall Stones P.S.C. No Obstruction PBC- (AMA, IgM) Infiltrative Disease HCC (AFP)

16 Childs Pugh Liver Tests and Prognosis Ascites None Slight Moderate + Encephalopathy None Slight Moderate + Bilirubin < >30 Albumin > <28 ProthrombinTime >6 Score Child Pugh Class Prognosis (1 year) (2 years) 5-6 A 100% 85% >9 B 81% 57% C 45% 35% Operator dependent, 3 categories only, difficult to decide on severity

17 Liver Tests and Prognosis - MELD Model End Stage Liver Disease Formula: 3.8 x log (e) (bilirubin mg/dl) x log (e) (INR) log (e) (creatinine mg/dl) Consistent, Reproducable, Non-Operator Dependent or use your I-PHONE app!!

18 Liver Tests and Prognosis - MELD

19 SOMETIMES IT S NOT THAT EASY!

20 Cirrhosis New Ideas about Cirrhosis 1. Labs can fool you 2. Fibroscan Very Helpful 3. Concept changes

21 Cirrhosis Child s & MELD are static pictures and may over or under diagnose cirrhosis -based on sampling errors at biopsy Cirrhosis may be clinically unnoticeable (compensated) or decompensated Compensated cirrhosis may have varying levels of portal hypertension (HVPG) Am J. Gastroenterol 2002, Hepatology 2006

22 How can we document in cirrhosis (easily) FibroScan measures the liver stiffness and quantify the hepatic fibrosis in a non-invasive and painless way.

23 Explored volume Probe positioning and measurement point 25 to 65 mm 3 cm 3 Explored volume is 3 cm 3 with M probe examination

24 Examples in human liver V S = 1.1 m/s E ~ 3 kpa V S = 1.7 m/s E ~ 9 kpa V S = 3.6 m/s E ~ 40 kpa E V S 2

25 Correlation between LSM and Fibrosis stages

26 Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis Histological F1-F3 F4 Clinical Non-cirrhotic Compensated Compensated Decompensated Decompensated Symptoms None None (no varices) None (varices present) Ascites, VH, Encephalopathy Infection Renal Failure Sub-Stage Stage 1 Stage 2 Stages 3 and 4 Stages 5 and 6 Hemodynamic (HVPG, mmhg) >6 >10 >12 Biological Fibrogenesis and Angiogenesis Scar and X-linking Thick (acellular) scar and nodules Insoluble scar Insoluble scar ORIGINAL ALTERED BY R.J.BAILEY HepatologyVOL 51;pages HEPATOLOGY 2010; 51: Am J Gastroenterol 2010; 105:

27 Clinical Stage 1 Compensated Cirrhosis Mortality 1% per year

28 Clinical Stage 2 Compensated Cirrhosis with Varices Mortality 3-4% per year

29 Ascites Mortality 20% per year

30 GI Bleeding Mortality 57% per year

31 Infection/Renal Failure Mortality 67% per year

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33 SOMETIMES IT S NOT THAT EASY!

34 What Do You Think? Male 47 years Alcohol 3 bottles of a beer a day Past Seizures- (dilantin controlled) lbs Ultrasound- Normal Labs Bilirubin(20) 40 AST (50) 57 ALT (40) 42 Alk Phos (130) 130 GGT (70) 487 Alcoholic Hepatitis Drug Induced Metabolic Syndrome Gilbert s Cirrhosis

35 Male 47 Years lbs Physical Exam Normal Ultrasound- non homogenous Labs Bilirubin 22 ALT (40) 62 AST (50) 62 Alk Phos (130) 137 GGT (70) 102 Ferritin (30-300) 962 Hep C Ab Pos Hemochromatosis or Hepatitis C

36 Ferritin Elevation Intracellular Iron Storage (hemochromatosis) Acute Phase Response Hemochromatosis? or Hepatitis C? Genetics Hepatitis C RNA

37 Hepatitis C Hep C Ab 75% Hepatitis C 25 % Hepatitis C Cleared Genotypes 1-6 Influences therapy IL-28 CC CT TT RX Coming Pegylated Interferon Ribavirin Boceprevir or Telaprevir Sofosbuvir Semiprevir

38 Hepatitis B Hep B S Ag Hep BV DNA Hep B e Ag Hep B e Ab ALT Fibroscan Rx for life positive 20,000 IU 2,000 IU 20,000 IU 2,000 IU 30 for men 20 for women F1 F2 F3 F4 Entecavir Tenofovir

39 Liver: Abnormal Enzymes: Thank you R.J.Bailey MD