Patient. Marcie Tomblyn, MD, MS Tandem BMT Data Managers. February 2009

Transcription

1 Liver Toxicity in the HCT Patient Marcie Tomblyn, MD, MS Tandem BMT Data Managers Meeting February 2009

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3 Basic Functions of the Liver Production of: Bile Coagulation (clotting) factors Albumin Storage of: Glycogen (glucose) Vitamins A, D, B12 Iron Copper Metabolism of: Carbohydrates Protein Lipids Drugs Hemoglobin Immunologic functions as part of reticuloendothelial system

4 Causes of Liver Toxicity in HCT Patients Drug Toxicity Infection Sinusoidal Obstructive Syndrome AKA Veno-occlusive disease GVHD Acute Chronic Others: cirrhosis, iron overload

5 Physical Findings of Liver Toxicity Ascites Build-up of fluid in the abdominal cavity Jaundice and Icterus Yellowing of the skin and sclera due to increased bilirubin Hepatomegaly Liver enlargement Abnormal portal vein flow Hepatic encephalopathy

6 Summary of Laboratory Tests of Liver Function Amino Transferases (Transaminases) ALT (SGPT) AST (SGOT) Bilirubin Conjugated Unconjugated Alkaline Phosphatase (AP) Synthetic function Albumin Prothrombin (Factor II) Other Clotting Factors V, VII, IX, X

7 Laboratory Tests of Liver Function: Hepatocyte (liver cell) damage Transaminases Alanine aminotransferase (ALT, SGPT) Aspartate aminotransferase (AST, SGOT) Elevations Due to leakage from liver cells (hepatocytes) into the bloodstream Indicates damage to liver cells or liver necrosis (death)

8 Laboratory Tests of Liver Function: Cholestasis Cholestasis Occurs when bile cannot flow through the bile ducts to the duodenum for excretion Tests Alkaline phosphatase (AP) Bilirubin Gamma glutamyl transpeptidase (GGT) 5 Nuclotidase

9 Laboratory Tests of Liver Function: Synthetic Function Prothrombin Time Measure of extrinsic coagulation pathway Prolonged due to deficiency in the synthesis of Factor VII Also due to malabsorption and vitamin K deficiency Albumin Blood plasma protein produced by the liver Can also be decreased in malnutrition and malabsorption

10 Hyperbilirubinemia Bilirubin: breakdown product of hemoglobin Total bilirubin (what is generally measured) includes: Conjugated (direct) bilirubin Increased in liver parenchymal disease or biliary obstruction Excreted in urine Unconjugated (indirect) bilirubin Increased in disorders of high bilirubin production (ex. hemolysis) Bound to albumin

11 AE Albumin <LLN 3g/dL AP or ALT or AST Bilirubin (total) CTC AE v3.0 Liver Related Values Grade >ULN - 2.5X ULN >ULN 1.5X ULN <3 2g/dL >2.5 5X ULN X ULN <2g/dL - >5 20X ULN >3 10X ULN >20X ULN >10X ULN Bilirubin >ULN 15 >3 10X >10X Liver - Jaundice Asterixis Encephdysfunction alopathy /failure or coma Grade 5 = death

12 So what do the forms actually ask.

13 Baseline 2000 Form: Co-existing Diseases prior to HCT 119. Liver Disease Drug toxicity HAV = Hepatitis A virus HBV = Hepatitis B virus HCV = Hepatitis C virus Other, specify Note: These items can all occur post-hct as well

14 Baseline 2000: Laboratory Values questions AST U/L or µkat/l Date measured ULN for your institution Bilirubin mg/dl or µmol/l Date measured ULN for your institution

15 Why do we care about pre- existing liver disease? May have increased susceptibility to hepatic toxicity Contributes to the co-morbidity index May be options to minimize the potential risks i.e. Treatment t with lamivudine for HBV control

16 Form 2100: Question 474 Did the recipient develop non-infectious liver toxicity (excluding GVHD) after the start of the preparative regimen to the data of last contact? If th A ti 475 If yes, then. Answer questions

17 Form 2100 Date of diagnosis: Month, day, year Etiology Cirrhosis Sinusoidal obstructive syndrome/veno-occlusive disease Other unknown

18 Form 2100 Specify diagnosis by clinical signs, symptoms, or evaluation Ascites Bilirubin >2.0 mg Elevated liver enzymes Hepatomegaly RUQ pain/tenderness Weight gain >5% Autopsy Biopsy Elevated hepatic venous pressure gradient Ultrasound/doppler with abnormal portal vein flow Other, specify

19 Specific etiologies of liver toxicity

20 Drug Toxicity Occurs due to metabolic pathways of medications via the liver Multiple medications have potential liver toxicities including Chemotherapy Cylcosporine Azole antifungals Oral contraceptives Usually manifests as increase in liver transaminases and/or bilirubin

21 Spectrum of Drug Toxicity Subclinical Primarily increase in ALT but usually <3X ULN Acute liver injury Hepatocyte damage or hepatocellular necrosis Increase in ALT, AST usually >3X ULN Cholestasis Increase in bilirubin, AP Mixed Steatosis

22 Sinusoidal Obstructive Syndrome (SOS) [AKA Veno-occlusive Disease (VOD)] Physical findings: Hepatomegaly (enlarged liver) Right upper quadrant (RUQ) pain Ascites Hyperbilirubinemia (Jaundice) Weight gain Associated organ dysfunction including renal and pulmonary

23 SOS/VOD Usually begins within first 3 weeks following HCT (median day 6) Weight gain (avg 11 kg) Occurs in >90% of patients with VOD Tender liver enlargement Occurs in >90% of patients with VOD Lab abnormalities Increased ALT, AST Increased bilirubin (primarily conjugated) May see increase in Prothrombin time

24 SOS/VOD: Diagnosis Generally clinical based on physical exam and laboratory findings Ultrasound with doppler Abnormal portal vein waveform Reversal of flow in the portal vein Hepatic artery resistance index >0.75 Liver Biopsy (rarely done) Measurment of portal hepatic-venous pressure gradient Pressure >10 mmhg corresponds with VOD

25 SOS/VOD: Prevention Ursodeoxycholic acid (ursodiol) RCT demonstrated decreased incidence ce of VOD in patients ts on prophylaxis Low dose heparin Mixed results regarding benefit

26 SOS/VOD: Treatment Currently supportive Europe has Defibrotide available for treatment teat e t Await results of definitive US trial Promising in the setting of severe VOD with Multisystem organ failure in phase II studies

27 Form 2100: VOD/SOS questions questions Did the recipient receive treatment for VOD Yes No Did VOD resolve by day 100 Yes No Maximum bilirubin in first 100 days:

28 Cirrhosis Due to chronic liver dysfunction Replacement of liver tissue with fibrous scar and regenerative e e nodules Leads to liver failure Multiple physical findings but for the forms: Ascites Increased bilirubin Biopsy findings

29 Hepatitis A Hepatitis B or C Infection: Viral May occur from reactivation or new transmission Other viruses including the herpes virus families (CMV, HSV) can cause a hepatitis

30 Hepatitis B Diagnostic tests for prior infection Hepatitis B core Antibody (HBcAb) Hepatitis B surface Antigen (HBsAg) Hepatitis B envelope Antigen (HBeAg) Hepatitis B DNA Diagnostic test for prior infection OR prior immunizationi Hepatitis B surface Antibody (HBsAb)

31 Hepatitis C Diagnostic test for infection Hepatitis C Antibody (HCAb) Hepatitis C NAT No immunization available If HCAb is positive, patient has an infection with viral Hepatitis C

32 Bacterial Infection: Other Sepsis or septic shock due to bacterial infection Cholestatic picture Bacterial abscesses Fungal Hepatosplenic candidiasis Persistent fevers with RUQ pain and evidence of microabscesses on ultrasound

33 Infections Pre-transplant Infections Viral Hepatitis A, B, C HBV and/or HCV: supplemental hepatitis infection insert Fungal infections in the liver Post-transplant Infections Reported in the infection section of the follow-up form Site: Liver

34 Form 2100: Acute GVHD Liver (question 254) No liver agvhd/bilirubin level not attributable to agvhd Stage 0: bilirubin <2 mg/dl Stage 1: bilirubin 2 3 mg/dl Stage 2: bilirubin mg/dl Stage 3: bilirubin mg/dl Stage 4: bilirubin >15 mg/dl

35 Form 2100: Chronic GVHD Liver In patients with chronic GVHD, then specific questions about organ/systems involved Question 308: Liver Yes No Question 309: If yes, was involvement proven by biopsy Yes No

36 Summary Multiple causes of liver toxicity Most manifest in lab value abnormalities Increased Bilirubin GVHD Cholestasis from medications or TPN VOD Cirrhosis Ph i l fi di f j di Physical exam findings of jaundice, ascites, and hepatomegaly are important

37 Questions