Liver Toxicity in the HCT Patient

Transcription

Liver Toxicity in the HCT
Patient
Marcie Tomblyn, MD, MS
Tandem BMT Data Managers
Meeting
February 2009
Basic Functions of the Liver
Production of:
Bile
Bil
Coagulation
((clotting)
g) factors
Albumin
St
Storage of:
f
Glycogen (glucose)
Vitamins A, D, B12
Iron
Copper
Metabolism of:
Carbohydrates
Protein
Lipids
p
Drugs
Hemoglobin
Immunologic
functions as part of
reticuloendothelial
system
Causes of Liver Toxicity
y in HCT
Patients
Drug Toxicity
Infection
Sinusoidal Obstructive Syndrome AKA
Veno-occlusive disease
GVHD
Acute
Chronic
Others: cirrhosis, iron overload
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
Summary
y of Laboratory
y 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
g Factors V,, VII,, IX,, X
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
I di t d
damage tto li
liver cells
ll or liver
li
necrosis (death)
Laboratory
y 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
Laboratory
y 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
l b
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
E
t d iin urine
i
Unconjugated (indirect) bilirubin
Increased in disorders of high bilirubin
production (ex. hemolysis)
Bound to albumin
CTC AE v3.0
Liver Related Values
AE
1
2
Grade
3
4
Albumin
<LLN –
3g/dL
<3 –
2g/dL
<2g/dL
AP or ALT
or AST
>ULN 2.5X ULN
>2.5 –
5X ULN
>5 – 20X >20X
ULN
ULN
Bilirubin
(total)
>ULN –
1.5X ULN
1.5
1
5–
3.0X ULN
>3 – 10X >10X
ULN
ULN
-
Jaundice
Asterixis
Liver
dysfunction
/failure
-
Encephalopathy
or coma
Grade 5 = death
So what do the forms
actually ask…….
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
Baseline 2000: Laboratory
y Values
questions 141 - 146
AST
U/L
/ or µkat/L
k /
Date measured
ULN for your institution
Bilirubin
mg/dL or µmol/L
Date measured
ULN for your institution
Why
y do we care about prep
existing liver disease?
May have increased susceptibility to
hepatic toxicity
Contributes to the co-morbidity
index
May be
b options to minimize the
h
potential risks
i.e.
i
Treatment
T
t
t with
ith lamivudine
l
i di
ffor
HBV control
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 yes, then….
th
Answer
A
questions
ti
475 496…
Form 2100
Date of diagnosis:
g
Month,, day,
y, year
y
Etiology
Cirrhosis
Sinusoidal obstructive
syndrome/veno-occlusive disease
Other
unknown
Form 2100
Specify diagnosis by clinical signs, symptoms,
or evaluation
Ascites
Autopsy
Bilirubin >2.0 mg
Biopsy
Elevated liver enzymes
Elevated hepatic venous
pressure gradient
Hepatomegaly
Ultrasound/doppler with
abnormal portal vein flow
RUQ pain/tenderness
Other, specify
Weight gain >5%
Specific
p
etiologies
g
of
liver toxicity
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
Spectrum
p
of Drug
g Toxicity
y
Subclinical
Primarily increase in ALT but usually <3X
ULN
Acute liver injury
Hepatocyte damage or hepatocellular
necrosis
Increase in ALT
ALT, AST usually >3X ULN
Cholestasis
Increase in bilirubin, AP
Mixed
Steatosis
Sinusoidal Obstructive Syndrome
y
(SOS)
(
)
[AKA Veno-occlusive Disease (VOD)]
Physical findings:
Hepatomegaly (enlarged liver)
Right
Ri ht upper quadrant
d
t (RUQ) pain
i
Ascites
Hyperbilirubinemia (Jaundice)
Weight gain
Associated organ dysfunction including
renal and pulmonary
SOS/VOD
Usually begins within first 3 weeks
following HCT (median day 6)
Weight gain
Occurs in
Tender liver
Occurs in
(avg 11 kg)
>90% of patients with VOD
enlargement
>90% of p
patients with VOD
Lab abnormalities
Increased ALT, AST
Increased bilirubin (primarily conjugated)
May see increase in Prothrombin time
SOS/VOD: Diagnosis
g
Generally clinical based on physical
exam and laboratory findings
Ultrasound with doppler
Abnormal portal vein waveform
Reversal of flow in the portal vein
Hepatic
p
artery
y resistance index >0.75
Liver Biopsy (rarely done)
hepatic-venous
venous
Measurment of portal hepatic
pressure gradient
Pressure >10 mmHg corresponds with VOD
SOS/VOD: Prevention
Ursodeoxycholic acid (ursodiol)
RCT demonstrated decreased
incidence
c de ce of
o VOD
O in patients
pat e ts on
o
prophylaxis
Low dose heparin
Mixed results regarding benefit
SOS/VOD: Treatment
Currently supportive
Europe has Defibrotide available for
t eat e t
treatment
Await results of definitive US trial
Promising in the setting of severe
VOD with Multisystem organ
failure in phase II studies
Form 2100: VOD/SOS
/
q
questions
questions 477 - 481
Did the recipient receive treatment
for VOD
Yes
No
Did VOD resolve by day 100
Yes
No
Maximum bilirubin in first 100 days:
Cirrhosis
Due to chronic liver dysfunction
Replacement of liver tissue with fibrous
scar and
sca
a d regenerative
ege e at e nodules
odu es
Leads to liver failure
Multiple physical findings but
but… for the
forms:
Ascites
Increased bilirubin
Biopsy findings
Infection: Viral
Hepatitis A
Hepatitis B or C
May occur from reactivation or new
transmission
Other viruses including the herpes virus
families (CMV, HSV) can cause a
hepatitis
Hepatitis B
Diagnostic
g
tests for p
prior infection

Hepatitis
Hepatitis
Hepatitis
Hepatitis
B
B
B
B
core Antibody (HBcAb)
surface Antigen (HBsAg)
envelope Antigen (HBeAg)
DNA
Diagnostic test for prior infection OR
prior
i iimmunization
i ti
Hepatitis B surface Antibody (HBsAb)
Hepatitis
p
C
Diagnostic test for infection
Hepatitis C Antibody (HCAb)
Hepatitis
p
C NAT
No immunization available
If HCAb is positive, patient has an
infection with viral Hepatitis C
Infection: Other
Bacterial
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
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
f ll
follow-up
f
form
Site: Liver
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 3.1 – 6 mg/dL
Stage 3: bilirubin 6.1
6 1 – 15 mg/dL
Stage 4: bilirubin >15 mg/dL
Form 2100: Chronic GVHD Liver
In p
patients with chronic GVHD,, then specific
p
questions about organ/systems involved
Question 308: Liver
Yes
No
Question 309: If yes, was involvement
proven by
p
y biopsy
p y
Yes
No
Summary
Multiple
p causes of liver toxicity
y
Most manifest in lab value abnormalities
Increased Bilirubin
GVHD
Cholestasis from medications or TPN
VOD
Cirrhosis
Physical
Ph i l exam fi
findings
di
off jaundice,
j
di
ascites, and hepatomegaly are important
Questions