Transcript Abnormal Liver Function

Evaluation of abnormal liver
associated enzymes
Objectives
Define “liver associated enzymes”
Differentiate:
– Hepatocellular vs. cholestatic
Radiographic/pathology images
Specific liver diseases
Liver associated enzymes
& assessment of liver function
Commonly used in reference to:
– Alanine aminotransferase (ALT)
– Aspartate aminotransferase (AST)
– Alkaline phosphatase (AP)
– Gamma glutamyl transpeptidase (GGT)
– Bilirubin
Markers of synthetic capacity
– Albumin/pre-albumin
– Prothrombin time/INR
Aminotransferases
Elevation reflects hepatocyte injury
ALT relatively liver specific
AST may be found in skeletal and cardiac
muscle, blood cells
Hepatocellular injury ALT:AP >5
If ALT/AST elevation >1000
– Ischemia, virus, toxin, less commonly CBD
stone, AIH
Alkaline Phosphatase (AP)
Found in liver, bone, placenta, neoplasms
AP increased 3x in adolescence/ also
increased in late pregnancy
AP half-life 1 week (remain elevated after
relief of biliary obstruction)
AP elevations seen with infiltrative hepatic
disorders
Cholestatic injury ALT:AP ratio <2
Gamma Glutamyl Transpeptidase
GGT derived primarily from hepatocytes
and biliary epithelia
Useful to confirm hepatic origin of AP (may
also use a 5’ nucleotidase)
Microsomal enzyme inducible by ETOH,
Coumadin and anticonvulsants
Bilirubin
Derived primarily from the catabolism of
hemoglobin
– Water soluble, conjugated “direct”
Impaired biliary excretion (obstruction)
Bilirubin in urine always conjugated
– Water insoluble, unconjugated “indirect”
Increased production with hemolysis, ineffective
erythropoiesis, hematoma resorbtion
Increased LDH, decreased haptoglobin, increased AST,
increased retic count
Hemolysis will not elevate bilirubin >5 mg/dl
Albumen
Serum concentration falls with hepatic
parenchymal disease
Half Life 20 days
Negative acute phase reactant
May be depressed with poor nutrition,
renal losses (nephrotic syndrome)
History
Duration of LAE abnormality
– Acute <6 months
– Chronic >6 months
Medication history (with special attention
to new medications)
– Cholestasis with estrogens, anabolic steroids,
erythromycin, amoxicillin-clavulanate
Family history of liver diseases
– 2-3 generations/second degree relatives
History
Jaundice (bilirubin >3 mg/dl)
Arthralgias
Weight loss
Changes in urine color (direct bilirubin
only)
Physical Exam
Temporal/proximal muscle wasting
Spider Nevi
Palmer erythema
Gyncomastia
Dupuytren’s contractures
Testicular atrophy
Unknown
Up to 42% of those
with this condition
have elevated LAE
Associated with
neuropathy
May have iron and
folate deficiency
NAFLD/NASH
Macro vs. microvesicular fatty change
Less than 20-30 grams of ETOH per day
Metabolic syndrome
TPN
Drugs: amiodarone, tamoxifen,
glucocorticoids, estrogens
ALT>AST
NAFLD
Diagnosis
– Echogenic liver by
ultrasound
– Liver <15 HU/spleen
– Liver biopsy
Treatment:
– Modification of risk factors
– Pioglitazone/Vitamin E
– Gastric Bypass
Alcoholic Liver Disease
AST:ALT ratio >2 (established disease)
Elevations in AP/GGT
Macrocytic anemia
Thrombocytopenia
Elevated triglycerides
Higher rates Caucasians/lesser for Asians
Alcoholic Liver Disease
Discontinuation of ETOH/Detox program
Monitor for complications:
– Pancreatitis
– Cirrhosis, HCC and decompensations
Maddrey discriminant function 4.6 x (PTPT control) + bilirubin >32 give 4 week
course of prednisolone
Pentoxifylline 400mg TID
No ETOH 6 months->transplant evaluation
Hepatitis A
Fecal-Oral transmission
High rates daycare/prisons
Associated with contaminated water and
shellfish
Liver injury secondary to host immune
response
Hepatitis A
Children <5 asymptomatic 90%
Adults 70-80% symptomatic
If >40 1% mortality >50 2-3% mortality
Usually aminotransferases normalize by 2
months
No increase in severity with pregnancy or
increased fetal loss/abnormalities
Hepatitis A
Relapsing hepatitis resolution 4-15 weeks with
recurrence
Prolonged cholestasis (rare)
Diagnosis IgM anti-HAV with clinical features of
disease
May consider Immunoglobulin if exposure within
2 weeks (vaccine alone usually effective)
Vaccine 2 doses immunity 90-98%
Treatment supportive care rare need in
cholestasis for cholestyramine
Hepatitis B
Prevalence 5% of world population
1-1.25 million in U.S. chronically infected
as indicated by HBsAg positive
Most common in SE Asia/ China/
Philippines/ Middle East/ Africa
Lower prevalence: safe sex/vaccination
Only DNA Virus
Hepatitis B
Chronic infection more likely when
exposed as child
Increased vertical transmission with high
viral load and HBeAg positive mothers
Rare fulminant hepatic failure
(encephalopathy within 8 weeks of onset
of sxs)
Hepatitis B Serologies
Hepatitis B
Universal immunization of 11-12 year olds
HBIG used for neonatal prophylaxis, post
exposure prophylaxis, post transplant
prophylaxis
Therapy with interferons or nucleoside
analogues
Unknown
shiny, flat, polygonal,
violaceous
papules.Courtesy of Beth G
Goldstein, MD and Adam O
Goldstein, MD.
Hepatitis C
RNA virus
3-4 million persons
infected in U.S.
50-85% of infections become chronic
Decreasing incidence due to improved
medical practices, blood donor screening,
syringe exchange programs
Not efficiently spread via sexual relations
Majority of patients asymptomatic
Extrahepatic manifestations
Membranoproliferative glomerulonephritis
Essential mixed cryoglobulinemia
Porphyria cutanea tarda
Leukocytoclastic vasculitis
Lichen planus
Diagnosis
– Enzyme immunoassay (EIA) screen
– Virologic confirmation via PCR amplification
Hepatitis C
Genotype 1
– Telaprevir, Boceprevir therapy approved FDA
May 2011
– Response guided therapy
– Still requires Peg-IFN/RBV
Genotype 2,3
– Peg-IFN/RBV
– 24 weeks therapy
Hepatitis E
Endemic disease geographically
distributed around the equatorial belt
High fatality rate (0.5-4%) with pregnant
women at a fatality rate of 20%
Fecal-oral/rain season transmission
Dx by anti-HEV IgM
Autoimmune Hepatitis
Etiology-viral, drug, toxic or environmental
agent that resembles a self antigen
(molecular mimicry)
Type 1 AIH-most common in U.S./all ages
>75% female
ASMA/ANA
Acute onset 40%-rarely fulminant
If UC consider PSC overlap
Autoimmune Hepatitis
Type 2
Affects mainly children (2-14 years)
In Europe 20% adults/ U.S. 4% adults
Antibodies to LKM-1
Autoimmune Hepatitis
Predominantly hepatocellular inflammation
Fatigue, abd pain, hepatomegaly
AP elevated in 81% however usually less
than 2x normal (only 10%>4x normal)
Elevated gammaglobulinemia 92% usually
IgG
Autoimmune Hepatitis
Treat if:
Aminotransferases > 10 fold normal
Aminotransferases > 5 fold normal with
immunoglobuline >2 x normal
Incapacitating symptoms
Bridging necrosis by liver biopsy
Pediatric patients
Unknown
47 year-old WM with
chronic elevation of
LAE and joint pain
otherwise
asymptomatic
What is the disease
and likely genetic
mutation?
Hemochromotosis
Prevalence of 1:200-300 Northern
European descent
AR homozygous mutation C282Y >80%
Smaller proportion C282Y/H63D
Increased intestinal iron absorption
Hemochromotosis
Diabetes
Heart failure (cardiomyopathy)
Arthralgias
Amenorrhea/impotence
Increased skin pigmentation
Hemochromotosis
Phlebotomy to ferritin <50 ng/ml
Usually 0.5-1 unit of PRBC each week
Each unit of PRBC=250 mg of iron
Ferritin will drop 30 ng/ml for every unit of
PRBC removed
Deferoxamine (usually secondary iron
overload)
Wilson Disease
Prevalence 1:30:000 AR
Symptomatic usually 6-40 years
Chronic or fulminant liver disease
Mood disorder/movement disorder
Kayser-Fleischer ring/sunflower cataract
Hemolytic anemia
Wilson Disease
AST>ALT (similar to ETOH)
Low AP
Elevated bilirubin
Low ceruloplasmin in 95%
Serum copper concentration low
Urinary copper elevated
Hepatic copper concentration >250
mcg/gram
Wilson Disease
Treatment Penicillamine, trientine
(primarily increase urinary excretion)
Zinc-induces metallothionein which binds
copper in lumen
Liver transplant->fulminant hepatic failure
Alpha-1 Antitrypsin Deficiency
Predisposes adults to liver disease and
emphysema
Alpha-1 antitrypsin functions to protect
tissues from proteases
Phenotype PiMM normal/ PiZZ 1:2000
Dx with alpha-1 AT phenotype
determination (alpha-1 AT level may be
falsely elevated with inflammation)
Alpha-1 Antitrypsin Deficiency
Avoid tobacco
Infusions of alpha-1 AT derived from
pooled plasma
OLT recipient assumes Pi phenotype of
donor
Basilar emphysema
Celiac Sprue
Small intestinal malabsorbtion after
ingestion of gluten (wheat/rye/barley)
Highest in Celtic and Northern European
populations 1:122-1:1000
Classic sxs diarrhea, steatorrhea, weight
loss, short stature
Extraintestinal-anemia (iron/folate/b-12),
osteopenia, coagulopathy, infertility
Celiac Sprue
Aminotransferase elevations found in 42%
of celiac sprue patients
DX with anti tTG, endomysial antibodies
Associated with Dermatitis Herpetiformis
Autoimmune disease IDDM, thyroid
disease, IBD, PBC
Increased rate of SI lymphoma
TX Gluten free diet
Dermatitis Herpetiformis
Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology - 5th
Ischemic Hepatitis
Preceded by hypotension/hypoxemia
Most common co-morbidity
AMI/arrhythmia, sepsis
Significant elevation of aminotransferases
and LDH (distinguish from viral hep)
Often with transient elevated Cr
Budd-Chiari Syndrome
Impediment to flow from the hepatic veins
to right atrium
May present as chronic, acute or fulminant
liver dysfunction
Ascites, tender hepatomegaly
Hepatocellular injury>cholestasis
Budd-Chiari Syndrome
DX-doppler ultrasound
– absence of waveform in the hepatic veins
– hypertrophy of the caudate lobe
Alternative modalities=CT/MRI
Tx- thrombolytics, anticoagulation, surgical
portocaval shunt, TIPS-bridge to OLT,
balloon angioplasty
Sclerosing Cholangitis
Intrahepatic and extrahepatic bile duct
stricturing, fibrosis and inflammation
Name the association->
Primary sclerosing cholangitis
Portal bile duct with
periductal sclerosis
associated with
degeneration of the
bile duct epithelium.
Courtesy of Robert Odze, MD.
Secondary Sclerosing cholangitis
Cholangiographic pattern may be seen
with:
– Neoplasm
Cholangiocarcinoma
HCC
Mets
– Ischemia
– Chronic Pancreatitis
– HIV (cmv, cryptosporidium)
– Choledocholithiasis
PSC
80% have IBD (more commonly UC)
– Consider rectal/sigmoid biopsy
3-6% of UC patients have PSC Present
with jaundice, pruritus, abd pain
AP usually elevated 3-5x may be 20x
May have increased direct bilirubin
P-ANCA 65%-84%
PSC
DX by ERCP (gold
standard)
Histology onion skin
fibrosis
Elevated copper due
to impaired secretion
Biopsy may detect
small duct PSC
PSC
If sudden deterioration suspect
cholangiocarcinoma
Therapy possible benefit UDCA
Liver transplant
Harrison's Principles of Internal Medicine - 16th Ed.
Objectives
Define “liver associated enzymes”
Differentiate:
– Hepatocellular vs. cholestatic
Radiographic/pathology images
Specific liver diseases
References
(1) Davern T., Scharschmidt B., Biochemical
liver tests. Sleisenger and Fordtran’s
Gastrointestinal and Liver Disease (2002). 7th
edition pp 1227-1239.
(2) UpToDate online Pratt DS.,Approach to the
patient with abnormal liver function tests. Last
revision April 2006
(3) Braunwald E., Houser S., Fauci A., Longo D.,
Kasper D., Jameson J., Approach to the patient
with liver disease. Harrison’s Principles of
Internal Medicine (2001). 15th edition pp 17071737.
Zachary and William Bassett