4 - Jaundice & LFTs Flashcards
Elevated ALT - Cause
I don’t fucking know. That shit just happens sometimes
15% of patients with Chronic Liver disease (HCV or NAFLD)
Have NORMAL liver tests despite having histologic damage
New Recommendations for the cut off for aminotransferases
Men - 31
Women - 30
Dangerzone - Hepatocytes
Well-differentiated 80% of cytoplasmic mass Have the ability to replicate in injury Secrete bile acids Take up digested material Synthesize albumin Metabolize and detoxify exogenous compounds
Dangerzone - Biliary Tree
Bile is secreted by hepatocytes
Cholestasis is caused by alterations in microfilaments surrounding bile canaliculus
Alterations can be induced by toxins, infection or obstruction
Obstruction may be intrahepatic or extrahepatic
Liver Functions
Measure of SYNTHETIC activity, not inflammation!!!!!!
“True” liver function tests measure
Protein synthesis (albumin, coag factors)
Nutrient Metabolism (Gluconeogenesis - the last thing to go)
Biotransformation (bilirubin glucoronidation)
Immune Defense
Bile Acid Synthesis
Synthetic Function Tests
PT - Production of coag factors
Most have half-lives between 6 - 96 hours and prolonged within a day with hepatic synthetic dysfunction
Albumin - Produced in hepatocytes half life is 20 days but not specific can be abnormal because of the other factors that can lower, including poor nutrition,
Bilirubin Test
Can be a marker of impaired synthetic function
Labs - Bilirubin
Breakdown product of heme cells released from senescent red blood cells and from hemoprotein in the liver
Natural compound circulates with albumin and is taken up by liver and secreted in the bile
If bile secretion is impaired, conjugated bilirubin may leak into plasma and cause jaundice
Alkaline Phosphatase
A family of isoenzymes that catalyze the hydrolysis of phosphatase esters
Found in liver, bone, intestine, placenta, kidney, leukocytes
In liver associated with sinusoidal and canalicular membranes
Obstruction to bile flow causes an increase in AP secondary to the induction of AP synthesis
Aminotransferases (AST, ALT)
Naturally found in the serum at low levels
AST is also found in cardiac muscle, skeletal muscle, kidney, pancrease, lungs, leukocytes
Both enzymes are released in the blood in increasing amounts when the hepatocyte membraen is damaged
Correlated in injury byt not to chance of recovery
INR of 2
Bad
γGlutamyl Transpeptidase (GGT)
Catalyzes transfer of glutamyl groups of peptides suc has glutathione to other amino acids
Found in liver, kidney, seminal vesciles, liver, spleen, heart, brain, not bone
VERY SENSITIVE, limited specificity
AST - Location
Mitochondria and cytosol of hepatocytes, heart and muscle
ALT - Location
Cytosol of hepatocytes
Alk Phos
Microvilli of the bile canaliculi, bone, placenta
Hepatocellular Pattern
AST +++ ALT +++ Alk Phos + TB + GGT +
Cholestatic Pattern
AST + ALT + Alk Phos +++ TB +++ GGT +
Infiltrative Pattern
AST + ALT + Alk Phos +++ TB + GGT +
Ultrasound - Use
Biliary Obstruction, Masses, Vasculature
$
Biliary Tree:
Rule out obstruction
Evaluate for presence of stones
Vasculature:
Evaluate flow, rule out obstruction
Screen for thrombus
Screen for stricture
CT or MRI/MRCP - Use
HCC, Mets
$$
3D imaging Demonstrates morphology of the liver Evaluate for size, position Evaluate for bleeding Evaluate for tumors, both benign of malignant
Will not evaluate for liver function and is not sensitive enough to detect fibrosis of the liver
Rarely reveals exact etiology of disease
ERCP - Use
Evaluate and Treat Biliary Obstruction
$$$$
Endoscopic cannulation of the ampulla with injection of contrast into the biliary tree
Diagnosis and therapy
EUS
Endoscopy using ultrasound technology to locate masses, lymph nodes, evaluate bile ducts
Liver biopsy
Provides diagnostic and prognostic information
Performed if expected benefit exceeds risk of procedure
Complications requiring hospitalization (1.4 - 4%)
Severe hemorrhage, pneumo, peritonitis (.1 - .3%)
Mortality rate of 9/100,000
Disease Identification - Hepatocellular Disease
History, Serology, Virology, Biopsy
```
Viral Hepatitis
A, B, C, D, E, EBV, CMV
Drug Induced Liver Disease
(Acetaminophen, INH)
Autoimmune Hepatitis
~~~
Disease Identification - Cholestatic Disease
Imaging
Obstruction of Biliary Tree
Gallstones, Pancreatic Mass, Ampullary Mass
Drug Induced Liver Injury
(Augmentin)
Disease Identification - Infiltrative DIsease
Imaging, Biopsy
Sacroid, Tuberculosis, Fungal Infections, Lymphoma
Painless Jaundice
Double Duct Sign
Know what that means I was scanning my shit
Elevated Unconjugated Bilirubin
Kids with something
Conditions overwhelming the system:
Sickle Cell Patients
ABO Mismatch blood transfusions –> Massive hemolysis
Approach to Jaundice
Indirect/Unconjugated OR Direct/Conjuaged
Jaundice - Indirect/Unconjugated
Hemolysis
Defect in Conjugation
Jaundice - Direct/Conjugated
Hepatocellular
Cholestatic
Jaundice - Direct/Conjugated - Cholestatic
Intrahepatic
Extrahepatic
Drug Induced Liver Injury (DILI)
Liver is the most common target organ for toxicity
Hepatotoxicity has been linked to over 1000 drugs
Accounts for >50% of cases of acute liver failure
Most common cause of death from acute liver failure
Most frequent reason for withdrawal of drugs from the market
Natural History of DILI
Wide spectrum of presentation from asymptomatic to fulminant hepatic failure
Mortality 8 - 10%
Mortality rate is higher in patients with jaundice at presentation
Factors associated with injury - DILI
Female Gender Age Diabetes Obesity Chronic Viral Disease Alcohol** Possible Nutritional Deprivation Renal Function
Causative Agents - DILI
73% of cases are from a single prescription agent:
Antimicrobials - 45% CNS agents - 15% Immunomodulatory Agents - 5.5% Analgesics Antihypertensives Antineoplastic Lipid Lowering Agents - 3.4%
9% dietary supplements
Mechanisms of Liver Injury
Binding of Drug to intracellular proteins:
Ionic gradients
Decline in ATP
Actin disruption, cell swelling & cell rupture
Drugs that affect transport proteins at the canalicular membrane
Drugs bound to enzymes (adducts):
Antibody Formation
Direct cytolytic T-Cell Responses with cytokine formation
Activation of TNF receptor or FAS
Inhibition of mitochondrial function
Types of hepatotoxicity - Intrinsic
More predictable Affects all individuals Cause toxicity in dose-dependent manner liver as target-injury to the tissue occurs at doses below those that are lethal Predictable pathology
Sensitivity to Intrinsic Hepatotoxins
Inflammatory Stress - LPS
Environmental Cofactors - Alcohol (Induction of CYP2E1 - increased reactive metabolite)
Acetaminophen Toxicity
Cluguronide and sulfate metabolites (85 - 95%)
Toxite Metabolite NAPQI
Mercapturic Acid Cysteine Conjugates (5 - 10%)
NAPQI leads to depletion of intracellular glutathione which inactivates the potent electrophile. This electrophile then binds to cell macromolecules and disrupts mitochondrial function
Types of hepatotoxicity -Idiosyncratic
Infrequent Attacks susceptible individuals Not clearly dose related Variable Onset (average 5 - 90 days) Variable Pathology Not predictable with animal testing
Idosyncratic Liver Injury - Allergic Reactions
Fever, rash, eosinophilia
Latency 1 month or less
Rapid recurrence after re-exposure (example, sulfa drugs)
Idiosyncratic Liver Injury - Non-Allergic
No features of hypersensitivity Long latency (often many months) Re-challenge does not consistently reproduce the injury (example amiodarone)
Stevens Johnson Syndrome
Sulfa Drugs
Phenytoin
