B5.024 Big Case: Jaundice/Abnormal LFTs/Dark Urine Flashcards
major functions of the normal liver
- synthesis of plasma proteins
- metabolism
- biotransformation
- bile salt synthesis and bile formation
- immune: reticulo-endothelial function
- storage
what proteins does the liver primarily synthesize
albumin
coagulation factors
what metabolic functions does the liver participate in
cholesterol synthesis and uptake glucose production, glycogen storage conversion of ammonia to urea endogenous hormone balance lipoproteins synthesis of non-essential amino acids
biotransformative functions of liver
bilirubin conjugation
drugs
ethanol
immune functions of liver
clearance of damaged cells, proteins, drugs, and activated clotting factors
clearance of bacteria and antigens from the portal circulation
storage functions of liver
glycogen: liver stores enough glucose in the form of glycogen to provide a day's worth of energy fats iron copper vitamins A, D, K, and B12
2 patterns of liver injurt
- hepatocellular
2. cholestatic
liver function tests
albumin
PT/INR (coagulation factors)
bilirubin
serum albumin measurement
quantitatively the most important plasma protein synthesized by the liver
serum levels are affected by: synthesis, distribution, catabolism
why is albumin important
provides osmotic pressure
acts as a transport system within the serum
PT/INR measurement
excellent test of hepatic synthetic capacity (liver makes coag factors 1,2,5,7,9, and 10)
predictor of liver dysfunction but NOT a predictor of bleeding tendency
hepatocellular injury
elevated ALT/AST
injury to hepatocytes
cholestatic injury
elevated alk phos/bilirubin decrease in bile flow due to -impaired secretion by hepatocytes OR -obstruction of bile flow through intra- or extra-hepatic bile ducts
possible causes of acute hepatocellular injury
viral hepatitis ischemia autoimmune hepatitis acetaminophen/toxins drugs
possible causes of acute cholestatic injury
any biliary obstructive process
PBC/PSC
drugs
sepsis
ALT test
more specific for liver
located in hepatocyte cytosol
AST test
present in liver, heart, skeletal muscle, kidney, brain, lungs, leukocytes
in hepatocyte cytosol and all mitochondria
not as specific as ALT, but equally as sensitive
discuss ALT/AST test results
elevated to some extent in almost all liver diseases
normal: 10-50
highest elevations (over 1000) causes by a few conditions
most other diseases give moderately elevated levels (50-200)
what are the causes of the highest ALT/AST elevations
acute viral hepatitis
toxin-induced necrosis (APAP, mushrooms)
ischemia
autoimmune hepatitis
acute biliary obstruction ALT/AST results
most patients have high levels which decline rapidly in 24-72 hours
features of alcoholic hepatitis
10-35% of drinkers who consume 30-50g alcohol daily > 5 years
characterized by inflammation and injury to the liver (mild to severe)
often underlying cirrhosis
mortality rate 30-60%
histologic characters of alcoholic hepatitis
ballooned hepatocytes
Mallory-Denk hyaline
steatosis
major alcohol metabolism pathway
ethanol>acetaldehyde via alcohol dehydrogenase
acetaldehyde > acetate via aldehyde dehydrogenase
acetate > H2O and CO2 via oxidation in peripheral tissues
2 alternative pathways from ethanol > acetaldehyde
- MEOS pathway (CYP2E1)
2. peroxisomal catalase
alcohol dehydrogenase pathway
as alcohol is oxidized, NAD is converted to NADH
increased ration of NADH/NAD leads to alcoholic fatty liver
microsomal ethanol oxidizing pathway (MEOS)
inducible p450 pathway
CYP2E1: implicated in tolerance to various drugs in alcoholics and increased susceptibility to toxicity
peroxisomal catalase pathways
<2% of overall in vivo alcohol oxidation
alkaline phosphatase test
found in or near the canalicular membrane
mainly present in liver, bone, placenta, intestine
typically: 70-159
-less than 3 folds elevation in most liver disease
-> 3-4 fold elevations are typically seen in infiltrative liver diseases or disease of bile ducts
GGT test
found in bile duct epithelium and in ER of cholangiocytes
found in multiple organs but not in bone
sensitive indictor of cholestasis with poor specificity
typical outcome of acute liver injury
may experience full recovery OR fulminant hepatic failure
typical outcome of chronic liver injury
often develop hepatic fibrosis/cirrhosis
causes of acute liver injury
drugs
toxins
ischemia
viral hepatitis
causes of chronic liver injury
alcohol autoimmune hepatitis non-alcoholic fatty liver PSC/PBC chronic viral hep B or C
definition of jaundice
a medical condition with yellowing of the skin or whites of the eyes, arising from excess of the pigment bilirubin and typically caused by obstruction of bile duct, by liver disease, or by excessive breakdown of RBCs
levels normally 1 mg/dL and levels over 2-3 mg/dL are typically needed to cause jaundice
symptoms associated with jaundice
dark urine
light colored stool
overview of bilirubin processing
- breakdown of RBCs heme to bilirubin occurs in macrophages of the reticuloendothelial system
- unconjugated bilirubin is transported through blood (complexed to albumin) to the liver
- bilirubin taken up via facilitated diffusion by the liver and conjugated with glucuronic acid
- conjugated bilirubin secreted into bile and then intestine
- in intestine, glucuronic acid is removed by bacteria and bilirubin is converted to urobilinogen
- some of urobilinogen is reabsorbed and enters portal blood (some is excreted in kidneys)
- remaining urobilinogen in GI is oxidized by bacteria to brown stercobilin
heme to biliverdin enzyme
heme oxygenase
total serum bilirubin components
conjugated (direct) + unconjugated (indirect)
pre-hepatic/hemolytic causes of hyperbilirubinemia
extrinsic causes external to blood cells
OR
intrinsic defects in RBCs
intra-hepatic/ hepatocellular causes of hyperbilirubinemia
pathology is located within the liver and due to disease of hepatic parenchymal cells
post hepatic/cholestatic hyperbilirubinemia
pathology is located after conjugation in the liver caused by an obstructive process
genetic causes of pre-hepatic hyperbilirubinemia
spherocytosis sickle cell thalassemia G6PD deficiency Wilson's disease
autoimmune causes of pre-hepatic hyperbilirubinemia
hemolytic anemia
drug induced
infectious causes of pre-hepatic hyperbilirubinemia
malaria
traumatic causes of pre-hepatic hyperbilirubinemia
extra vascular blood loss
drug causes of pre-hepatic hyperbilirubinemia
dapsone
rifampin
characteristics of a G6PD deficiency
genetic disorder, occurs almost exclusively in males (X-linked)
affects 400 million worldwide (North Africa, Middle East, Mediterranean)
function of G6PD
normal function to produce compounds which prevent ROS build up in RBCs
in deficiency , ROS build up and cause hemolytic anemia
certain drugs/infections/foods can increase ROS
genetic causes of hepatocellular hyperbilirubinemia
hemochromatosis
Wilson’s disease
Gilbert’s syndrome
crigler-najjar syndrome
autoimmune causes of hepatocellular hyperbilirubinemia
autoimmune hepatitis
PBC
PSC
IgG4 cholangiopathy
infectious causes of hepatocellular hyperbilirubinemia
viral hepatitis
hepatic abscess
vascular causes of hepatocellular hyperbilirubinemia
impaired flow
drug/toxin causes of hepatocellular hyperbilirubinemia
APAP
INH
idiosyncratic drug reactions
alcohol
malignant causes of hepatocellular hyperbilirubinemia
HCC
cholangiocarcinoma
lymphomas
metastatic disease
50/50 ratio of direct to indirect bilirubin in lab testing
intra-hepatic cause of hyperbilirubinemia
physiologic jaundice of the newborn
increased enterohepatic circulation of bilirubin
-lack of intestinal flora to convert bilirubin conjugates
-decreased hepatic levels of UDP1A1 activity
-inability to pass meconium (contains significant amount of bilirubin)
impacts 60% of newborns
breast milk jaundice
cause unknown, persists after physiologic jaundice
from weeks 2-12
don’t stop breastfeeding
breast feeding jaundice
decreased hepatic levels of UDP1A1 activity, more pronounced in premature infants
not enough milk: keep trying or supplement
treatment for physiologic jaundice of the newborn
hydration
adequate nutrition
bili lights (phototherapy)
exchange transfusion
kernicterus
severe unconjugated hyperbilirubinemia
yellow staining of basal ganglia, hippocampus, cerebellum, and nuclei of the floor of 4th ventricle
clinical features of kernicterus
high pitched cry, hypotonia, vomiting, hyperpyrexia, sluggish Moro, seizures, paresis of gaze, and death
survivors can have choreoathetosis, spasticity, and sensorineural hearing loss
congenital causes of post-hepatic hyperbilirubinemia
bilirary atresia
malignant causes of post-hepatic hyperbilirubinemia
HCC cholangiocarcinoma pancreatic cancer lymphoma ampullary cancer
infectious causes of post-hepatic hyperbilirubinemia
clonorchis
opisthorchis
anatomic causes of post-hepatic hyperbilirubinemia
biliary strictures
mirizzi syndrome
cholelithiasis
what is mirizzi syndrome
gallstone not in duct but in outflow portion of gallbladder
still causes obstruction
epidemiology of HCC
6th most common malignancy and leading cause of mortality in patients with cirrhosis
risk factors: cirrhosis HBV, HCV, NAFLD, M>W
diagnosis of HCC
multi phase imaging with IV contrast
often secrete alpha-fetoprotein (AFP)
treatment of HCC
chemotherapy (TACE)
tumor ablation
surgical resection
liver transplantation
histo findings of cirrhosis
hepatic fibrosis
regenerative nodule formation
etiologies of cirrhosis
viruses (hepatitis B and C) ethanol misuse NAFLD chronic biliary obstruction autoimmune hepatitis storage disease chronic CHF
primary complications of cirrhosis
- loss of hepatocytes (decrease in liver function)
- portal hypertension and portal-systemic shunting
- hematologic abnormalities
portal venous system
begins in capillaries in the intestine and terminates as the hepatic sinusoids
nutrients from the GI tract and hormones from pancreas are delivered to the liver
manifestations of portal hypertensions
ascites
varices
hepatic encephalopathy
hepatorenal syndrome
development of ascites
sodium and water retention in conjunction with increased intrahepatic resistance and increased sinusoidal pressure
esophageal varices
portal systemic collaterals
hepatic encephalopathy
derangement of mental function caused by acute liver failure or by cirrhosis with portal system shunting
cirrhotic liver fails to detox portal blood toxins which then interact with the CNS
compensated cirrhosis
- increased intrahepatic vascular resistance, moderate portal hypertension
- splanchnic arterial vasodilation
- low effective arterial blood volume
- increased cardiac output and plasma volume
- restoration of effective arterial blood volume
decompensated cirrhosis (hepatorenal system) (HRS)
- disease progression, severe portal hypertension, bacterial translocation
- severe splanchnic arterial vasodilation
- markedly reduced effective arterial blood volume, increased CO and plasma volume insufficient to normalize effective arterial blood volume, activation of sodium retaining and vasoconstrictor systems
- sodium and water retention and ascites formation
- further activation of vasoconstrictor systems & impairment in CO
- renal failure
clinical picture of hepatorenal syndrome
oliguria, increased BUN and creatinine, concentrated urine in a patient with decompensated chronic liver disease
- ascites
- tubular function intact
- no glomerular injury
- similar to dehydration clinically
hematologic complications of cirrhosis
anemia
thrombocytopenia
leukopenia
