Pathology Of The Liver And Biliary Tract 2 Flashcards
What are the two major functions of hepatic bile?
1) emulsification of dietary fat in the lumen of the gut via bile salts
2) elimination of bilirubin, excess cholesterol and other waste products that cant be excreted into urine
Jaundice
Occurs when there is increased bilirubin production
- red cell hemolysis, hepatocyte dysfunctions, obstruction of bile flow are the big three causes
4 major steps of metabolism of bilirubin
1) uptake from the circulation
2) intracellular storage
3) conjugation with glucuronic acid
4) biliary excretion
* is end of product of heme degredation
How is most of the bilirubin-glucuronide complexes formed in the liver deconjugated?
Via gut lumen bacterial B-glucuronidases
- produces urobilinogens which are excreted in feces
What are the two primary human bile acids?
Glycocholic acid and taurocholic acid
- formed by glycine and taurine molecules (similar to bile salts as well)
What percentage of bile acids are reabsorbed?
95% via the hepatic portal vein into the enterohepatic circulation
What happens with unconjugated bilirubin?
It is insoluble and bound to plasma albumin
- required to have a small amount in the plasma in order to act as a free anion
- if these levels rise, can cause toxic injuries due to diffusion into tissues*
- these levels are seen in severe hemolytic disease, protein-binding drugs
if unconjugated bilirubin builds up in infants and diffuses Into the brain, it produces “kernicterus” which is severe jaundice and brain damage due to bilirubin build up
Normal serum bilirubin levels are what?
- 3-1.2 mg/dL
* jaundice is seen one levels rise to 2-40 mg/dL
Why do neonates always show with mild unconjugated hyper bilirubinemia?
termed neonatal jaundice
Due to the hepatic machinery required to excrete bilirubin is not fully mature until about 2 weeks of age
Gilbert syndrome
Common (7%) inherited condition where unconjugated bilirubin levels are high due to mildly decreases hepatic levels of glucuronosyltransferase enzymes
This is a direct cause of UGT1A1 mutations
there are no other associated morbidities
Crigler-Najjar syndrome type 1
Rare form of Gilbert disease where the mutations are way more prominent and the unconjugated hyperbilirubinemia is very severe (like off the charts)
- has almost no glucuronosyltransferase enzymes
almost always fatal in infancy
Dublin-Johnson syndrome
Autosomal recessive defect in transport proteins responsible for hepatocellular excretion
exhibits CONJUGATED/direct hyperbilirubinemia
Hepatomegaly and dark livers are seen, but usually asymptomatic outside of that.
Cholestasis
Condition caused by extrahepatic or intrahepatic obstruction of bile channels or defects in hepatocyte bile secretions
Can present with:
- jaundice
- pruritus
- skin xanthomas
- intestinal malabsorption
- deficency in DAK vitamins
Diagnosis:
- symptoms
- also elevated serum alkaline phosphatase and GGT enzymes in both hepatocytes and cholangiocytes
What are the most common causes of bile duct obstruction?
Adults = gallstones, malignant obstructions and post surgical strictures (in this order)
Children = biliary atresia, CF, choledochal cysts (in this order)
most of these are reversible, but if not fixed will cause cirrhosis
What is ascending cholangitis?
Secondary bacterial infections that get into the biliary tree and that either causes duct obstruction or compounds already present duct obstruction
Symptoms:
- fever
- chills
- ab pain
- jaundice
- *becomes suppurative cholangitis if Purulent bile fills (this is the most severe form of cholangitis)**
- usually also presents with sepsis
What is the most common treatment for extrahepatic biliary obstruction?
Surgical treatment
note you CANT use this for intrahepatic cholestasis
What are the two most common autoimmune cholangiopathies?
1) primary biliary cholangitis
2) primary sclerosing cholangitis
Primary biliary cholangitis (PBC)
Disease of middle aged women primarily
- 6x more likely in 40-50 yr old females
- most prevalent in Northern European countries and northern United States (Minnesota)
Is a progressive disorder tied well to sjogren syndrome (70%) and thyroid disorders (20%)
- also mild ties to sclerosis, RA, raynaud phenomenon and celiac disease
Unknown trigger but always presents with anti-mitochondrial antibodies (AMA) and “florid duct lesions” in histology of interlobular bile ducts
What happens in PBC if it is not treated?
Follows one of 2 pathways
1) classic pathway = widespread intrahepatic duct loss leading to cirrhosis and cholestasis
2) alternative pathway = same as classical pathway except it ends with cirrhosis and portal HTN
Symptoms of PBC
Most are asymptomatic
Most are determined based on a work up for unrelated issues
- shows serum alkaline phosphatase
- also always shows anti-mitochondrial antibodies (AMA)
If symptoms are present, its usually increased fatigue and pruritus
Treatment for PBC
Early treatment = oral ursodeoxycholic acid
- doesnt cure and usually only delays progression
Late stage treatment = liver transplantation
What are secondary features of PBC (even with treatment)?
Skin hyperpigmentation
Xanthelasmas
Steatorrhea
Vitamin D malabsorption
Osteomalacia
Primary sclerosing cholangitis (PSC)
Inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts
- causes dilation of preserved segments
More common in males in the 30-50s
shows “beading” of the intrahepatic and extrahepatic biliary tree
(Looks like beads lodged in the hepatic tree)
most commonly associated with IBD (especially Ulcerative colitis (70%)) and pancreatitis (25%)
Diagnosis = radiographic imaging of the biliary tree ducts (look for beading)
What are pathogenic features of PSC?
Believed to be T-cell mediated autoimmune process that get activated from the mucosa of patients with UC or pancreatitis
These T-cells migrate to the liver where they cross-react with bile duct antigens and initiate autoimmune assaults
- pANCA is the most heavily tied autoimmune antibody to PSC (80% of PSC patients have this)