Term
| What are the 5 important functions of bile synthesis in the liver? |
|
Definition
Hepatocytes get bile acids from cholesterol and enterohepatic circulation from small bowel/portal vein.
1) Dietary lipid emulsion and absorption
2) ADEK vitamin absorption
3) Bilirubin excretion
4) Excretion of cholesterol
5) Excretion of lipophillic drugs, toxin, xenobiotics |
|
|
Term
What high-affinity anion carriers are present on the basolateral hepatocyte membrane?
What happens to bile acids and bilirubin once they enter the hepatocyte. |
|
Definition
Enterohepatic circulation delivers secondary BA from small bowel to liver via portal vein
1) Bile acid-sodium transporter (NTCP) utilizing Na/K ATPase (very efficient)
2) Organic anion-transport (OATP) which takes up bilirubin that has been released from heme in senescent RBCs
3) Once in hepatocyte, ligandin binds and transports hydrophobic BA and bilirubin to ER, where they undergo UDP-GT conjugation, producing water-soluble "direct" bilirubin.
- Conjugated bilirubin is then exported actively into bile canaliculus by Bile salt export pump (BSEP) against concentration gradient |
|
|
Term
True or False:
Inhibition of NCTP transporter will cause jaundice |
|
Definition
| Probably not on its own, but if their is also overload, it might. |
|
|
Term
| What happens to bile after it is conjugated to bilirubin in hepatocytes? |
|
Definition
1) Actively secreted into canalculi via BSEP pump (promoted by presence of BA- bile acid-dependent flow and enhanced by secretin)
2) In ducts, water is removed with NaCl (concentrating bile) and HCO3- is added.
3) In gall bladder, further concentration occurs.
**meal-induced gallbladder contraction by CCK and relaxation of sphincter of Oddi allows bile to flow into duodenum** |
|
|
Term
| What clinical findings are characteristic of cholestasis and hyperbilirubinemia? |
|
Definition
1) Jaundice (bilirubin 2-4 mg vs. 0.3-1.5)
2) Pruritis
3) Dark urine (water soluble bilirubin)
4) Light colored stool- loss of bile pigments from lumen of GI
5) Pain- mechanical obstruction. |
|
|
Term
Patient presents with jaundice, but normal ALP/GGT levels. Urinalysis reveals bilirubin level of 3.
What is the most likely cause? Would the urine be dark? |
|
Definition
Pre-hepatic (no cholestasis) Hemolysis with overflow of unconjugated bilirubin.
**most likely due to drugs of glucose 6-P deficiency.
Urine would not be dark, because excess bilirubin is uncongugated and not water soluble. |
|
|
Term
Why is it worrisome if an infant presents with persistent jaundice?
How would you treat? |
|
Definition
1) May have Criggler Najar Type 1, with absent UDPGT.
Baby cannot conjugate and dispose of bilirubin and they commonly get Kernicterus (encephalopathy).
2) Treat with Phototherapy or Phenobarbital (induces UDPGT)
- May need plasmapherisis and Orthotopic liver transplant.
Older individuals might have AR Gilbert's syndrome, with lowered UDPGT, which requires no treatment and is generally asymptomatic |
|
|
Term
| What is a common cause of uncongugated hyperbilirubinemia in adults >18 years old? |
|
Definition
Gilbert's syndrome with AR inheritance and reduced UDPGT (less severe than Crigler-Najjar type 1)
Usually asymptomatic or fasting-induced jaundice and requires no treatment. |
|
|
Term
| What are 3 congenital causes of conjugated hyperbilirubinemia? How do you manage them? |
|
Definition
1) Dubin-Johnson (PFIC)
- rare and benign AR condition with impaired storage or excretion presenting as mixed hyperbilirubinemia
- Can give phenobarbital to reduce levels
2) Rotor's syndrome
- Rare and benign AR condition do to impaired intracellular storage of organic anions because of glutathione S-transferase deficiency.
- No treatment
3) Byler's disease (Progressive familial intrahepatic cholestasis)
- Defect in secretion of conjugated BA across canalicular membrane, presenting with severe watery diarrhea and cholestasis |
|
|
Term
| What are the 2 pathophysiological mechanisms that produce Cholestasis? |
|
Definition
Increased serum bilirubin, ALP, GGT, 5'-NT and only mild increase in ALT, AST)
1) Intra-hepatic
- Dysfunction in hepatocyte uptake, processing and excretion of bilirubin
- If defect occurs prior to conjugation, you get elevated indirect
- If defect occurs after conjugation, you get elevated "direct"
2) Extra-hepatic
- Delivery of bile from canaliculi to duodenum
- Can be "obstructive"
- Produce AEDK deficiency, steatorrhea, xanthomas, jaundice and pruritis. |
|
|
Term
| How can intra- and extra-hepatic cholestasis be differentiated? |
|
Definition
Biochemical patterns of cholestasis are overlapping.
- Order US, followed by either CT, MRCP or ERCP (useful for extra-hepatic, especially)
1) Extra-hepatic will show dilation of biliary tree and/or pancreatic ducts due to gallstones or tumor.
- PBC, PSC, CBD sontes, pancreatic carcinoma
2) Intra-hepatic will not have tree/pancreas dilation
- Viral or alcoholic hepatitis
- Drugs, hormones, toxins. |
|
|
Term
| Describe a basic algorithm for evaluating patients with Jaundice. |
|
Definition
1) History, Physical, Labs (AST, ALT, ALP, Bilirubin)
2) If ALP, ALT are abnormal, you think biliary obstruction and should order abdominal US (low risk) or ERCP (high risk)
**IF ducts are dilated on US, order ERCP**
3) If obstruction is present on ERCP, extract or stent! |
|
|
Term
A 45 year-old college professor sees his PCP sudden onset of jaundice
Recent urinary tract infection; received trimethoprim-sulfamethoxazole (Bactrim)
Urine is normal color
Total bilirubin = 4.4
Direct bilirubin = 0.2
Serum AST=28, ALT =24, ALP=100, GGT=38, LDH =800 (105-333)
What is going on? |
|
Definition
No cholestasis (normal urine and ALP/GGT), so this is pre-hepatic.
Most likely hemolysis from 6GP deficiency (UDP-GT) or drugs (Bactrim in this case causes bilirubin to dissociate from albumin)
Diagnose with LDH, Haptoglobin and peripheral smear |
|
|
Term
A 45 year-old college professor sees his PCP sudden onset of jaundice
Recent urinary tract infection; received trimethoprim-sulfamethoxazole (Bactrim)
Urine is normal color
Total bilirubin = 4.4
Direct bilirubin = 0.2
Serum AST=28, ALT =24, ALP=100, GGT=38, LDH =800 (105-333)
What is going on? |
|
Definition
No cholestasis (normal urine and ALP/GGT), so this is pre-hepatic.
Most likely hemolysis from 6GP deficiency. |
|
|
Term
76 year-old male complaining of dark urine, anorexia and weight loss of 30 lbs
ALT = 56, AST = 50, ALP=320, GGT=350, Total Bili = 6.5, Direct Bili = 5.5
Hgb=14.0
What next? |
|
Definition
Cholestatic picture with HIGH direct bilirubin, suggesting an issue after conjugation occurs in hepatocyte. You suspect extrahepatic cholestasis so you:
1) Ultrasonography of the right upper quadrant of the abdomen- found dilated common bile duct, no gallstones
2) CT scan of abdomen- found mass in the head of the pancreas |
|
|
