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207 Cards in this Set

  • Front
  • Back
What are the constituents of bile?
bile acids (54%),
phospholipids (18%),
electrolytes (17%),
cholesterol (8%),
bilirubin (3%)
Jaundice is caused by a change in bile ____?
flow
Gall stones are caused by a change in bile ____?
contituents
What is the function of bile?
enhancement of intestinal absorption (lipids, and fat soluble vitamins and minerals, Ca, Fe); and excretion of solutes not cleared by the kidney (bilirubin, cholesterol, protein bound minerals, drugs)
What are the five defects that can lead to clinical jaundice?
1. hemolysis
2. decreased hepatocyte uptake
3. conjugation defect
4. excretion defect (hepatocell dz)
5. secretion defect (biliary obstruction)
what is the normal function of the gall bladder?
bile storage
What is the mediator for gall bladder contraction?
CCK
Where is CCK produced?
duodenem
CCK is produced in response to?
Fat or protein rich chyme entering the duodenum
A. What parts of bile are 'recycled' via intrahepatic circulation?
B. What parts of bile are excreted in the stool?
A. Recycled= bile salts
B. Stool= bilirubin and cholesterol
How does a patient with gall stones present?
- Usually asymptomatic! (60-80%)
- Biliary colic= pain in epigastrum, RUQ... NOT COLICKY.... but "cresendo-plateau-decresendo" for 30 minutes.
- pain often at night, w/ nausea, vomiting
What is MURPHY's sign?
Halting inspiration because it's too painful.
This might occur with gallstones (although most gall stones are asymptomatic)... it's more likely a sign of complication.
What are four complications of gall stones?
1. Acute cholecystitis
2. Gall bladder perforation
3. Cholangitis
4. Acute pancreatitis
What are the top two causes of pancreatitis?
1. Alcohol
2. Gallstones
Symptoms of acute cholecystitis?
Fever, very ill (likely biliary pain)
Symptoms of cholangitis?
Charcot's triad:
1. RUQ pain
2. Jaundice
3. Fever
Also inc. WBCs and mental status changes.
What is cholangitis?
Infection of the biliary tree; often a complication of gall stones.
When are complications of gall stones NOT preceded by attacks of biliary 'colic'?
Old age, immunodeficiency, DM, chronic renal failure.
What are the four major steps in gallstone formation?
1. supersaturation of bile (cholesterol)
2. Nucleation/Crystal formation
3. Crystal entrapment in mucus/sludge
4. Stasis/aggregation (microlithiasis to macroscopic gallstones)
What are the two major types of gallstones?
1. Cholesterol (80-90% of stones are this)... taking up >50% of composition.
2. Pigment stones (calcium/bilirubin) (10-20%).
How is diagnosis of gall stones made?
Best= ultrasound

May incidentally be seen on X-ray
What are treatment options for gall stones?
1. Surgery (w/ cholycystectomy)
2. ERCP sphincterotomy/extraction (for larger stones in common bile duct... not great for small stones, higher up)
3. ERCP stenting (not often used)
4. Percutaneous extraction (T-tube)
5. ESWL- extracorporeal shock wave lithotripsy. for large stones. used as adjuvant therapy.
6. Dissolution (ursodeoxycholic acid Rx)
When is surgery automatically indicated with gall stones?
If there are signs of complication...
Fever, WBCs, jaundice, murphy's sign, wall thickening, swelling.
What are the risks of gall stones?
Forty, Fat, Fertile, Female, Fam Hx (or Fair)

Fam Hx= Chron's, diabetes, native american
What are the causes of cholesterol supersaturation?
hypersecretion of cholesterol
hyposecretion of bile salts
What three major defects lead to CHOLESTEROL gall stone formation?
Bile supersaturation w/ cholesterol.
Increased cholesterol nucleation
Gall bladder dysmotility
How does HMG CoA reductase influence gall stone formation?
It's the rate limiting enzyme in cholesterol formation...
So increased HMG CoA reductast will give increased cholesterol, thus possibly supersaturation
How does 7alpha hydroxylase influence gall stone formation?
It's the rate limiting step of bile acid formation from cholesterol. So decreased 7alpha hydroxylase will predispose the pt to cholesterol stones.
Define nucleation time (in reference to gall stone formation)
Time for crystals from supersaturation bile precipitate out into submicroscopic nucleus.
What are possible nucleation factors?
PGs==> mucus release
Bacterial nidus==> accelated crystal growth

Also dilution, cholesterol concentration and bile salt concentration.
Factors associated with cholesterol gall stone formation
 Cholesterol Conc. In Bile
-Estrogens, Obesity
-Age, OCP
-High Polyunsaturated Fat
Diet
-Marked/rapid wt. loss
Bile Acid Synthesis:
-Age
-Ileal disease/bypass
-PBC: Primary Biliary Cirrhosis
-Cholestyramine treatment
Contractility of GB
-Progestins
-Increased cholesterol in bile
Factors associated with black pigment stones
 in Unconjugated Bilirubin
-Congenital Abnormalities, Hemolysis
-Liver Diseases, Fasting
Factors associated with brown pigment stones
Infection in Biliary Tree--- Must have INFECTION!
Factors leading to bile salt hyposecretion
Hypersensitive Bile Salt Feedback (Constitutional, racial)
Impaired Bile Salt Synthesis (12-hydroxylase deficiency
Cholestatic Liver disease)
AbN Intestinal Bile Salt Loss (
Ilieal Disease/Resection)
How do lipoprotein uptake and ACAT relate to cholesterol secretion?
Increased lipoprotein ==> increased secretion
Decreased ACAT==> increased secretion (ACAT normally esterifies cholesterol)
What are the labs you would expect w/ gallstones?
Increased aminotransferases first (AST, ALT)
Increased Total Bilirubin and alkaline phosphatase with BOTH cholecytitis and Common duct stone/ascending cholangitis
Continued rise in Bilirubin / jaundice with CBD stone
What is Acalculous Cholecystitis?
Complication of other medical or surgical problem. Greater morbidity/mortality.
What is the presentation of acalculous cholecystitis
Similar to 'normal' cholecystitis
What patients get acalculous cholecystitis?
Seen in patients with Severe acute systemic/chronic illnessses
Bacterial sepsis
Burn Victims
Trauma
ICU patients: parenteral (IV) feeding without oral feeding-stimulated gallbladder contraction
What is the main difference between acute and chronic pancreatitis?
Chronic can give permanent and progressive change to pancreas function and morphology
How does acute pancreatitis generally present?
1. Pain in epigastric area--- radiating to the pt's BACK! (b/c of panc inflammation)
2. Nausea/vomitting (intestine hypomotility from inflammation)
How do you predict the severity of acute pancreatitis?
1. Is necrosis present?
2. Are there secondary inflammatory mediators?
(3. is it affecting other organs?)
What are local complications of acute pancreatitis?
1. Necrosis! (is it sterile or infected?)
2. pseudocysts (panc secretions w/o epithelial lining... resolve, but may be painful, give nausea/vomitting, infection, bleeding.)
Acute pancreatitis:
- How do you check for necrosis?
- What are the steps you should follow if you find it?
- CT scan.
- If necrosis, give antibiotics prophylactically and do percutaneous sampling.
- If infected, surgical debridement is necessary!
What are systemic complications of acute pancreatitis?
-Coagulopathy
-GI bleed
-Hypotension
-Shock
-Pleural effusion/capillary lead
-Volume depletion
-Hyperglycemia
-Hypocalcemia
Why do systemic complications of pancreatitis occur?
Because of inflammatory mediators!
(which are highly correlated w/ pancreatic necrosis).
What are the four main categories of etiology of acute pancreatitis?
Obstructive
Toxins
Metabolic
Idiopathic
What are the specific etiologies of acute pancreatitis?
I GET SMASHED
I - idiopathic
G - gallstone. Gallstones that travel down the common bile duct and which subsequently get stuck in the Ampulla of Vater can cause obstruction in the outflow of pancreatic juices from the pancreas into the duodenum. The backflow of these digestive juices causes lysis (dissolving) of pancreatic cells and subsequent pancreatitis.
E - ethanol (alcohol)
T - trauma
S - steroids
M - mumps (paramyxovirus) and other viruses (Epstein-Barr virus, Cytomegalovirus)
A - autoimmune disease (Polyarteritis nodosa, Systemic lupus erythematosus)
S - scorpion sting (e.g. Tityus trinitatis), and also snake bites
H - hypercalcemia, hyperlipidemia/hypertriglyceridemia and hypothermia
E - ERCP (Endoscopic Retrograde Cholangio-Pancreatography - a procedure that combines endoscopy and fluoroscopy)
D - drugs (SAND - steroids & sulfonamides, azathioprine, NSAIDS, diuretics such as furosemide and thiazides, & didanosine) and duodenal ulcers
What three general processes initiate acute pancreatitis?
1. ductal obstruction
2. pancreatic ischemia
3. premature activation of cymogens and panceatic enzymes.
Explain autodigestion in acute pancreatitis
Pancreas injury/insult==>
premature zymogen activation (trypsin/ogen/PLA2)==>
circular event, more activation==>
acinar cell secretion inhibition==>
autodigestion from retained activated enzymes==>
localized inflammation
How do you diagnose acute pancreatitis?
Pancreatic enzyme elevation (lipase, amylase).
CT only for CAUSE, not Dx.
What is the treatment for acute pancreatitis?
Based on severity:
- Pain control
- Bowel rest (TPN, NPO, IV fluids)
- ERCP (endoscopic sphincterotomy/stone extraction)
- Debridement/Antibiotics (imipenem) if infected necrosis.
What phyical exam finding will you notice w/ acute pancreatitis?
Exam – abdominal distension, tenderness, guarding, hypoactive bowel sounds
When should you suspect necrotizing pancreatitis?
No improvement after 5-7 days, fever.
Check via CT scan.
What do you do if you find necrotizing pancreatitis?
Antibiotics.
Take sample- If sterile, watch. If infected, debridement.
What are the presenting symptoms of chronic pancreatitis?
1. Pain (multifocal- pressure, inflammation, etc.)- worse w/ eating
2. Malabsorption (diarrhea)-- occurs after 90% destruction
3. Diabetes (occurs at 80-90% destruction)
What is the cause of chronic pancreatitis?
1. Alcohol! 70-80%
2. idiopathic (10-30%).

- Obstruction--- usually rare because must be there for a LONG time!
How does genetics affect chronic pancreatitis?
- Hereditary pancreatitis (autosomal dominant)
- chronic pancreatitis from CF gene.
What is the pathophysiology of chronic pancreatitis?
Alcohol= DIRECT TOXIN ==> inc. secretion of proteases, amylase, and lipase.
Localization of enzymes gives autodigestion.
Panc juice secretion= rich viscous protein==> protein precipitates, plugs small, large==> inflammation, fibrosis, scarring.

Alcoholics/chronic pancreatitis pts have decreased lithostatin which normally inhibits panc stone formation.

Obstruction, fibrosis, scarring, necrosis==> permanent changes==> exocrine/endocrine func affected.
How do you diagnose chronic pancreatitis?
IMAGING! (not panc. enzymes like acute pancreatitis- b/c they'll likely be normal or low here). ---
can see calcification w/ xray, US, CT, etc.

GOLD STANDARD= endoscopic pancreatography.
What is the gold standard for pancreatic function evaluation?
Secretin test-
Secretin given, (normally stimulates pancreas), then measure bicarb, lipase, and trypsin. All are decreased in chronic pancreatitis.
What is treatment for chronic pancreatitis?
Tx of pain/panc. insufficiency:
- analgesia.
- synthetic enzymes
- celiac plexus block (pain)
-dilation/stone removal/etc. if indicated.
- if obstruction w/ dilation= pancreatojejunostomy
- if local disease- Whipple (head of panc. removal)

- W/ total removal= brittle diabetes!
If you have any problem with the pancreas where will the pain you feel be?
Epigastic and back pain!
Most common type of pancreatic cancer?
Ductal adenocarcinomas (exocrine)
Where do pancreatic neoplasms occur?
70% head
30% body/ tail/ diffuse
How do patients w/ pancreatic neoplasms present?
- 50% w/ jaundice (bile duct goes thru panc. head).
- Courvoisier gall bladder (palpable, non-tender gall bladder).
-Pain (epigastric/back)
- New-onset glucose intolerance
- weight loss, fatigue, anorexia
Less common=
acute pancreatitis secondary to obstruction
gastroparesis secondary to splanchnic neural infiltration
migratory thrombophlebitis (Trousseau's syndrome- blood clots in portal vessels- deep veins of extremities, superficial veins)
depression
meat aversion.
What are risk factors for pancreatic cancer?
Age!
TOBACCO.
high fat/meat diet
chronic pancreatitis
DM (association, not causation)
low SES.
Males.
African Americans

Genetic= K-ras, tumor suppressor genes.

Hereditary chronic pancreatitis= abnormal trypsin
How do you diagnose pancreatic cancer?
Endoscopic ultrasound, CT, CEA, CA 19-9 serum test.
(ERCP- only if stenting)
How is staging of pancreatic cancer achieved?
CT scan or PET scan
Hint: sometimes must do surgery to determine staging!
When are pancreatic cancers deemed unresectable?
-Presence of metastasis OR
- locally advanced dz, local invasion.
What is the survival like w/ pancreatic cancer?
80% dead w/in 6 months w/o surg.
only 20% of surg pts get cure.

5% chance of 5 year survival.
What is treatment for pancreatic cancer?
Surg= only cure. (Whipple- pancreatoduodenectomy or distal pancreatectomy). Still survival is only 10-25%

If non-resectable= radiation + chemo (5FU or gemcitabine)

If mets= chemo.
Pancreatic cyctic neoplasms:
Name the three types
Serous cystadenomas, mucinous cystic adenomas (adenocarcinomas), intraductal papillary neoplasms.
Serous cystadenomas-
A. Presentation
B. Dx
C. Prognosis
A. 50%= incidental imaging; 50% mass effect (nausea, vomiting, pain, bleeding)
B. EUS and CT: MICROcystic, multiple small cysts; larger lesions have central fibrotic or calcified scar. Fluid= no malig cells/tumor markers.
C. Good; Tx= observation
Mucinous cystic adenomas (adenocarcinomas)
A. Presentation
B. Dx
C. Prognosis
A. 50%= incidental imaging; 50% mass effect (nausea, vomiting, pain, bleeding)... WOMEN>men (9:1!)
B. EUC and CT: MACROcystic w/ discrete cuboidal cavities of varying size; mass, focal thickening, irregularity suggest malignancy., elevated CEA and low amylase.
C. Consider as premalignant or malig. Tx= surg. resection b/c of malig. risk.
5year survival=50%
Intraductal papullary mucinous neoplasm:
A. Presentation
B. Dx
C. Prognosis
A. men=women. Old age! Acute pancreatitis, chronic pancreatitis, and ab pain from mucin production.
B. ERCP!!!!! "fish mouth"- mucin from papilla. , diffuse ductal dilation, cystic dilation of side prances, mucin filling defects.
C. premalig to malig. Tx based on malig suspicion and pt health... if healthy= surgery!
5 yr survival >50%!
What are the three most common pancreatic neuroendocrine tumors?
1. Gastrinoma (ulcer dz, diarrhea)
2. Insulinoma (hypoglycemia)
3. VIPoma (watery, secretory diarhhea, dehydration)
What are the symptoms of neuroendocrine tumors of the pancreas?
Sx from excess hormone production or from tumor mass effect.
How do you diagnose neuroendocrine tumors of the pancreas?
1. Excess hormone production in serum.
2. Chromagranin protein in serum.
3. Localize w/ CT, EUS, somatostatin receptor scintigraphy (not insulinomas).
What is the treatment of neuroendocrine tumors of the pancreas?
1. Correct hormone imbalance
2. Surgical resection.

--- Most insulinomas (90+%) are benign... other "-omas" of pancreas (50-100%) are malignant and should be resected if found.
What part of the body does primary biliary cirrhosis affect?
small intrahepatic ducts
What part of the body does primary sclerosing cholangisit affect?
intra and extra hepatic ducts!
Where does cholangiocarcinoma occur?
anywhere in the BILIARY system--- intrahepatic, extrahepatic or at bifurcation of left and right hepatic ducts (Klatskin tumor).
What is the typical presentation of Primary Biliary Cirrhosis?
- Usually asymptomatic...
- found by elevated alkaline phosphatase
- Pruritis (50%)
-Jaundice (<25%) (later)
-Steatorrhea, elevated cholesterol, vit def, weight loss, osteomalacia. (later)
-liver failure/hepatic dysfunction (later)
What is the clinical course of Primary Biliary Cirrhosis?
How is it best predicted?
- slowly progressive.
- Sx w/in 2-4 yrs of Dx.
- after Sx present, 10-12 yrs survival

- BILIRUBIN predicts survival best.
- if bili is >10 or cirrhosis present, survival is <2 yrs w/o liver transplant.
Who does Primary Biliary Cirrhosis usually affect?
WOMEN!
- 60-70 y.o.
- usually w/ other autoimmune diseases (Sjogrens, scleroderma, autoimmune thyroiditis)
What are three things that contribute to inflammation and immune response in Primary Biliary Cirrhosis?
IgM hypergammglobulinemia
circulating immune complexes
decreased number/func of suppressor T cells
What is the result of Primary Biliary Cirrhosis?
bile duct injury/destruction
=>obstructs bile ducts
=> cholestasis
=> hepatocyte injury
=>portal hypertension/cirrhosis/liver failure

dec bile salts to intestines gives weight loss, malabsorption, steattorhea, vit deficiences, elevated cholesterol.
How is Dx of Primary Biliary Cirrhosis made?
THREE THINGS:
A. Abnormal liver enzymes (esp alkaline phosphatase!)
B. Antimitochondrial antibodies (AMA)
C. pathognomonic liver biopsy= "patchy destruction of intrahepatic bile ducts w/ mononuclear inflammatory infiltrate." Granulomas support Dx.
What is the treatment of Primary Biliary Cirrhosis?
Primary= UDCA!!!

If liver failure; Transplant.
What is the transplant survival of Primary Biliary Cirrhosis? (relative)
HIGHEST post transplant survival of any dz!
The overall etiology of Primary Biliary Cirrhosis is?
AUTO-IMMUNE DISEASE!
What is the overall etiology of primary sclerosing cholangitis?
AUTO-IMMUNE DISEASE!
What is the typical presentation of primary sclerosing cholangitis?
10% asymptomatic
Sx usually later:
Cholestasis (jaundice, pruritus, cholangitis)
Liver failure/portal hypertension
Fatigue, weight loss, ab pain
What is the clinical course of primary sclerosing cholangitis?
slow, unpredictable.
two outcomes: secondary biliary cirrhosis or cholangiocarcinoma.
Who is the typical pt that gets primary sclerosing cholangitis?
Men (2:1)
<45 y.o.
Caucasians
What evidence is there for primary sclerosing cholangitis being immune mediated?
Pts will have:
-hypergammaglobulinemia
- autoantibodies
-P-ANCA
-leukocyte antigen DRx52a
-HLA-DR4 (more progressive dz)
- circulating immune complexes/antibodies (cross react w/ colon => IBD (esp. ulcerative colitis)
What dz is often concommitant w/ primary sclerosing cholangitis?
IBD, esp. Ulcerative Colitis!!!!! (cross reacting immune complexes/autoantibodies)

"sclerosing cholanGItis; ulceratic coLItis" chant!!!!
What has been suggested as the antigen source for primary sclerosing cholangitis?
portal bacteremia
How is primary sclerosing cholangitis diagnosed?
LABS:
inc. alkaline phosphatase
inc. transaminases, bilirubin, prothrombin, and low albumin.
P-ANCA (not specific)

GOLD STANDARD= cholangiography showing "beading"-- multifocal structuring w/ intervening normal or dilated ducts.
What is the treatment for primary sclerosing cholangitis?
A. SUPPORTIVE!!!!!
B. can try UDCA.
C. ERCP w/ stenting, stone removal, etc.
D. Liver transplant
When does cholangiocarcinoma usually present?
What is the exception to this?
60-70 y.o. pts.
Earlier if risk factors:
primary sclerosing cholangitis
clonorchiosis
choledochal cysts.
What is the presentation of cholangiocarcinoma?
A. Jaundice!!!!
B. non-spec: ab pain, weight loss, anorexia.
What is the etiology of cholangiocarcinoma?
ongoing inflammation of the bile duct.
How does one diagnose cholangiocarcinoma?
Hx of jaundice
Tumor markers: CEA and CA19-9
Imaging: CT (first), then ERCP or PTC for definitive cytology/biopsy.
What is the treatment for cholangiocarcinoma?
Only Definitive Tx= surgical resection.
Palliation (stenting)

Chemo and radiation NOT EFFECTIVE
When is a cholangiocarcinoma non-resectable?
if it invades both lobes or major vessels.
What is the survival for cholangiocarcinoma?
resectable tumor= 3yrs
unresectable= 1 yr.
What is found in areas of necrosis in primary sclerosing cholangitis?
CD8 lymphocytes.
What are the complications of primary sclerosing cholangitis?
Cholangiocarcinoma
Liver failure
Dominant stricture
Cholesterol/pigment stones
Cholangitis/fever (rare to spontaneously occur)
What is the median survival time for primary sclerosing cholangitis?
12 years (about the same for primary biliary cirrhosis)
What sex is more likely to get cholangiocarcinoma?
males
Primary biliary cirrhosis occurs as a result of what situation?
Exposure to environmental stimulus in a susceptible individual.
Primary biliary cirrhosis is associated with what other disease?
Other autoimmune diseases.
Why does bone disease occur in primary biliary cirrhosis?
Vit D malabsorption=> osteomalacia/osteoporosis.
What is the survival in pts with asymptomatic primary biliary cirrhosis?
Normal!
(altho 40% will develop symptoms in 5-7 years and then have 11-12 yr survival after that).
Liver function tests:
The following lab indicates what possible problem?
AST/ALT/LDH
Hepatocyte injury
Liver function tests:
The following lab indicates what possible problem?
ALP/GGT/5'NT
Biliary tree injury/ cholestasis
Liver function tests:
The following lab indicates what possible problem?
INCREASED SERUM CONJUGATED BILIRUBIN
impaired hepatocyte and/or biliary excretory function
Liver function tests:
The following lab indicates what possible problem?
Prolonged PT-INR
Decreased hepatocyte synthestic function ONLY IF still prolonged after Vit K admin
Liver function tests:
The following lab indicates what possible problem?
DECREASED SERUM ALBUMIN
Decreased hepatocyte synthetic function
Liver function tests:
The following lab indicates what possible problem?
INCREASED SERUM AMMONIA
Decreased hepatocyte function and portal-systemic function
Where are ALT, AST and LDH located?
hepatocytes: All= cytosol.
AST is also in the mitochondria.
They are also present in striated muscles (skeletal/myocardial).
What lab value can help you determine if ALT/AST changes are due to hepatocytes or striated muscle?
CPK (creatine phosphakinase). It's NOT elevated w/ hepatocyte injury (but is w/ striated muscle injury)
Which of ALT and AST is more characteristic of liver/hepatocyte injury? Why?
ALT- it's present in higher quantities in the liver than in other organs.
What does the ratio of AST:ALT tell you?
2:1 and under 400 leads to alcoholic liver disease. (lack of ALT enzyme activity b/c B6 deficiency)
What diseases/conditions lead to LDH elevation?
ischemic liver injury ("shock liver"
drug induced acute liver failure (APAP overdose)
Hemolysis
Cancer
What causes elevated alkaline phosphatase?
Cholestasis (Obstruction!)- intra or extrahepatic.
Is elevated ALP (alkaline phosphatase) in cholestasis from increased synthesis or decreased removal?
Increased synthesis mediated by bile acids.
When are low levels of ALP (alkaline phosphatase) observed? why?
Zn deficiency or Wilson's disease

ALP requires Zn!!!
In Wilson's dz the Cu deposition replaces the Zn in ALP and decreases its enzymatic activity.
What is GGT (Gamma-glutamyl transpeptidase) useful for?
Determining that increased alkaline phosphatase is of hepatobiliary origin.
What does an elevated alkaline phosphatase with a normal gamma-glutamyl transpeptidase suggest?
the Alkaline phosphatase was likely extrahepatic-- bone, gut, placenta
When is gamma-glutamyl transpeptidase elevated, but NOT necessarily indicative of liver cell injury?
ALCOHOLICS and pts on phenytoin or phenobarbitol.
When alkaline phosphatase is elevated but 5NT is normal what does it suggest?
Liver disease is unlikely; ALP was likely elevated physiologically (from placenta and bone formation in fetus)
Describe the metabolism of Bilirubin
1. Catabolism of heme=> CO and unconjugated bilirubin release
2. Unconjugated bili binds to albumin (making the bili no longer toxic)
3. Albumin/unconj bili back to liver.
4. unconj bili binds to glutathione S-transferase, they go to ER.
5. In ER, unconj bili and glucuronic acid conjugation occurs.
6. Conj bile to cannaliculi, to intestines.
--- some to urobilinogen (then to serum to urine)
What does conjugated bilirubin in the urine suggest?
conjugated hyperbilirubinemia.
This is ABnormal.
What does conjugated bilirubin test for?
Excretory function!
When is serum bilirubin of prognostic value?
Chronic liver disease (NOT ACUTE)
What are two situations that lead to unconjugated hyperbilirubinemia?
hemolysis and gilbert's syndrome (dec. glucoronyl transferase which conjugates bili)
What coagulation factor is not synthesized in the liver?
VIII
Why is PT-INR measured to determine hepatocyte dysfunction?
VII is liver synthesized and has VERY short half life (a few hours).
What must be excluded before attributing a long PT-INR to hepatocyte dysfunction?
VIT K DEFICIENCY!!!! or D.I.C.
What does a long PT/PPT, with decreased numbers of Factor VIII indicate?
DIC or Vitamin K deficency, but NOT liver dysfunction b.c factor VIII should be normal (it's not produced in the liver)
When is albumin a good indicator of liver disease?
When is it not?
good- chronic (it correlated w/ prognosis)
not good indicator in acute dz.
Which is more sensitive in detecting hepatobiliary dz? bile salts or bilirubin? Why?
Bile salts, b/c they have larger pool.
How is ammonia produced and then metabolized?
- Formed by gut bacteria
- Absorbed in portal blood
- Hepatocytes remove ammonia and metabolize it by urea and glutamine synthesis.
Which hepatocytes can NOT synthesize urea?
those around the central vein/terminal hepatic venule.
What does increased ammonia give?
encephalopathy.
When does increased ammonia occur?
liver dysfunction and portal systemic shunt.
OR
major GI hemorrhage!
What are causes of unconjugated hyperbilirubinemia in a newborn?
A. Physiologic jaundice (and exagerrated- breat feeding jaundice)
B. Breast milk jaundice
C. Hemolysis (ABO incompatibility)
D. Decreased conjugation (Gilberts syndrome, Crigler-Najjar)
What is the treatment for unconjugated hyperbilirubinemia in a newborn?
A. Phototherapy
B. Formula trial (if breast milk jaundice)
C. Exchange transfusions if extremely high unconj bili
What occurs with bilirubin toxicity in the newborn?
Kernicterus:
Free bilirubin crossing BBB=> deposits in basal ganglia=> encephalopathy.

Signs:
1st- lethargy, hypotonia, poor suck
2nd- hypertonia, opisthotonos (back bend), high-pitched cry

If survive, sequelae= deafness, athetosis (hand/foot mvmnt), dental dysplasia, limited upward gaze, developmental delays.
Compare/contrast breastfeeding and breast milk jaundice
Breastfeeding: occurs EARLY (3-5 days) "exagerrated physiologic jaundice"--- poor intake, thus increased cycling.

Breast milk: later (10-15 days). UGT1 inhibition by some women's breast milk
What is Gilberts syndrome?
mild enzyme deficiency of glucoronyltransferase
Compare the prognosis of Gilbert's syndrome and Crigler-Najjar.
Gilbert- mild, common, benign
CN- rare inherited disorder
Type 1- absent enzyme; severe
Type 2- variable/partial enzyme.
What is the presentation of biliary atresia?
- CONjugated hyperbilirubinemia.
-Baby= normal at birth.
Jaundice at 2 mos.
What is the treatment of biliary atresia?
Liver biopsy.
exploratory laparotmy w/ cholangiogram.
If bile duct is absent or fibrosed, do portoenterostomy "kasai" procedure.
Liver transplant (Most require this)
What should be done if conjugated hyperbilirubinemia is found?
Ultrasound.
Liver biopsy.
Check for gall bladder!
What are the 6 major categories of conjugated hyperbilirubinemia?
1. Extrahepatic obstruction: Biliary atresia! (Most common cause!)
2. Neonatal infections (sepsis, TORCH)
3. Metabolic diseases (Galactosemia, tyrosinemia, hypothyroidism)
4. Defective cannilicular excretion of bilirubin (Dubin-Johnson, Rotor Syndromes)
5. Iatrogenic
6. Genetic/syndromic causes (alpha-1-antitrypsin, CF)
When is jaundice abnormal?
before 36 hours.
persists >10 days
total bili>12
conjugated>2
What labs should be ordered for a baby w/ jaundice?
bilirubin fractionation (unconj vs. conj)
liver tests/ INR
bile analysis
gene tests (crigler-najjar)
Why has the incidence in celiac disease risen since 1950s?
Crosby capsule- allows for small intestine biopsies.
What are the two main theories to explain the cause of celiac disease?
1. autoimmune- chronic inflamm, mucosal atrophy=> malabsorption
2. antigen driven from immune response to dietary gliadin.
What is the presentation of celiac disease?
VARIABLE!
Asymptomatic or...
Diarrhea, fatigue, weight loss
(IBS-like, failure to thrive, etc.)
Describe the spectrum of celiac disease presentation
Latent: pos. serology only
Silent: Asymp, positive serology, abnormal biopsy.
Minimal: Fe, folate deficiency, bone disease, bloating, cramping.
Severe: megaloblastic anemia, neuro (b12) dz, profound diarrhea, weight loss
What are complications of celiac disease?
osteoporosis
short stature
chronic anemia
microscopic colitis,
pancreatic insufficiency
lactose intolerance

Cancer- lymphoma!! and also adenocarcinoma of GI tract.

Ulceratice jejunoileitis

Refractory Sprue (or collagenous sprue)... doesn't respond to removing gluten from diet.
What is dermatitis herpetiformis? What dz is it associated with?
Pruritis papulovesicular rash on extensor surfaces.

-Celiac sprue.
(if have the dermatitis, likely have celiac, but the reverse is NOT true)
What is the pathogenesis of Celiac disease?
Allergic rxn to gluten.
Small bowel (duodenum)
intraepithelial lymphocytes (gamma-delta T cells)
Anti-gliadin antibody is produced in the mucosa. (note- 20% of pts are IgA deficient)

Environmental: Alpha gliadin from wheat.

Molecular mimicry: alpha-gliadin is similar to E1b protein of human adenovirus 12. (ad12). The E1b protein causes inflammation in celiac pts.
What are the genes associated with celiac disease?
Chromo 6... HLA class I and II
Gives HLADQ2 molecule....
Most pts with HLADQ2 do NOT get sprue! but if have sprue, likely have HLADQ2 (95% of time!)
How is Dx of celiac disease made?
SCREENING- antiTTG (tissue transglutaminase) antibody IgA.
(also anti-endomysial antibody IgA)
-----Hint---- 2% of celiac pts are IgA deficient and these will be falsely negative! so check the IgG on them).

GOLD STANDARD for Dx:
Small bowel biopsy:
"Villous atrophy"
"Crypt hyperplasia"
"mucosal inflammation"
"increased intraepithelial lymphocytes"
What is the treatment for celiac disease?
Avoidance of gluten. (limit milk/lactose to start).
What the general causes of acute hepatic failure?
infection by hepatotropic viruses, non-hepatotropic viruses, auto-immune diseases, toxins.
What is a synonym for acute hepatic injury?
Acute liver failure...
(sudden loss of liver mass)
What is the sequalae for acute hepatic injury?
Most= self-limited.
Some= fulminant hepatic failure or submassive hepatic necrosis.
What is the clinical presentation of acute hepatic injury?
ALT/ASTs suddenly increased (previously normal) to 10 to 25 times normal.
What viruses can give acute hepatic injury?
Hepatotropic= HAV, HBV, HCV, HDV, HEV
non-hepatotropic= EBV, CMV, HSV. (esp w/ immunocompromised hosts)
How does liver anatomy relate to acute hepatic injury?
Zone 3 (perivenular- terminal hepatic venule)= most injured w/ hypoxia (i.e. from shock, cocaine hepatotoxicity)
most injured by P450 toxic metabolites (APAP poisoning)
What does icteric mean?
Jaundice
How is Hep A Virus transmitted?
Fecal/Oral
What is the incubation period for Hep A Virus?
28 days
When does fecal shedding of Hep A Virus occur?
7-10 days before and after onset of jaundice.
What are ALT/AST levels in Hep A Virus?
usually greater than 1000
What is the prognosis for Hep A Virus?
Good... RARELY they'll develop fulminant hepatic failure. Some relapse 7-10 weeks post recovery.
NO carrier state.
NO chronic hepatitis/cirrhosis.
NO hepatoma
What is the incubation period for Hep E Virus?
40 days
What is the prognosis for Hep E Virus?
Good.
Cholestatic jaundice, but FULL recovery occurs.
What is the exception to good prognosis for Hep E Virus?
PREGNANCY!
Hep E occurs more often in pregnant women and is more severe.
Fulminant hepatic failure occurs often in third trimester.
What hepatitis virus is especially harmful during pregnancy?
Hep E Virus (can give fulminant hepatic failure---- normally it doesn't have any serious sequelae).
Define Fulminant Hepatic Failure
most severe, potentially lethal complication of acute hepatic injury.
Hepatic encephalopathy w/in 8 wks of symptomatic hepatocellular disease in a previously healthy person.
severe coagulopathy ALWAYS coexists.
Define Submassive Hepatic Necrosis
Same as fulminant hepatic failure, but SLOWER in onset. acute hepatic encephalopathy occurs within 9 to 24 weeks.
severe coagulopathy ALWAYS coexists.
Describe the grades of encephalopathy in acute hepatic injury
1. subtle changes, minimal consciousness changes, w/ or w/o asterixis
2. Disorientation to person, place, time. drowsiness, innappropriate behavior, emotional lability, asterixis
3. Marked confusion, incoherent speech, sleeping most of time- altho arousable, asterixis
4. Comatose
How does one predict the outcome of fulminant hepatic failure and submassive hepatic necrosis?
Quick onset= better prognosis.
More advanced stage= worse prognosis.
What is the SINGLE MOST DANGEROUS COMPLICATION of fulminant hepatic failure?
Cerebral Edema giving inc. intracranial pressure.
Can give seizures, pupillary response changes, cerebral posturing.

.... make sure to exclude hypoglycemia....
What is the SINGLE MOST COMMON cause of fulminant hepatic failure?
Acetaminophen toxicity (usually accidental missuse)
What is the definition of chronic hepatitis?
ongoing inflammation toward the hepatocytes until stimulus is removed or inflammatory response is diminished.
What are the causes of chronic hepatitis?
ABCD
A.Autoimmune,
B. hep B virus
C. hep C virus
D. hep D virus, Drugs, hepatolenticular Degeneration (inc. Cu)

NOT hep A!!!!
Where does the inflammation of chronic hepatitis start?
portal tract.
What cells are mostly found in the inflammatory infiltrate of chronic hepatitis?
lymphocytes and plasma cells.
What two compenents help define cirrhosis?
Fibrosis + regenerative nodule.
Name five disorders that may SIMULATE chronic liver disease
Alpha 1 antitrypsin deficiency
Hereditary hemochromatosis
Alcoholic hepatitis
Non-alcoholic steatohepatitis
Cholestatic liver diseases.
What are the major features of autoimmune hepatitis?
Leads to chronic hepatits.
-Female predominance
-Circulating autoantibodies/polyclonal hyperglobulinemia.
- good response to immunosuppression
- cells= T-cells and plasma cells.
What are the autoantibodies associated with autoimmune hepatitis?
ANA, ASMA, anti-LKM1p, anti-SLA,
What other diseases are associated with autoimmune hepatitis?
Other autoimmune diseases- autoimmune thyroiditis, RA, UC, Graves, etc.
What is AMA associated with?
Primary biliary cirrhosis.
How does the damage occur with hepatits viruses in chronic hepatitis?
--- the viruses are NOT cytopathic... the damage is mediated by primed lymphocytes! Our immune system is damaging ourselves!!!
What is the treatment for autoimmune hepatitis and chronic viral hepatitides
Autoimmune= immune suppresion
HBV= tx if active (HBV DNA); nucleoside analogs (antivirals), interferon (immune-modulators)
HCV= PEG interferon (immune-modulator), no alcohol, no Fe supplementation.
Ground glass hepatocytes are indicative of what disease?
Hep B (HBsAg)
Diabetes and cirrhosis should make you think of_____?
Hereditary Hemochromatosis (HFE gene) increased Fe absorption (altho dec. in crypt cells).