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Block 4a: GI > Week 4: Pancreatic Adenocarcinoma/Liver & other PATH > Flashcards

Week 4: Pancreatic Adenocarcinoma/Liver & other PATH Flashcards

1
Q

Compare and contrast DNA Polymerase Alpha vs. DNA Polymerase Delta

What is the helpful process that occurs after DNA Polymerase Delta activity?

A

DNA Polymerase Alpha: low fidelity copying, lacks proofreading, will be replaced

DNA Polymerase Delta: high fidelity DNA copying with proofreading function; reaches RNA primer, displaces it and inserts proper deoxyribonucleotides

MMR is the additional process after DNA Polymerase Delta activity, w/ almost no mutations

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2
Q

What are the components of the preinitiation complex?

A

General Transcription Factors

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3
Q

What are the functions of enhancers and silencers?

A

Enhancers enhance the effect of promoters, can fold in ways to end up near promoter and transcription initiation complex. Alone, they cannot effectively induce transcription but transcription factors can bind to them.

Silencers antagonize the effect of promoters. Repressors can bind to silencers.

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4
Q

What are Zn fingers?

A

DNA binding proteins that hold structure together by coordinating with cysteine side chains

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5
Q

What are dimerization domains? What results from their formation? Give an ex.

A

Proteins that recognize DNA can form homodimers or heterodimers via a dimerization domain to generate a hydrophobic effect

Ex: Leucine Zipper

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6
Q

What are the different types of transcription factors? How do they compare?

A

Activators (bind DNA)
Repressors (bind DNA)

Co-activators (↑ transcription rate but don’t bind DNA)
Co-repressors (don’t bind DNA)

General TF’s: part of Transcription Initiation Complex

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7
Q

What happens to RNA immediately after transcription? Why?

What is another event that occurs for a similar purpose? How is the site determined?

A

Capped w/ 7-methyl guanosine (m7G), required for export

Poly(A)-tail site determined by polyadenylation signal, also required for RNA export

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8
Q

What is alternative splicing and how is it modulated?
Is alternative splicing synonymous with mutation?

A

Physiological process of splicing RNA in different way bc of the presence of different set of splice activator and splice repressor proteins that bind to RNA

Alt splicing changes protein sequence through deletion/addition of residues or via a shift in codon reading frame

Alt splicing isn’t synonymous w/ mutation, even though mutation can generate a new splice site or alter a normally used one so that a cryptic splice site comes into use

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9
Q

What is the relationship between antibiotics and protein synthesis?

Give 3 classes of antibiotics (and ex’s) that can inhibit bacterial translation

A

Selectively inhibit protein synthesis by ribosomes in bacteria rather than human cells

Aminoglycosides: Gentamycin, Tobramycin, Amikacin
Chloramphenicol
Macrolides: Erythromycin, Clarithromycin, Azithromycin

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10
Q

What are the 2 main components of Heme?
What are 2 things heme constitutes?

A

components: protoporphyrin and Fe2+/Fe3+
constituents: CytP450 Enzymes and Hemoglobin

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11
Q

Where is most heme made? Where is its secondary source?

A

Most heme is made in bone marrow, as part of hemoglobin synthesis
Less heme made in liver as cytochrome P450 synthesis

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12
Q

Describe the steps in Heme Synthesis: a) general
b) components

A

Synthesis from succinyl co-A and glycine w/ 3 consecutive condensation reactions that follow.
COOH groups trimmed & concludes w/ Fe insertion

(mit): glycine+succinyl COA-> ALA (->cytosol)

(cytosol) : ALA->
* *Porphobilinogen->
* *Hydroxymethylbilane->
* *Uroporphyrinogen III->
* *Coproporphyrinogen III->

(mit)

  • *Protoporphyrin IX** -> +Fe2+
  • Heme!*
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13
Q

How is Heme synthesis regulated by products from the liver and RBC’s?

A
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14
Q

Describe prophyrias in general terms

What are related lab findings?

A

Diseases of heme synthesis from enzyme deficiencies in synthesis pathway

PBG in urine/blood
Porphyrins in blood, urine and or feces;
ex: Coproporphyrin
Hydrophilic->Urine; ex’s: Uroporphyrin
Hydrophobic->(Bile)->Feces; ex: Protoporphyrin

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15
Q

Describe the pathogenesis of acute attack in AIP
with underlying genetics

A

PBG deaminase deficiency
AD Inheritance
Haploinsufficiency
Reduced penetrance

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16
Q

How can acute AIP present?
Rx?

A

ALA and PBG: neurotoxic
Seizures, respiratory failure possible
Abdominal pain (abdomen non-tender), anxiety, depression, psychosis
Tachycardia

Tx: ~400 g glucose/dose: hyperglycemia

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17
Q

What should AIP patients avoid?

A

Smoking
Alcohol: induce cyt P450
Drugs metabolized via Cyt P450: ex’s
diclofenac, chloramphenicol, erythromycin, lidocaine, barbiturates, sulfonamides, spironolactone, nifedipine, progesterone, progestins, sulfonylureas
Fasting/low carbohydrate intake (X Atkin’s Diet)

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18
Q

How can porphyrinogens become pathologic in Porphyria Cutanea Tarda?

A

Porphyrinogens can spontaneously form porphyrins
Porphyrins can then leak into blood and reach skin
Light can induce porphyrins to inflict oxidative damage

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19
Q

Describe the pathogenesis of PCT and other features

A

Deficiency of uroporphyrinogen III decarboxylase
that can cause light-induced skin lesions
Liver porphyria (like AIP) but is NOT acute

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20
Q

Compare and contrast inherited vs. acquired PCT

A

Inherited (20%): AD, haploinsufficiency
*Decreased Uroporphyrinogen decarboxylase activity in RBC’s

Acquired (80%): RF’s
Hepatitis C Virus
Smoking
Fe Overload (Hereditary Hemochromatosis)
Excessive alcohol intake (+ another RF)
*Normal Uroporphyrinogen decarboxylase activity in RBC’s: damage only affecting liver​

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21
Q

How do porphyrins in urine appear in PCT?

What are other lab findings in PCT?

A

Dark or fluorescent

↑ total porphyrins in urine
w/ more carboxylated porphyrins (esp uroporphyrin)
than coproporphyrin
mildly ↑ ALA and PBG

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22
Q

How is acquired PCT Tx?
Other recommendations?

A

Treat underlying cause
Phlebotomy for Fe overload

Avoid sun exposure
Beta-carotene: antioxidant effects and can reduce damage

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23
Q

Describe the enterohepatic circulation of bile salts?

A

Distal ileum absorbs primary and secondary bile salts via a Na-driven transporter (ASBT) and releases bile salts into blood so that they can move back to the liver and be re-secreted into bile

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24
Q

What are RF’s for cholesterol gallstones?

A

High bile concentration in gallbladder
Gallbladder empties at low rate
Bile system w/ low motility
Excess cholesterol secretion from fibrates: (gemfibrozil, fenofibrate) ↑ expression of cholesterol export proteins (PPAR alpha TF)
Decreased bile salt secretion from liver dysfunction or decreased bile salt reabsorption

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25
Q

What are the Rx’s of biliary colic from gallstones?

A

Surgery

  • *Ursodeoxycholic Acid**: MOA=?
  • *Ezetimibe**: inhibits cholesterol uptake
26
Q

Globally, what is the viral agent most responsible for liver disease?

A

Hepatitis B Virus

(Also major cause of Hepatocellular Carcinoma, even in absence of cirrhosis)

27
Q

What is the most troubling aspect of the HBV replication cycle?

A

cccDNA template doesn’t go away even after infection resolves, despite Tx’s

Can reactivate in immunosuppressed setting

28
Q

Describe the Phases of Chronic HBV Infection

A

Immune Tolerant: usually perinatal but adults also possible; mild histology w/o inflammation

  • *Immune Active:** when Tx is applicable; active histology; hepatocellular necrosis->cirrhosis (possible)
  • *Inactive (Carrier):** cccDNA still present, risk of developing liver cancer
29
Q

Describe the Natural Progression of Chronic HBV

A
30
Q

Describe the serologic markers of HBV in stages

A
31
Q

What is the significance of the gene product CA19-9 in IHC?

A

Tumor antigen shed by tumor cells into serum
↑ for many reasons: GI cancer: pancreatic, colorectal; esophageal, HCC
also pancreatitis, cirrhosis, bile duct diseases & obstruction
BUT
NOT for dx purposes bc many false +/-‘s

32
Q

What is the significance of the gene product CEA in IHC?

A

Glycoprotein on GI surface during embyronic dev
↑ can signal as tumor marker for many GI malignancies: colon & rectum-most freq
also pancreas, stomach, breast, lung, medullary carcinoma of thyroid & ovarian
benign ↑: smoking, infections, IBD, pancreatitis, cirrhosis

NOT for dx purposes but monitoring, non-SP/SN

33
Q

What is the significance of the gene product B72.3 in IHC?

A

tumor associated glycoprotein (mucin like molec)
(TAG-72) on cancer cells
marker can be shed & enter blood; target for anti-cancer monoclonal antibodies

34
Q

What is a common mutation in pancreatic cancer?

A

kRAS mutation: oncogenic form encodes K-RAS protein->uninhib RTK pathways->prolif
common in pancreatic cancer

35
Q

What is the significance of a p53 mutation?

A

tumor suppressor gene: “genome guardian;” preserves stability & prevs muts
activates DNA repair prots, cell cycle arrest at G1/S interface, apoptosis initation

36
Q

What is the significance of a p16 mutation?

A

p16 (CDKN2A) mut: tumor suppressor gene; cyclin dependent kinas
prevs interaction btwn CDK 4/6 with Cyclin D, inhibiting cell from progressing from G1->S

37
Q

What is the significance of the gene product Smad4 on IHC?

A

Tumor suppressor gene that encodes a key intracellular transcription factor
inv TGF-beta signaling cascade that mediates epithelial cell growth; disruption from missense, nonsense, frameshift mutations

55% of pancreatic cancers w/ mutation or deletion of Smad4
Assoc w/ juvenille polyposis syndrome, ↑ risk for GI cancers (ie: colorectal)

38
Q

What is the significance of the gene product Mesothelin on IHC?

A

Protein encoded by MSLN gene, expressed in mesothelial cells
may relate to cell adhesion; overexpressed in tumors incl pancreatic adenocarcinoma, mesothelioma & ovarian tumors
interaction w/ other membrane proteins & help peritoneal spread of tumors by cell adhesion

39
Q

Following a Whipple procedure to remove a pancreatic mass, what chemotherapy regiment could be given with post-operative radiation?

Describe MOA, DLT/AE

A

Gemcitabine & Fluorouracil (5-FU)
S Phase Specific Antimetabolites;
Pyrimidine Analogues (T/C)

Gemcitabine’s AE’s: flu-like prodrome, diarrhea

5-FU: MOA- inhibits thymidylate synthase
DLT: myelosuppresion, mucositis, diarrhea, hand-foot and palmar-plantar syndrome
*Leucovorin & 5-FU synergistically ↑ cytotoxicities

40
Q

What is the chemo drug under preliminary study for pancreatic cancer?
Class
MOA
DLT

A

Irinotecan: S Phase Specific Topoisomerase I Inhibitor

MOA: interferes w/ coiling & repair of DNA in S phase
DLT: myelosuppresion & diarrhea

41
Q

What are the 1st line agents vs. HBV infection?

A

Tenofovir and Entecavir

42
Q

How is unconjugated hyperbilirubinemia measured?
Describe it’s pathophysiology

A

Indirect, i ↑ >80% of increased total bilirubin

↑ bilirubin production; hemolysis, hemolytic anemia (w/ schistocytes), resorbing hematoma: overwhelming conjugation system

↓ glucoronosyltransferase: impaired bilirubin uptake

  • Gilbert’s*: benign no sx; jaundice in times of stress
  • Crigler Najaar*: premature death in babies who can’t conjugate
43
Q

How is conjugated hyperbilirubinemia defined?
​Describe it’s pathophysiology

A

Direct Hyperbilirubinemia

↑ from impaired hepatic secretion, enlarged portal tract may be seen on US
extrahepatic obstruction: stones, tumors, strictures
obstructive jaundice, physical block of flow into duodenum

intrahepatic obstruction: hepatocellular, canalicular, ductular damage

*↓ hepatic uptake of conjugated bilirubin: advanced liver injury*

44
Q

Compare and contrast Acute Vs. Chronic Hepatitis

Time course
Lab findings
Symptoms

A

Acute Hepatitis:
Clinical/biochemical evidence of liver dis < 6 mo’s
↑ aminotransferase (>1000 IU/L)
Low grade fever, N/V, RUQ pain +/- jaundice

Chronic Hepatitis:
Clinical/biochemical evidence of liver dis > 6 mo’s
Hyperbilirubinemia, Hypoalbuminemia
Early: fatigue, jaundice, pruritus, cachexia
Adv: Na & H2O retention-ascites/edema
*Portal HTN: GI bleeding, hypersplenism
Synthetic Dysfunction
*Hepatocellular Carcinoma (RF: Cirrhosis)

45
Q

In setting of acute hepatitis, when is hospitalization indicated?

A

Poor PO intake

Encephalopathy

Synthetic Dysfunction, ↑ INR (liver failure)

46
Q

What is the #1 cause of acute liver failure in the US?
What is the inciting agent?
How can it be reversed?

A

Drug Induced Liver Injury (DILI)
Acetaminophen
N-acetylcysteine

47
Q

What is the most common cause of ↑ LFT’s in blood donors and “cryptogenic cirrhosis?”

Give risk factors

How would you differentiate between its two types?

A

Non-Alcoholic Fatty Liver Disease
RF’s: Dyslipidemia, Obesity, Non-insulin dependent Diabetes, Glucose intoleerance

Histologically resembles alcoholic liver disease; liver biopsy differentiates steatosis vs. steatohepatitis

Steatosis: fat (-) inflammation, (-) fibrosis, assumed non-progressive

Nonalcoholic Steatohepatitis (NASH): fat + inflammation, central hyaline sclerosis (chicken-wire fibrosis), assumed progressive, acute inflammatory cells (PMN’s) even though chronic diease, mallory hyaline, balloon liver cells

48
Q

What liver condition does this represent?

A

Steatosis

Fat w/o inflammation
No fibrosis
(Non-progressive)

49
Q

What liver condition does this represent?

A

Nonalcoholic Steatohepatitis (NASH):

fat + inflammation, central hyaline sclerosis (chicken-wire fibrosis), assumed progressive, acute inflammatory cells (PMN’s) even though chronic diease, mallory hyaline, balloon liver cells

50
Q

For fulminant hepatic failure, note:
Time Course
Causes
Lab
Px
Tx
Note?

A

Within 6 weeks of liver disease onset (jaundice), encephalopathy (confusion/frank coma)

Causes: DILI, viral hepatitis, toxins (Amanita-fungus)

Lab: Elevated aminotransferases and INR

Px: Cerebral Edema, usual cause of death

Tx: supportive management, emergent liver transplant

Note: Bilirubin will be ↑ bc of liver failure, can’t excrete bc of liver necrosis

51
Q

Autoimmune Liver Diseases

Primary Biliary Cholangitis (PBC) vs. Primary Sclerosing Cholangitis (PSC)

EPI
Lab
Serology
Dx
Tx

A
52
Q

Describe biliary colic

A

Intermittent obstruction of cystic duct

53
Q

Describe acute cholecystitis
How is it diagnosed?

A

cystic duct obstruction but no px of jaundice bc flow from liver unimpeded
HIDA Scan

54
Q

When is surgery indicated for acute cholecystitis?

A

RUQ pain, fever, WBC count that doesn’t improve

55
Q

Describe ascending cholangitis
What procedure can be performed?

A

CBD obstruction, so obstructive jaundice possible
ERCP can extract impacted stone

56
Q

What is the most common cause of acute pancreatitis in the US?

A

Gallstones

57
Q

What are 4 types of liver cells?

A

Hepatocytes
Stellate
Endothelial
Kupffer Cells

58
Q

What is the condition when Fe is found in the liver and the spleen?

A

Hemosiderosis

59
Q

What is the condition when Fe is found in the liver and the pancreas?

A

Hemochromatosis

60
Q

Although PSC doesn’t have specific Tx, if cholangitis develops-how should patient be managed?

A

Antibiotics and decompressions w/ ERCP

61
Q

How would acute cholecystitis present on HIDA scan?

A

Absence of gallbladder visualization, sign that cystic duct is blocked

Liver and small intestine will fill but gallbladder won’t*

62
Q

Describe bile salt synthesis

A

Block 4a: GI (5 decks)

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