Course Guide High Yield Flashcards
1
Q
PARASITIC PROTOZOA
A
one celled organisms with a facultative anaerobic metabolism, free oxygen being limited in the host.
2
Q
“flask-shaped” lesions
A
- Entamoeba histolytica* is the causative agent of amebic dysentery
- trophozoites attach and invade intestinal mucosa causing the formation of amebic ulcers in the large intestine primarily in the cecum or sigmoidorectal area, appendix and ascending colon less frequently
3
Q
“ground glass” cytoplasm and a single
nucleus with central karyosome and evenly distributed chromatin
What do cysts look like?
A
Entamoeba histolytica
cysts are spherical with 1 to 4
nuclei, and may contain sausage
shaped chromatoid bodies.
4
Q
Acanthamoeba
A
- free-living protozoans
- associated with improperly sterilized contact lenses
5
Q
Naegleria fowleri
A
- free-living amoeba is found in warm fresh water
- primary amebic meningoencephalitis
6
Q
most common intestinal protozoan infection in US
A
Giardia lamblia-a flagellate
7
Q
cyst is football-shaped with 2-4 nuclei (each cyst with 2 individuals) and axonemes.
A
Giardia lamblia
8
Q
-oval-pear-shaped trophozoites, with one nucleus
motile by four flagella, and characteristic undulating membrane
A
Trichomonas vaginalis- common sexually transmitted flagellate
9
Q
- Oocysts are tiny (4-6 um) and round
- acid fast nature helps to identify in stained preparations.
A
Cryptosporidium sp.-
10
Q
Cyclospora cayetanensis:
A
Similar to Cryptosporidium (except larger)
Also acid fast oocysts
Contaminated food (fruit) from South America, Asia
11
Q
Isospora belli
A
In US, major problem is in AIDS patients. Diagnostic form is large, oval shaped oocyst, often with 2 embryos. Acid fast.
12
Q
Balantidium coli:
A
- only known ciliate to cause human disease
- Major reservoir is swine
- similar to Entamoeba histolytica (dysentary), but almost never invades beyond gut wall
- Cyst is diagnostic and infectious stage
13
Q
Cestodes
A
tapeworms
- characterized by bodies with 3 principal features. First a scolex (head) with specialized attachment organs (hooks and/or suckers),
- second, a neck or immature region giving rise to the
- third region called a strobila.
- lack of a digestive tract
14
Q
Nematodes
A
round worms
basic body plan is a tube within a tube, the outer tube is the body wall, inner tube is the digestive system.
larvae undergo a series of molts (shedding of outer cuticle)
L1 larvae referred to as rhabditiform, L3 larvae are referred to as filariform (infective).
15
Q
world’s most common parasite
A
Enterobium vermicularis -(pinworm)-affects mostly children
16
Q
rare autosomal dominant genetic disease
(LKB1/STK11 mutation)
A
PEUTZ-JEGHERS SYNDROME
branching smooth muscle
fibers, proliferated complex glands and increased mucin
mucocutaneous pigmentation,
gastrointestinal hamartomatous polyps and increased risk of malignancies in organs such as colon, pancreas, breast, ovary and testis
17
Q
Extra-intestinal manifestations include congenital hypertrophy of retinal pigment epithelium (CHRPE), osteomas, epidermal cysts, desmoid tumors and CNS tumors.
A
FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
18
Q
autosomal dominant germline mutation in one of
the multiple mismatch repair genes (MLH1, MSH2
A
HEREDITARY NON-POLYPOSIS COLON CARCINOMA
Lynch syndrome
19
Q
most common malignancy of the GI tract
A
COLORECTAL ADENOCARCINOMA (CRC)
third most common malignancy in either gender, and second most common cause of cancer-related mortality
20
Q
Name 4 drugs that Induction Immunosuppression
A
- Anti-lymphocyte globulin (ATGAM and Thymoglobulin)
- Alemtuzumab (Campath)
- Basiliximab (Simulect)
- Methylprednisolone
21
Q
Calcineurin inhibitors
A
Cyclosporine
Tacrolimus
22
Q
Antimetabolites
A
Azathioprine
Mycophenolate
23
Q
mTOR inhibitors
A
Sirolimus
Everolimus
24
Q
Alemtuzumab
(Campath®)
A
Humanized monoclonoal antibody against CD52
Binds to CD52 on lymphocytes, monocytes, macrophages, and natural killer cells, which causes cell lysis
25
Basiliximab
| (Simulect®)
**_BAS_**ically, an **_IL_**-2 receptor-**_I_**nhibitory chimeric (**_XI_**) **_MAB_**
**IL-2 Receptor Blockade** - monoclonal antibodies (mAb) against the alpha subunit of IL-2.
Binds to the alpha unit of the IL-2 receptor inhibiting binding of IL- 2 thereby preventing activation of lymphocytes
Similar to Daclizumab
26
Methylprednisolone
| (Solu-Medrol®)
Corticosteriods - Blocks cytokine gene expression resulting in a decreased immune response
27
Tacrolimus (Prograf®, TAC, FK 506)
MOA
Major TOX
* blocking calcineurin - Binds to FKBP and inhibits calcineurin (same mechanism as cyclosporin)
* **Along with Cyclosporine, belongs to NIH**
* **NEPHROTOXICITY**
* Neurotoxic
* Increased cholelithiasis in children
* **Hyperglycemic**
28
Cyclosporine
(Neoral®,
Sandimmune®, CsA)
Major TOX
Calcineurin Inhibitor - prevents bindig to transcription factor NF-AT.
**This cycle belongs to the NIH**
* **Nephrotoxicity**
* **I**ncreased cholelithiasis in children
* **H**ypertension, hyperglycemia
29
Mycophenolate
Mofetil (Cellcept®,MMF)
Mycophenolate
Sodium
(Myfortic®,MPA)
MOA
TOX
Metabolized to mycophenolic acid in liver. **It Acts within B and T lymphocytes to *inhibit inosine monophosphate* dehydrogenase**, involved in GMP synthesis in the de novo pathway of purine synthesis - Decreases DNA synthesis in B and T cells - cellular proliferation is decreased.
Clinical use - **Immunosuppresant in transplant patients; autoimmune disorders.**
**GI intolerance**, bone
marrow suppression
30
Azathioprine
Major TOX
| (Imuran®, AZA)
Anti-Metabolites Inhibits proliferation of T and B cells by preventing RNA and DNA synthesis
GI intolerance, bone
marrow suppression,
_**elevated liver
transaminases**_
31
Sirolimus
TOX
| (Rapamune®)
mTOR Inhibitors - Binds to FKBP-12 forming a complex that inhibits the target of rapamycin which proliferation of T and B-cells
* **Anemia**
* **impaired wound**
* **healing**
* **proteinuria**
32
Everolimus
TOX
| (Zortress®)
mTOR Inhibitors - Binds to FKBP-12 forming a complex that inhibits the target of rapamycin which proliferation of T and B-cells
* **Anemia**
* **impaired wound healing**
33
Glycopyrrolate MOA
Anti muscarinic - Block direct muscarinic stimulation of parietal cells, decreasing acid
34
Sucralfate (Carafate)
Cytoprotective - Polymerizes into a protective gel to protect against gastric acid
Gel inhibits back diffusion of H+ and reduces pepsin activity
35
Cisapride MOA
Prokinetic - facilitates ACh release
36
2 Approved treatments for H. Pylori
2 approved treatments
* **Bismuth subsalicylate** (Pepto Bismol), **metronidazol**e and **tetracycline** (2 antibiotics) for 14 days
* **Omeprazole** and clarithromycin for 14 days
37
Metoclopramide
cholinomimetic agent and a D2 receptor blocker
Promotes the release of acetylcholine from
myenteric neurons - Increases LES pressure and relaxes pyloric sphincter
Use: Diabetic gastroparisis and GERD
38
Under restricted use due to association with torsades de pointes
Cisapride
– Facilitates acetylcholine release from myenteric plexus
39
* Mg citrate
* Sodium Phosphate
Osmotic/ (Saline)
40
Docusate
Surfactant - Sm & large Intestines, Detergent: facilitates mixture of fat and water to soften stool
For painful hemorrhoids
Used to prevent constipation,
only a weak stimulant
Commonly given to
hospitalized pts to minimize
straining
41
Bisacodyl
Stimulant - Colon, Stimulate smooth Ms peristalsis.
42
Diphenoxylate (with Atropine-Lomotil)
Antidiarrheal
meperidine (related piperidine opioid)Acts at mu receptors on enteric neurons
43
Loperamide (Imodium)
Does not cross the BBB
Increase transit time, antidiarrheal
44
Bismuth Subsalicylate (Pepto Bismol)
Salicylate is involved in anti-motility, anti-secretory, anti inflammatory effects
salicylate so Reyes’ syndrome warnings also apply
45
hepatitis shows greater predisposition to hepatocellular
carcinoma with or without cirrhosis.
46
ground glass hepatocytes
containing HBsAg) may be seen
Chronic HBV
47
Family that HBV belongs to
Hepadnavirus
48
% Adults with HBV that don't resolve?
10% persistent infection
90% Resolve
49
% of newborn HBV infections that don't resolve
**30-90% of newborn infections** (from exposure to infectious maternal blood) result in chronic infection
- immune system is not fully formed
- vaccination at birth can prevent infection
50
used as marker for active replication in HBV
HBeAg (e antigen) - soluble, not associated with virion
51
DNA genome of HBV
**partially double stranded** in the virion.
3.2 kb DNA; **smallest DNA virus genome**
52
HDV Genome
* **Genome is small, single strand RNA, circular**
* Genome contains a **ribozyme (RNA)** sequence that cleaves the long RNA into unit length pieces and ligates the ends to recreate a circle.
* Similarities to plant viroids
* **Needs HBsAg coat to make infectious particles**
53
Hepatitis A virus:
Family
Genome
Picornaviridae
ssRNA (+)
54
**Hepatitis B virus**
Family
Genome
Hepadnaviridae (DNA)
partially ds DNA
55
**Hepatitis C virus**
Family
Genome
Flaviviridae
ssRNA (+)
56
**Hepatitis D virus**
Family
Genome
Viroid (depends on HBV)
circular ssRNA (-)
57
**Hepatitis E virus**
Family
Genome
Hepevirideae
ssRNA (+)
58
Hepatitis viruses that have a ssRNA(+) Genome
"ACE in the ssReally Positive"
59
Causes chronic hepatitis (85% of infections)
Hepatitis C virus
Can progress to cirrhosis, then to liver failure, or carcinoma
60
HCV was THE major cause of post-transfusion hepatitis after HBV was removed from the
blood supply
What was done to solve this problem?
HCV antigen is now used to detect anti-HCV antibodies in blood supply:
has eliminated HCV contaminated blood and most post-transfusion hepatitis
61
Treatment for HCV
**alpha-interferon** for 6 months
40% of patients: ALT levels decrease to normal during therapy
10% to 30% have long-term response/resolve the infection
Many side effects
**Interferon + ribovirin**: allows lower dose of interferon, fewer side-effects
62
mortality in pregnancy, up to 25% (3rd trimester infections)
Hepatitis E virus
63
PARTIAL MUCOSAL INVASION
Organisms
Clinical illness
Ingested organisms divide and attach to mucosa. Cause
mucosal ulcerations but invade no deeper.
*Shigella, Campylobacter jejuni, Clostridium difficile, invasive E.
coli, Entamoeba histolytica*
Incubation period is 2-4 days. Dysentery with blood and pus in stools. Of all infectious diarrheas, these are most associated with grossly bloody stools
64
TOXIN MEDIATED DIARRHEA
Organisms
Clinical Illness
Toxin produced by organism, organism does not invade
and may not even be ingested
*Vibrio cholera, enterotoxigenic E. coli, Staphylococcus aureus, Bacillus cereus, Clostridium perfringens*
Acute, short incubation (2-24 hours), watery diarrhea. Minimal local inflammatory response (0 or few RBCs/WBCs in stool) and usually no fever. Typically, last 2-5 days. Major risk is dehydration.
65
COMPLETE MUCOSAL INVASION
Most often site?
Organisms?
Ingested organism attaches and invades full thickness of
bowel, into regional lymphatics, and occasionally into bloodstream
Site - Colon
* Salmonella typhi, Yersinia*
66
Viral agents that cause viral diarrhea
Norwalk virus
Norovirus
Rotavirus
Adenoviruses
67
Reoviridae
Shape?
Gemone
Important members
* icosahedral, double capsid, no envelope
* double-stranded RNA, segmented (10, 11, or 12)
* ROTAVIRUS
68
Rotavirus
* Transmission*
* Highest incidence*
* Incubation*
* Symptoms*
* Important for recovery?*
* Major cause of gastroenteritis in infants and a significant cause of mortality of infants in developing countries (1 million fatalities/yr). Age \<2 yr, usually.
* Fecal-oral transmission
* Highest incidence in fall and winter (November – April)
* Incubation period: 24-72 hours
* Symptoms: vomiting, diarrhea, fever, dehydration.
* IgA is important in recovery, prevention
Therapy - rehydration, the diarrhea usually resolves in 2-7 days. Failure to rehydrate may lead to death, especially in infants. Live attenuated oral vaccine recently approved, now recommended for all infants.
69
**Adenovirideae**
* Important serotypes*
* Structure*
* Genome*
* Disease*
Adenovirus serotypes 40, 41, 42 [Serogroup F]
Icosahedral, No envelope
Linear, double-stranded DNA genome
**Serotypes 40, 41, and 42 cause acute viral gastroenteritis (fecal-oral spread) in infants
(usually under 1 yr old), often associated with a concurrent respiratory tract infection.**
70
Caliciviridae
* Shape*
* Genome*
* Transmission*
* Disease*
* Incubation*
Norovirus
no envelope - icosahedral
Positive single strand RNA genome
Food-borne/Fecal-oral
**Causes nonbacterial gastroenteritis in school-age children and adults**
Incubation period: short – 6-24 hours
71
How are viral gastroenteridites different from invasive bacterial GI infections?
All viral gastroenteridities cause **watery diarrhea without blood or WBCs in the stool.** Invasive bacterial GI infections (Campylobacter, Salmonella, Shigella) are characterized by GI inflammation, with blood and pus (WBCs) in stool (at least in serious cases) and always fever. Fever may be absent in viral diarrheas.
72
most common cause of liver disease in the United States
NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD OR
NASH)
rising in incidence.
73
ALPHA-1 ANTITRYPSIN DEFICIENCY
Inheritance
Characterized by:
Autosomal recessive disorder of protease inhibitor alpha-1 antitrypsin (from normal PiMM to PiZZ).
presence of **eosinophilic round large granules** in the cytoplasm of hepatocytes that are **PAS positive** and diastase resistant
74
FOCAL NODULAR HYPERPLASIA (FNH) OF LIVER
incidentally detected mass in young and middle aged
women with a **central stellate scar**.
abnormal large vessels and the surrounding
liver shows cirrhosis-like nodularity and cholangiolar
proliferation at the interface.
75
men may occur with the use of anabolic steroids
HEPATOCELLULAR ADENOMA
76
Second most common primary malignant tumor in the liver
Risk factors
Comparison to prognosis of HCC?
CHOLANGIOCARCINOMA
Risk factors include biliary diseases such as primary sclerosing cholangitis, congenital biliary diseases, cirrhosis and toxins
(West) and liver fluke parasite (Far East)
More aggressive than hepatocellular carcinoma with poor prognosis.
77
4th leading cause of cancer deaths in the US
PANCREATIC CARCINOMA
78
Alkaline phosphatase
Location?
Function
When elevated?
▪ Located on the canalicular surface
▪ Responsible for transport of bilirubin into bile
▪ Elevations seen in obstructive diseases
− Normal (children)
− Fracture
79
Lactate dehydrogenase (LDH)
▪ Glycolytic enzyme found in nearly all cells
▪ Five “isoenzymes” forms, LD1 – LD5
▪ **LD5 found in hepatocytes**, has a short t ½ and not markedly elevated in liver
disease
▪ LDH elevations are usually from heart, RBCs or tumors
80
Gamma glutamyltransferase (GGT)
▪ Located on canalicular surface and in microsomes
− Drug inducible
**▪ Not found in bone **− **Used to differentiate elevation in ALP of bone and liver origin**
▪ ALP and GGT are both elevated in cases of obstructive disease due to their location on canalicular surface of hepatocytes
81
SERMs
Raloxifene
Tamoxifen
Toremifene
82
Aromatase Inhibitors:
Anastrozole
Exemestane
Letrozole
83
Gonadotropin Releasing Hormone Agonists (synonymous with LHRH agonists):
o Goserelin
o Histrelin
o Leuprolide
o Triptorelin
84
Anti-androgenic Agents:
Bicalutamide
o Flutamide
o Nilutamide
o Abiraterone
o Enzalutamide
85
Fulvestrant
Degarelix
Estrogen Receptor Antagonist
Gonadotropin Releasing Hormone Antagonists
86
used to treat tamoxifen induced hot flashes
87
Raloxifene (Evista®)
SERM - receptor antagonist in breast and agonists in bone. Does not increase the risk of endometrial carcinoma because it is an endometrial antagonist.
perfectly safe for woman with intact uterus that wants to go on for prevention. (endometrial antagonist) Tamoxifen is partial agonist.
88
Prednisone Toxicity
"COACH PP says HI, wants you to take roids, (drinking pepsi, must be psychotic)":
* Cushingoid features;
* Osteoporosis;
* Acne;
* Cataracts;
* Hyperglycemia/DM;
* Psychosis;
* Peptic ulcer;
* HTN;
* Insomnia.
If on prednisone for \>3 months start prophylaxis bisphosphonate to prevent osteoporosis.
89
Toremifene (Fareston®)
Has shown no advantage over tamoxifen in treatment of breast cancer
90
Toxicities of SERMs:
* Hot flashes
* Nausea and vomiting
* Edema
* Thromboembolism
* Endometrial cancer
91
Treatment of breast cancer in premenopausal women
92
Treatment of Breast cancer in postmenopausal women
* An AI needs to be incorporated somewhere in the therapeutic regimen
* Endocrine agents are always given sequentially after chemotherapy
93
second-most common
type of secretory pituitary adenoma
Growth Hormone (somatotroph adenomas
40% have GNAS1 mutation (prevents GTPase activity on Gsα
94
Cushing syndrome
vs.
Cushing disease
hypercortisolism
95
Nelson’s syndrome
Development of large ACTH secreting adenoma after
removal of both adrenal glands for Cushing syndrome. No hypercortisolism develops because of lack of adrenals. Patients present with mass effect and hyperpigmentation.
96
Pituitary apoplexy
hemorrhage into pituitary gland, usually into a large adenoma
▪ Symptoms of headache, diplopia and hypopituitarism
▪ Neurosurgical emergency
97
Lymphocytic hypophysitis
Inflammatory lesion of AP gland
More common in women, especially peripartum
− Partial or total pituitary hypofunction
− Lymphoplasmacytic infiltrate of gland
− Causes pituitary hypofunction, occasionally headaches and visual field defects
− Autoimmune theory hypothesized
98
Craniopharyngioma
Types
Prognosis
HYPOTHALAMIC SUPRASELLAR TUMORS
* **Adamantinomatous** - Cysts filled with dark brown fluid (motor oil) and cholesterol crystals, +keratin, Local invasion brain
* **Papillary** - no keratin, cysts or motor oil
Good prognosis
99
Pineoblastoma
Pineocytoma
Constitute 45% of all pineal tumors
Typically found in children within the first two decades
of life
Pineocytoma - rare tumore
100
**Sulfonylureas**
Names
MOA
TOX
1st - **TOLBUTAMIDE, CHLORPOPAMIDE**
2nd - **GLY--IDE - GLYburIDE, GLImeprilIDE, GLIpizIDE**
MOA - 3 main mechanisms
**KATP channel blockade** - In pancreatic beta-cells, this decreases K+ efflux, increasing intracellular K+ depolarizing the cell membrane and activating VDCC, augmenting Ca2+ influx that promotes insulin secretion
1. **Stimulate insulin release - (Potassium channel)**
2. increase insulin action on target tissues by **prolonging binding of insulin to target receptors**
3. **reduce serum glucagon levels**
TOX - **Hypoglycemia**
101
Metformin
**_MET_**abolic **_FORM_**ation of glucose is **_IN_**hibited in the liver
biguanide
* **_INHIBITS HEPATIC GLUCONEOGENESIS_** and, thus, decreases hepatic glucose output
* **_INCREASING PERIPHERAL UTILIZATION OF GLUCOSE_ (increasing insulin sensitivity)** by adipose and skeletal muscle
* DECREASES Glucose absorption from GIT
* serious adverse effect of metformin is **lactic acidosis; GI upset**
102
Acarbose, Miglitol
**_A CAR_** from **_BOSE_** nd a **_MIG LITTLE B_**lock gluc**_OSE_** absorption in the intestin by inhibitng alpha-glucosidase and only a LITTLe glucose can MIGrate across the intestine via GLUT-5
**Alpha-glucosidase Inhibitors** - Alpha-glucosidase is an enzyme that is bound to the jejeunal brush border, and cleaves oligo to monosaccharides that are rapidly absorbed. These drugs are competitive inhibitors of the enzyme, and will delay but not prevent the absorption of the monosaccharide glucose.
Acarbose was the first available alpha-glucosidase inhibitor. Miglitol now available.
103
Sitagliptin/Saxagliptin
**dipeptidyl peptidase‐4 (DPP‐4) inhibitors**
```
GLP-1 secretion is deficient in type 2 diabetes. A class
of agents has been developed which **inhibit DPP-4** and thus **restore GLP-1** levels to normal. This has been shown to reduce blood glucose levels in type 2 diabetes with the same potency of other available oral agents.
```
104
Most common combination treatment for DM II
a drug to simulate insulin secretion, i.e., one of the sulfonylureas or a DPP-4 inhibitor with metformin. This regimen is highly effective and has an extensive clinical
experience.
105
MEN I, or Werner Syndrome
* Autosomal Dominant Trait
* The three P’s
▪ Parathyroids (primary hyperparathyroidism)
▪ Pancreas, endocrine tumors (gastrinomas)
▪ Pituitary gland (prolactinoma)
106
Zetia (Ezetimibe)
* Transport inhibitor - blocking the absorption of cholesterol by the brush border cells of the intestine.
* Used to reduce LDL.
107
Potency of statins
From Most to least = *RASP*
Lovastatin (mevacor) is prototype
* ****_R_**osuvastatin** (Crestor)
* ****_A_**torvastatin** (Lipitor)
* ****_S_**imvastatin** (Zocor)
* ****_P_**ravastatin** (Pravachol)
108
Nicotinic acid (Niacin)
MOA
What is the biggest advantage of this drug?
Much higher dosage, 1-3g, is used for hypolipidemic effect. Vitamin dose is only 20 mg.
Niacin is rapidly absorbed and eliminated by renal clearance.
Note: The acid form of the drug, Niacin or nicotinic acid, is active. The basic form of the drug, niacinamide or nicotinamide does not have hypolipidemic action.
**MOA _Decreasing lipolysis of adipose_ thus decreasing VLDL and LDL production and secretion.**
** Most effective agent for _INCREASING HDL 15%-35% decrease LDL levels_**
109
Gemfibrozil/Clofibrate
MOA
Main use
Adverse effects
**Fibrates** include ciprofibrate, bezafibrate, fenofibrate
* Decrease Fatty acid synthesis, and **stimulate lipoprotein lipase**-enhanced hydrolysis of TGAs into VLDL and chylomicrons
* Stimulates synthesis of apoA-1 (Gemfibrozil)
* Main use - **decrease TG 20-50%**
* DO NOT COMBINE WITH STATINS!
110
Vytorin
Statin and Ezetimibe (Zetia): This combination, Ezetimibe and simvastatin
## Footnote
the combination may be used to reduce potential side
effects of the statins by allowing for a lower dose of the statin drug to be used to obtain a specific reduction
in cholesterol
111
Optimal LDL level
Total cholesterol
Identifies LDL cholesterol ,\< 100 mg/dL
Total cholesterol \<200 desirable, \>240 is High
112
Major Risk factors that modify LDL goals
Smoking
HTN
Low HDL
Family history
Age
113
Incidence of Thyorid Carcinomas
▪ Papillary carcinoma (\>85%)
▪ Follicular carcinoma (5 – 15%)
▪ Medullary carcinoma (5%)
▪ Anaplastic carcinoma (\< 5%)
114
Primary hyperparathyroidism incidence
115
**Rosiglitazone**
SD
MOA
CU
TOX
**Similar drugs** - **thiazolidinediones** include pioglitazone and troglitazone
MOA - **binding to PPAR-gamma**, results in upregulation of multiple genes that **decrease insulin resistance**
CU - non-insulin dependent type 2 diabetes
TOX - **Hypoglycemia; edema**; liver damage (troglitazone - withdrawn)
116
Atorvastatin
*Similar drugs* - **HMB-CoA reductase inhibitors** include **pravastatin, lovastatin, rosuvastatin, simvastatin, fluvastatin**
MOA - **Inhibit HMG-CoA reductase** and **_increase the concentration of LDL receptors on hepatocytes_**, incresing the liver's ability to extract LDLD and VLDL from the serum.
CU - **decrease total cholesterol and LDL levels**. TG mildly decrease with this drug
SE - **Myopathy; abnormal liver function tests**; teratogen
**Ezetimbe** is a cholesterol-lowering medication that decreases cholesterol absorption from the GI tract - **decrease in LDL levels**
117
Cholestyramine
Similar drugs - **bile acid resins** - colestipol and colesevelam
MOA - **inhibit reabsorption of bile acids in jejunum and ileum**
CU - **decrease LDL levels**
SE - **GI upset,** bile stone risk
118
**Treatment of hyperthyroidism**
**Treatment of hypothyroidism?**
**Propylthiouracil** - Similar drugs - Methimazole
MOA - **inhibits thyroid peroxidase**, enzyme involved in organification, by coupling iodotyrosines - results in inhibition of thyroid hormone synthesis in thyroid and **inhibiting peripheral conversion of T4 to T3.**
CU - hyperthyroidism
**_Levothyroxine_** is **synthetic form of T4** (thyroid hormone) used to **treat hypothyroidism**
119
Flutamide
MOA - **competitive antagonist at the androgen receptor** - decreasing growth effects of testosterone on prostate. Body detects low testosterone and increases serum LH. Because LH increases, flutamide is always administered with leuprolide
CU - **prostate cancer**
**Danazol** - **mild agonist at androgen and progesterone receptors - treat endometriosis.**
120
**Leuprolide**
Similar drugs - nafarelin and goserelin
MOA - **GnRH agonist** - initial increase in LH and FSH when first administered, eventually downregulates receptors and LOW LH and FSH ensue.
CU - **metastatic prostate cancer, leiomyomas, treatment of infertility when administered intermittently**
SE - impotence, hot flashes
Clomiphene - partial agonist at estrogen receptors in pituitary - inreasing release of gonadotropins
121
Lipoprotein lipase
* **Activated by _apo C-II_** - resulting in fatty acid release to heart, skeletal muscle, and mammary glands.
* **Hydrolyzes TAGs** in chylomicrons;
* **Stimulated by fibrates** (Gemfibrozil) breaking down TAGs into VLDL and chylomicrons which are removed - **DECREASE TAGS**
* attached to luminal surface of vasculature of cardiac muscle, skeletal muscle, and adipose tissue.
* Deficiency results in **hyperchylomicronemia** (type I hyperlipoproteinemia)
122
Lecithin cholesterol acyl transferase (LCAT)
Plasma enzyme that **esterifies HDL cholesterol** - **_activated by apo A-1_** (Put A1 steak sauce on Cat)
123
**Apo B100**
* **LDL clearance from serum;**
* located on LDLs,
* **mediates VLDL secretion**
* binds to LDL receptor on plasma membrane.
* Allows **extrahepatic tissue to take up cholesterol.**
* **Abetalipoproteinemia** - hereditary inability to synthesize lipoproteins due to deficiencies in apoB100 and apoB-48
124
**Apo B48**
* **Chylomicron clearance from serum**
* unique to chylomicrons;
* **abetalipoproteinemia** - deficiency of apoB48 and apoB100 -**can't export absorbed lipid as chylomicrons**
125
2 main causes of esophageal hematemesis
lacerations (M-W syndrome)
Varices (cirrhosis)
126
Process occuring
Barrett’s Esophagus with low grade and high grade **dysplasia** (these changes only seen microscopically)
127
Diagnosis?
Esophageal adenocarcinoma in the distal esophagus
128
Diagnosis?
**Autoimmune gastritis** is an uncommon cause of chronic gastritis (\<10%)
**Autoantibodies against parietal cells** and intrinsic factor This causes hypochlorhydria and anemia
129
Type of disease in top image vs. bottom?
Gastric carcinoma - Localized or intestinal type
Gastric carcinoma - Diffuse infiltrating (linitis Plastica)
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Type of cancer in each? Characteristics?
**Intestinal type** shows **gland formation on top**
* Male\>female 2:1
* 50-60s
* H pylori or BE
* localized mass
* geographic variation
**Diffuse infiltrating** shows **signet ring cells** on bottom
* Male=female
* 40s
* unknown
* no geographic variation
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most common location for extra-nodal lymphomas
**GI tract** is the most common location for extra-nodal
lymphomas and **stomach** is the most common GI site
132
Characteristic volcano-like ulcer exudates
Pseudomembranous Colitis
Characteristic volcano-like ulcer exudates (endoscopically pseudomembranous).
133
Compare MOA of cyclosporin and Tacrolimus
Which is more potent?
Cyclosporine binds cyclophilin
Tacrolimus binds FKBP-12
(both are calcineurin inhibitors)
Tacrolimmus more potent
134
Potency of immunosuppresants by class
**CNIs** (Tacrolimus, Cyclosporine) **\>**
**mTOR** Inhibitors (Siroliums, Everolimus) **\>**
**Antimetabolites\>**
**Corticosteroids**
135
specific polymorphism
in **NOD2 (nucleotide oligomer binding domain 2) gene**
Caucasians of European ancestry
**Crohn’s**
* Common family history
* 50% concordance in identical twins
136
Current theories on cause of IBDs
* Abnormal immune (T-cell) response
* Epithelial defects - Defects in tight junctions (‘leaky gut’)
* Abnormal response to normal flora
137
What is the disease?
Describe the findings and pathogenesis in each quadrant.
**Crohns**
A - **Small intestinal stricture** - full-thickness inflammation with knife-like fissures through mucosa, submucosa, muscularis propria and serosa!
B - Linear mucosal ulcers and thickened intestinal wall - **full-thickness wall involvement**
C - **Perforation and serositis** - all the way to the serosa! full thickness
D - **Creeping fat** - extensive fibrosis pulls on the fat that is in the mesentary!
138
**$ Describe the Adenoma-carcinoma sequence**
Describes molecular progression from normal colonic mucosa to adenomatous polyp to carcinoma
1. **_APC gene mutation_, a tumor suppresor, both copies must be knocked out** (sporadic or germline) **increase the risk** for formation of the polyp
2. **_K-ras mutation_** leads to the f**ormation of the polyp**
3. **_p53 mutation_** and **_increased expression of COX_** allows for progression to carcinoma
139
Type of polyp
**adenomatous polyp** - neoplastic proliferation of glands, second most common, benign, may probress to adenocarcinoma with the AC sequence.
140
Most common risk factors for HCV infections
1. **IV drug abuse (54%)**
2. Multiple sex partners (36%)
3. Unknown (32%)
4. Surgery (16%)
141
Tissue type? Injury?
**Chronic hepatitis** ( in this case HCV)
* Inflammation predominantly involves **portal tracts** (center with apoptosis of hepatocytes)
* Less inflammation in lobules
142
Liver biopsy obtained, diagnosis?
Immunostain is positive for what?
**HBV "ground glass cells"**
Immunostain positive for **HBsAg**
143
What does the liver tissue show?
**Alcoholic hepatitis** - The cluster of inflammatory cells marks the site of a necrotic hepatocyte (arrow).
Swelling of hepatocytes is seen (white)
144
**$$$$$ This is the hallmark of what disease?**
**_Alcoholic hepatitis_ - Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous (Masson stain) tissue**
* **_Mallory bodies - damaged intermediate filaments (cytokeratin filaments)_** are located inside, necrosis, acute inflammation.
* Acetaldehyde mediates damage - chemical injury seen in binge drinking
145
Disease process that caused this appearance?
What is blue stain?
Alcoholic cirrhosis.
A, The characteristic diffuse nodularity of the surface reflects the processes of **nodular regeneration** and **scarring**. The greenish tint of some nodules is due to bile stasis. A hepatocellular carcinoma is present as a budding mass at the lower edge of the right lobe (lower left).
B, The microscopic view shows nodules of varying sizes entrapped in **blue-staining fibrous tissue.** The liver capsule is at the top (Masson trichrome). - Ischemic necrosis and fibrous obliteration of nodules eventually create broad expanses of tough, pale scar tissue (“Laennec cirrhosis”).
146
How is iron level normally controlled in the body?
Level of body iron is normally controlled by
**_increase or decrease in iron absorption_**
147
2 ways to create iron overload:
**_Hemosiderosis_** - **deposition of hemosiderin (iron) in tissues.**
**_Hemochromatosis_** - the disease, **abnormal increase in absorption causing _organ damage_**, genetic.
* *Can Cause Deposits* - **_C_**irrhosis, **_C_**HF,**_D_**M
* Clasic triad: micronodular Cirrhosis +skin pigmentation + Diabetes mellitus
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Normal total body iron pool
When does disease occur?
* Normal total body iron pool is 2-5 gm (0.5 gm in liver)
* Disease after **_20 gm accumulation_**
149
**Hereditary Hemochromotosis**
Age of Presentation
Defect? Inheritance?
**AR defect in iron absorption (primary)**
* After 40 years
* mutation 6p21.3 **HFE gene** (343 aa protein) Cysteine-to-tyrosine substitution at 282 (C282Y) in 70-100% cases
* Heterozygosity 1 in 9, **Homozygosity 1 in 200** (Commonest genetic disease in USA), but only **20% penetrance**
(disease in only 20% of homozygous population)
150
Diagnosis?
What is characteristic in the top image?
The EM image shows which organelle?
**α1-Antitrypsin deficiency -** **characterized by the presence of _round-to-oval**_ _**cytoplasmic globular inclusions in hepatocytes_, which in routine H&E stains are acidophilic** **and indistinctly demarcated from the surrounding cytoplasm - _STRONGLY PAS +_**
Periodic acid–Schiff **(PAS) stain** of the liver, highlighting the characteristic **red cytoplasmic granules**
Electron micrograph showing the **dilatation of the _endoplasmic reticulum_**
151
central stellate scar
**Focal Nodular Hyperplasia (FNH)** - Localized vascular alteration (Proliferated arteries around obliterated portal vein branches)
152
Diagnosis?
**Liver cell adenoma or Hepatocellular adenoma**
* Young women (\>30) who use oral contraceptives (\>7 yrs use)
* Rarely men who use anabolic steroids
* Mistaken for FNH or HCC
* **Risk rupture in pregancy and hemorrhage (20% mortality)**
153
Most common etiological agent that causes HCC
**_#1 HBV_** is the most common etiological agent (only 50% cases have cirrhosis)
**#2 Aflatoxin** (fungus Aspergillus flavus – contaminating peanuts and grains)
154
Diagnosis?
**Hepatocellular carcinoma.** A, Liver removed at autopsy showing a unifocal, massive neoplasm replacing most of the right hepatic lobe in a noncirrhotic liver; a satellite tumor nodule is directly adjacent.
B, Microscopic view of a well-differentiated lesion; tumor cells are arranged in nests, sometimes with a central lumen.
155
Most common histological type of pancreatic cancer?
ductal adenocarcinoma
156
Infectious form of diphyllobothrium latum
Diagnostic form?
**Plerocercoid** in undercooked fresh water fish
**Operculate eggs** (little trap door) or proglottid in stool
157
T. saginata proglottid vs
T. solium proglottid
T. saginata Proglottid \> 12 uterine branches
T. solium proglottid \< 12 uterine branches
158
**_Thin-walled_** oval eggs in stool
Hookworms - necator americanus and Ancylostoma duodenale
159
Infective Form - Flat-sided, embryonated eggs. Infectious 4 hours after deposit.
Enterobius vermicularis (Pinworm)
160
MOA Anti-lymphocyte globulin
Complement mediated cell lysis of circulating T-cells
161
MOA of corticosteroids as immunosuppresants
Anti-inflammatory response
**Reduced production of cytokines** (IL-1, IL-2, IL-6, IFN-γ and TNF-α)
**Impair monocyte/macrophage function**
Decrease the number of **circulating CD4+ T cells**
162
When would you use an mTOR inhibitor?
Delayed graft function (kidney transplant)
Underlying renal insufficiency (heart or lung transplant)
Drug intolerance (all transplants)
Calcineurin toxicity (all transplants, especially kidney)
Pancreas transplant
163
Typical maintenance regimens for Kidney and Liver transpants
Tacrolimus + mycophenolate + prednisone
164
Toxicity of Tacrolimus vs Cylosporine?
Tacrolimus is more neurotoxic and Hyperglycemic
165
Compare toxicities of Azathioprine and Mycophenolate
**Mycophenolate can cause diarrhea** (++) and azathioprine doesnt. "My diarrhea"
**Azathioprine can cause hepatotoxicity** (+); mycophenolate does not.
166
Immunosuppresant most likely to cause neurotoxicity?
Hirsutism
Hyperglycemia
Tacrolimus \> Cyclosporine
Cyclosporine \> Tacrolimus
Tacrolimus \> Cyclosporine
167
most common nosocomial infectious diarrhea and nosocomial toxic megacolon
Treatment?
Clostridium difficile
CDC and SHEA recommend **Metronidazole** as the first line agent
168
vehicles that transport cholesterol to the artery wall
Plasma lipoproteins that contain **Apo B100** including **LDL, VLDL , IDL**
169
most potent compound and used for osteoporosis in post-menopausal women
Alendronate
170
Inhibit activity of osteoclasts
Bisphosphonates: Alendronate, etidronate, pamidronate
171
inhibitor of bone resorption
Calcitonin - has been shown to reduce bone pain from osteoporotic vertebral compression fractures
172
Short acting insulin
Normal
Intermediate
Long acting
**_Rapid acting_: Lispro, Aspart, Glulisine, **3–6 hours
_**Short-acting**:_ Regular
**_Intermediate_: NPH**
**_Long acting_: Glargine, Detemir **24 hours
173
**Alpha fetoprotein**
Major plasma protein in fetal life (md/dL range)
• Concentration falls postpartum (ng/L)
_• **Increases in hepatocyte regeneration or proliferation**_
**– Acute hepatitis
– Recovery from hepatitis
– Liver neoplasm**
174
Clinical features of cushing syndrome
* **Obesity or weight gain (95%)**
* **Facial plethora (90%)**
* **Rounded face (90%)**
* **Decreased libido (90%)**
* Thin skin (85%)
* Menstrual irregularity (80%)
* Hypertension (75%)
* Hirsutism (75%)
* Depression (70%)
* Easy bruising (65%)
* Glucose intolerance (60%)
* Weakness (60%)
* *Osteopenia or fracture (50%)*
175
Treatment for adrenogenital syndromes (hyperplasia of adrenal glands)
exogenous glucocorticoids
176
Most common type of adrenocortical carcinomas
**METASTATIC CARCINOMAS** ARE **_SIGNIFICANTLY_** MORE COMMON THAN PRIMARY CARCINOMAS
177
Rule of 10s for pheochromocyoma
**•~90% arise in the medulla**
•~10% extra-adrenal location
**•~90% are sporadic**
•~10% familial
•~10% of sporadic are bilateral
•~10% are biologically malignant
•~10% do not have hypertension
178
Most common pheo associations
A.MEN syndromes
B.Type I neurofibromatosis
C.Von Hippel-Lindau disease
D.Familial paraganglioma
179
Frequency of Pituitary Adenoma Types
1. **30% Prolactin**
2. 25% Nonfunctioning (Null Cell)
3. 20% Growth Hormone
