Patho Exam 2

Infections proteins

Prions are similar to normal proteins in the brain, but they fold differently

Prions destroy the brain over time

Ex. Mad Cow Disease

Obligate intracellular proteins that can make their own DNA, RNA, and proteins, but need a host cell in order to replicate

Prokaryotes

Eukaryotic cells

Single cell eukaryotes

Worms

Lice is an example

Skin

Respiratory

GI

GU

Antimicrobial fatty acids and defensins (small peptides that are toxic to bacteria)

A break in the skin

Gastric acid

Mucus

Normal flora (good bacteria)

Pancreatic enzymes (break down viruses with envelopes)

They secrete things which raise the pH in the stomach

Fecal oral

Large particles can get stuck in the nasal mucosa

If the large particle goes farther down the respiratory tract then cilia will move it up and it is either swallowed or coughed up

Small particles can make it to the alveoli

Macrophages in the alveoli can prevent the spread of infection

Entry > uncoating > viral genome replication, mRNA synthesis > viral proteins

Some viruses can transform cells into tumor cells (Ex. Epstein Barr virus)

Some viruses prevent the cell from undergoing apoptosis (the virus can continue to hijack the cellular machinery and replicate

Gram positive bacteria have a more fluffy peptidoglycan layer

Gram negative bacteria have LPS

Antigenic variation

Capsules

Down regulation of MHC class I

Prevent fusion of lysosome and phagolysosome

Some bacteria and viruses undergo antigenic variation

Antigenic variation is when bacteria or viruses change their surface proteins (change cell surface to avoid antibodies)

Capsules are slimy and antibodies have a hard time binding to them

CD8 T cells do not know a cell is infected with a virus

Ex. Herpes

Activation of enzymes to chew up organism does not occur

The organism can escape in the cell and use cell machinery to continue to replicate and divide

Rhinovirus (common cold)- Usually no fever

RSV- Can be nasty in pediatric population

Adenovirus- URI that also causes pink eye

Parainfluenza virus

Bacterial influenza like illnesses

Edema and inflammatory cells

Hyaline membranes- Glassy homogenous appearance form proteins clumping together (bad sign)

Orthomyxoviridae family

Enveloped virus containing 8 segemented ss (sense RNA)

3 types: A, B, C

A and B

A

A and B

C

Antigenic differences in nucleoproteins and matrix proteins

Classified on the basis of the 2 surface antigens- HA and N

Type A, B, or C/Where first identified/# of isolates when first identified/Year isolated (Major type of HA, N)

Ex. A/Sydney/5/85 (H1N1)

16

5 (HA1, HA2, HA3, HA5, and HA9)

9

2 (N1, N2)

Binds to human cell surface and mediates binding and entry into the cell

Located on virus surface

When virus is ready to leave the cell N allows it to bud out of the cell

Located on the virus surface

Necessary for virus to uncoat itself when it's inside the human cell

Causes annual epidemics and the occasional pandemic

Epidemics generally occur in the Winter months in the U.S.

New viruses are generated through 2 distinct changes: Antigenic drift and Antigenic shift

Baby changes

RNA polymerase is sloppy (doesn't go back and proofread)

Mutations occur and change the virus

HA receptor can change (antibodies don't bind as well)

In the major antigenic variable regions

Allows the virus to invade the immune system

There are more than 100 national influenza centers in more than 100 countries that conduct year-round surveillance for influenza viruses

These labs will submit influenza viruses to 5 WHO centers (CDC Atlanta, London, Melbourne, Tokyo, Beijing)

WHO makes the recommendation and each country decides how to design an implement the vaccine

FDA does this in the U.S.

Grown in eggs

For propagation of influenza virus, pathogen-free eggs are used 11-12 days after fertilization

During the incubation period the virus replicates in the cells that make up the chorioallantoic membrane

As new virus particles are produced by budding, they are released into the allantoic fluid

Inject the virus into the egg and then isolate the virus from the egg

The virus may then be chemically treated to strip off surface proteins to make the flu vaccines

Whole process takes 7-8 months

Trivalent inactivated

Live attenuated

Quadrivalent inactivated

Live attenuated replicates in cooler temperatures (in the nasal mucosa and not in the lungs where it's warmer)

An IgG, IgA, and CD8 T cell response occurs (a more potent immune response)

Contraindicated in asthma and immunosuppression (HIV)

Protects against cardiovascular and cerebrovascular morbidity and mortality in patients with cardiovascular disease

Flu- Abrupt onset, Fever is common and lasts 3-4 days, Aches are common and severe, Chills are common, fatigue and weakness are common, sneezing, stuffy nose, and sore throat only occur sometimes, Chest discomfort and cough are common and can be severe, headache is common

Cold- Gradual onset, fever is rare, aches are slight, chills are uncommon, fatigue only occurs sometimes, sneezing, stuffy nose, and sore throat are common, chest discomfort and cough are mild to moderate, a hacking cough may be present, headache is rare

Prevents the virus from budding outside of the human cell

Shortens symptoms by a maximum of one full day

Category C, but would give to a pregnant woman because flu can kill the fetus or cause other complications

Many different animals including ducks, chickens, pigs, whales, horses, and seals

A major change in the genetic information of influenza virus

Ex.

Bird poops and pig sniffs it/eats it and human coughs on pigs

This creates a mixing vessel for a new strain of influenza (genetic re-assortment occurs)

The viruses enter a single cell together and a brand new virus is generated

A global disease outbreak

An influenza pandemic occurs when a new influenza A virus emerges for which there is little or no immunity in the human population, begins to cause serious illness and then spreads easily from person to person worldwide

Usually starts in china because flu season begins earlier there and there are a lot of farmers

A public health problem each year

Usually some immunity built up from previous exposures to the same subtype

Infants and elderly most at risk

Appear in the human population rarely and unpredictably

Human population lacks any immunity

All age groups, including healthy young adults

Influenza A viruses are found in many animals including ducks, chickens, pigs, whales, horses, and seals

All types of influenza viruses circulate in birds

Pigs can be infected with avian and human viruses

Often come from birds and pigs serve as the mixing vessel to create new strains

Birds- a-2, 3

Humans- a-2,6

Pigs- Both

Occurred in 1918

H1N1

20-40 million deaths

Occurred in 1957

H2N2

1-4 million deaths

Occurred in 1968

H3N2

1-4 million deaths

3 or 4 times each century

18-35 year olds

Secondary bacterial infections

One of the greatest pandemics in the history of mankind

Infected greater than 200 million people and 20-40 million were killed

More died in a year than in the four year peak of the Black Plague in the 14th century

People 15-34 years old were most affected (death rate 20 times higher than previous years)

Approximately half of soldiers who dies in WWI died of flu

Some evidence of strain first appeared in France in 1916

Infectious cDNA clones of complete 1918 strain recently finished- many similarities to current H5N1 avian flu

Could this happen again? Vaccine/therapeutic availability and knowledge of epidemiology make another flu pandemic of the same proportions unlikely, but possible

An entirely new virus

Genetic components came from flu viruses that infect pigs, birds, and humans

The virus was easily transmitted among humans

No one, except those who had been infected, or received vaccine is immune

Despite its name, this strain of swine flu wasn't spread from direct contact with pigs or pork, but rather was transmitted among humans

April 17th- Cases found in California and Mexico

April 26th- 2 countries, 38 cases

May 1st- 13 countries, 367 cases

May 9th- 29 countries, 3,440 cases

May 27th- 48 countries, 13,398 cases

October 24th- The president declared a national emergency

Because of patient education (hand washing and staying home if exhibiting symptoms)

A leading cause of vaccine-preventable death and illness worldwide

20 million affected worldwide annually

350,000 deaths annually in developing countries

Measles can harm the fetus during pregnancy (especially if before 12 weeks)

Single stranded RNA virus of the paramyxovirus family

1 serotype (1 type of virus)

Poor nutrition in developing countries leads to a poor immune response

Pneumonia

Respiratory droplets

Droplets containing measles are breathed in > Measles goes to the alveoli where there are macrophages and dendritic cells > Measles binds to SLAM receptor on dendritic cell > Dendritic cell travels to local lymph node > along the way to the lymph node measles replicates and gets access the lymphatics/blood and spreads throughout the body causing viremia

Macrophages/Dendritic cells

Croup (infection of the larynx)

Pneumonia (occurs commonly in developing countries)

Diarrhea with protein-losing enteropathy (causes edema)

Keratitis with scarring and blindness

Encephalitis (acute inflammation of the brain)

Measles can cause profound immunosuppression

Hypersensitivity reaction mediated by T cells

Cytokine production > Dilated skin vessels > leaky endothelium > edema

T cells are at the site and surround the vasculature in the skin

Typically occur a few days before the rash

Thought to be caused by neutrophils coming to the site and causing ulcerations

Clumping of macrophages form a giant cell

Like measles, a member of the paramyxovirus family

HA, NA surface proteins

Replicate in lymphocytes (activated T cells)

Spread through the blood, including salivary gland

Through respiratory droplets

Mumps likes to infect epithelial cells

Different types of epithelial cells line the salivary glands

Mumps infects and causes death of salivary epithelial cells by apoptosis or necrosis > Swelling/Edema

Neutrophils and macrophages come to the site and release cytokines > Swelling in the interstitium of the glands > Clamping of the ducts > more swelling

70%

Aseptic meningitis (meningitis caused by a virus)

Swelling of the testes

Mumps can infect the testes and cause diffuse swelling which compromises blood flow and can lead to scarring and atrophy of the testicles

Scarring and atrophy of the testicles can lead to sterility

Mumps infection of the ovaries

Measles Mumps Rubella vaccine

Live attenuated vaccine

In the U.S., 2 doses are recommended for children

First dose- 12 to 15 months old

Second dose- Before entering school (4 to 6 years old)

It may not be long lived (need titer)

Titer means you have IgG antibodies

Adults

Varicella can be lethal in adults

Discovered in 1976

Belongs to the Filoviridae family

5 types (4 cause disease in humans)

Single stranded RNA

Guinea, Africa

Infected animals to humans through close contact with body fluids (first case)

Human to human (after first case)

A bat may have started the first initial case

Incubation period of 2-21 days

Infectious

Sudden fever, fatigue, myalgias, HA, sore throat

Followed by vomiting, diarrhea, rash, acute renal failure, liver failure, hemorrhage

Ebola infects dendritic cells and tells them to go to sleep (cannot produce an immune response/activate T cells which are necessary to get rid of infection)

A good cell mediated response does not occur

Ebola can also infect monocyte macrophages and cause them to produce TNF-a and IL-6

This causes a crazy systemic response called a cytokine storm (endothelial cells become leaky > fluid is redistributed to other parts of the body and this allows ebola to infect other cells types causing viremia)

Patient goes into shock and bleeds out everywhere because of massive endothelial leakage (the RBC leak out)

Respiratory infection (usually a secondary infection)

Osteomyelitis

Skin infections (Some strains of staph produce lipases which break down lipids on the skin which can predispose to abscess)

Endocarditis

Food poisoning

Toxic shock syndrome

Staph typically colonizes on the skin

Not all strains of staph produce toxins

Some patients colonize staph in their nose

Staph can produce a polysaccharide capsule which makes it slimy > Antibodies don't want to bind because it's not so tasty

Staph can also bind to the Fc portion of the antibodies which prevents staph from being eaten

Hypotension

Shock

Multi-organ failure

Rash

Staph needs oxygen to grow (aerobic)

The vaginal environment in mainly anaerobic

Some tampons made in the 80's had a design which trapped oxygen

Blood is nutrient rich

Blood + oxygen from tampons = staph growth

Staph produces toxins (superantigens)

Staph can also produce an enzyme called cytolysin alpha-toxin which disrupts mucosal surfaces and allows toxins/staph to enter the blood stream

Superantigens hook up with APC and CD4 T cell

This is a nonspecific interaction

The superantigen binds to MHC Class II and TCR

This interaction causes a massive immune response because many T cells are activated which leads to a cytokine storm and shock

Staph can colonize and release toxins

Gastric juices don't destroy the toxins

N/V can occur 2-8 hours after eating

Symptoms usually resolve within 24-48 hours

C. diff

Flagellated protozoans

Most common pathogenic parasitic infection in humans

Spread through fecally contaminated water (Ex. Swimming in contaminated water and swallow some)

Resistant to chlorine

If pools are not filtered often G. lamblia can grow and cause infection

IgA and IL-6

They survive in cysts

Infect small intestinal cells and destroy the brush border causing malabsorption and diarrhea

They can change their flagella (surface proteins) which allows them to avoid immune response

They can survive for months

Gram negative bacilli

Two types- Non-typhoid and typhoid (causes systemic issues)

Non-typhoid S. enteritidis

1 million cases per year

Summer & Fall

Contaminated food

Chicken

M cells are lined throughout the intestines and bring in antigens (sampling)

Macrophages exist under the M cells and are there to eat things

Macrophages go to the Peyer's patches (lymph nodes in the gut)

Salmonella/Shigella have evolved ways to trick the cell to ingest it

Zipper mechanism- Bind to cell receptors > Trigger cytoskeleton rearrangement to allow engulfment of organism (endocytosis)

Trigger mechanism- Organism can trigger its way in to the cell with no receptor by injecting a hollow needle into the cell and injecting its own proteins into the cell > Hijacks the cytoskeleton > The organism tricks the cell to rearrange the cytoskeleton and engulf the organism

Some organisms have evolved ways to escape the endosome and cause infection

A type of secretion system for invading the cell

Organisms don't have receptors to invade the cell and will instead inject hollow needle into the cell

The ileum

Bacteria sense the environment of the gut (osmolarity, oxygen levels, etc.)

In the terminal ileum there is acetate and formate which salmonella like (allows salmonella to illicit a type 3 secretion system and invade)

Initially isolated during the Japanese red diarrhea epidemic of 1897

Gram negative bacilli

4 major strains

Unencapsulated, non-motile, facultative anaerobe (can live with or without oxygen)

One of the most common causes of "bloody diarrhea"

165 million cases worldwide

Colon (left side)

Diverticulitis may cause LLQ pain in caucasians

May cause right sided pain in asians

M cells sample antigens (shigella) > Shigella enters the M cell and a macrophage eats it > Shigella escapes the phagosome (no phagolysosome fusion) > Shigella binds to receptor on enterocyte and is taken up into cell (comes in as phagosome) > Shigella escapes the phagosome and hijacks the cytoskeleton of the cell (actin and microtubules) and uses it as a ladder to move throughout the cell > Shigella moves across the cell and infects adjacent cell > Shigella exits out into the GI lumen and causes infection

Fever, abdominal pain, bloody diarrhea

Acute colitis

Self-limiting usually, but can last as long as a month

Most common bacterial enteric pathogen in developed countries

Comma-shaped, flagellated, gram -

Chicken, unpasteurized milk, contaminated water

Causes traveler's diarrhea

Patho is poorly understood

4 virulence factors- Motility, adherence, toxin production, and invastion

Chicken, unpasteurized milk, and contaminated water

C. jejuni colonizes the GI tract of the chicken > The chicken poops and contaminates water > Human drinks the water and can get infected

A cow can drink the contaminated water > Unpasteurized milk can infect humans

C. jejuni can infect humans via uncooked chicken

It forms a biofilm on water which protects the organism so it can continue to replicate

C. jejuni circumvents the mucus layer in humans and interacts with the intestinal epithelial cells causing IL-8 production

C. jejuni enters the enterocyte > The enterocyte becomes angry and produces IL-8 which acts as both a cytokine and chemokine > In the subepithelium macrophages, dendritic cells, and neutrophils will influx and produce pro-inflammatory cytokines > T helper 1 specific immune response occurs > Inflammation > Clearance

NF-KB is a transcription factor (activates genes) which is important in activating genes responsible for an inflammatory cytokine response

Reactive arthritis (patients with the HLA-B27 gene are especially predisposed)

Linked to Guillain-Barre syndrome

Yes

Enterotoxigenic E. coli

Enterohemorrhagic E. coli

Enteroinvasive E. coli

Enterotoxigenic E. coli

Contaminated meat and many other ways

Via Heat-Labile toxin and Heat-Stable toxin

HL toxin has an A and B subunit

HL toxin binds to a receptor on the cell and is taken in as a phagosome/vesicle > HL has retrograde transportation into the golgi (goes to the golgi first rather than the ER) > Subunit A activates adenylyl cyclase > Activates cAMP (2nd messenger) > Protein kinase A gets activated > Increase activation of this pathway causes excretion of Cl into the gut via CFTR > Na and H20 are also excreted into the gut causing watery diarrhea)

HS toxin activates guanylyl cyclase and also leads to cAMP and protein kinase A activation > Watery diarrhea via same mechanism

Caused abdominal pain, diarrhea, and death

The source of the infection was apple juice from school

The apple juice was made from apples from an apple farm that would fall off the tree into deer poop

The E. coli from the deer poop got onto the apples and into the apple juice

The apple juice was not sufficiently pasteurized to kill any pathogens it contained

Cattle and other ruminants are the main E. coli carriers

Humans can get E. coli from uncooked meat and raw milk and fruits and vegetables

3 to 8 days

Stomach muscle spasms, diarrhea (sometimes bloody), fever, and vomiting

Complications- Hemolytic Uremic Syndrome (HUS)

Death rate- 3-5%

EHEC produces shiga toxin

EHEC enters the cell and gets access to circulation > Shiga toxin binds to receptor on endothelial cell > Shiga toxin is brought into the endothelial cell via a vesicle and is shuffled into the ER > Shiga toxin disrupts protein synthesis > Endothelial cells start to die > Platelet aggregation > Fibrin contributes to microthrombis forming in circulation > RBC that get stuck fragment and release hemoglobin > Fragments and hemoglobin wind up in kidney > Clog the kidney and cause acute renal failure

Infection leads to diarrhea and hypovolemia (dehydration) which can also cause acute renal failure

Acute renal failure can cause death

Similar to shigella

Does not produce toxins

Transmitted by food, water, or person to person

No

Neutrophils indicate bacterial infection

Lymphocytes indicate viral infection

The large intestine

Hyperemic colon walls and psudomembranes

Antibiotic use (specifically clindamycin)

C. diff normally lives in the gut > Antibiotics decrease good bacteria > C. diff proliferates

Oral vancomycin

C. diff colonizes on the mucosal surface and releases enzymes like proteases which allow it access to the epithelium > C. diff releases toxins A and B which are taken inside the cell and kill the cell via apoptosis and necrosis > Dead epithelium slough off and form pseudomembranes which consist of dead cells, neutrophils, and macrophages

Gram +, motile bacteria

Associated with advanced age, hospitalization and antibiotic treatment

30% of hospitalized patients are colonized with C. diff

Fever, leukocytosis, abdominal pain, cramps, and hypoalbuminemia

Epithelial cell death creates holes in the gut which allows albumin to leak into the gut

Albumin that is leaked into the gut is pooped out

How many times are you going a day? (15-20 times)

What does it smell like? (like death)

What does it look like? (watery)

There are trillions of bacteria in the ileum and colon

Bacteria colonize and protect against pathogens

Facilitate digestion, help with absorption of Vitamin K and folate, and shape development of intestinal epithelial cells

Mouth- Chew food, saliva (adds water and digests carbohydrates

Esophagus- Swallows

Stomach- Mix and dilutes chyme, gastric secretions (digest protein, add intrinsic factor, acidic)

Small intestine- Bile emulsifies fat, Pancreatic secretions, Intestinal secretions (digest fat, protein, and carbohydrate), absorption of nutrients

Colon- Absorbs water and electrolytes

Rectum- Storage until defecation

Released by salivary glands and the pancreas

Breaks down carbs

Distention > Release of gastrin > Gastrin produced by G cells stimulates production of acid in the stomach

Inner layer- Mucosa (Epithelium, lamina propria, muscularis mucosa)

Middle layer- Submucosa

Outer layer- Muscularis externa (longitudinal and circular muscle)

Outer serosa- Serous membrane consisting of mesothelium (also known as visceral peritoneum)

Production of mucus (protective coat), secretion of digestive enzymes to break down food, absorption of breakdown products

Lymphatics, blood vessels, connective tissue, nerves

Pick up absorbed nutrients and carry them back to the liver for processing

Responsible for peristalsis

Stratified squamous epithelium

Located near the basement membrane which provides nutrients to basal cells

Basal cells are like stem cells (they divide and form many layers)

To protect from acid

Parietal cells (secrete HCl)

Chief cells (secrete pepsinogen)

Endocrine cells (G cells) produce gastrin which tickles other cells in the stomach to produce HCl

Pepsinogen + HCl = Pepsin (degrades proteins)

Mucus (foveolar) cells

Secrete mucus to protect the stomach from acid

MI

PPI

Provides support and nutrition to the epithelium

Contains many different cells including fibroblasts, plasma cells, macrophages, etc.

Increasing cell number

Basal cell hyperplasia extending 20% into the epithelium (15% or less is normal) and papillae elongation

Hyperplasia occurs to accommodate damage from acid

Papillae elongate to provide more nourishment to the epithelium

Eosinophils recruited first followed by neutrophils

The more neutrophils coming to the site correlates with more extensive disease

Reflux of acid from the stomach due to reduced LES tone

Reflux of gastric juices is central to the development of mucosal injury

Sometimes bile from the duodenum can exacerbate damage

ETOH, smoking, obesity, and pregnancy can exacerbate symptoms

In many cases the cause is unknown

Barrett's esophagus

Chronic GERD

Metaplasia of the lower esophageal mucosa from stratified squamous epithelium to nonciliated columnar epithelium with goblet cells

Common in 50-60 year old white males

Increased risk of esophageal adenocarcinoma

Cancer

Neoplastic epithelium that remains confined to the basement membrane (has not invaded other structures)

Precancerous

Epithelial cells enlarged with enlarged hyperchromatic (nucleus is more dense- more chromatin from uncontrolled cell division) nuclei

Loss of cell polarity (loss of organization)

Ex. HCl should be secreted into the lumen of the stomach, but instead it would go to the other side of the cell

Adenocarcinoma

Squamous cell carcinoma

Cancer (adenocarcinoma)

Malignant proliferation of glands

Usually occurs in the distal 3rd of the esophagus (Barrett's)

Can invade adjacent gastric cardia

Tell your patients to eat fruits and veggies

Some strains of H. pylori decrease risk (cause gastric atrophy > decreased acid production > less acid to damage esophagus)

Most common in white males

Most common type of malignancy in the west

Glands in the esophagus enlarge (back to back glands) to try to protect the esophagus from acid

Indicative of high grade dysplasia (think cancer)

Beyond the basement membrane

Mutation of p53 early on (P53 is a tumor suppressor; if you can't suppress cell division you get cancer)

Amplification of c-ERB-B2, cyclin D1 and cyclin genes

Allelic loss of p16/INK4a

Increase expression of TNF alpha, NF-kB

Spread by mucosal lymphatic vessels

P53 is a tumor suppressor

If you can't suppress cell division, you get cancer

C-ERB-B2 is an oncogene (gene that can transform a cell into a tumor cell)

Amplification of ERB-B2 leads to cancer

Cyclin D1 and cyclin genes regulate the cell cycle

Amplification can lead to progression through the cell cycle without sufficient checking which can lead to cancer

Loss of p16/INK4a (cyclin dependent kinase inhibitor) leads to uncontrolled cellular proliferation and can cause cancer

TNF-a causes inflammation

Unchecked inflammation can cause cancer

NF-kB is a transcription factor

If NF-kB is activated all the time it goes and activates genes which can cause cause of expression of TNF-a

This can cause cancer

Malignant proliferation of squamous cells

Most common esophageal cancer worldwide

Arises in the upper or middle third of the esophagus

Late detection = poor prognosis

Progressive dysphagia (solids to liquids)

Weight loss

Hematemesis

Hoarse voice (because of recurrent laryngeal nerve involvement)

Upper 1/3- Cervical nodes

Middle 1/3- Mediastinal or tracheobronchial nodes

Lower 1/3- Celiac and gastric nodes

1-1.5 L

Anemia

Upper GI bleed

Colon cancer

From bleeding

Chronic alcohol abuse causing cirrhosis

From bleeding in the stomach

Stomach acid oxidizes hemoglobin into brown hematin (coffee ground appearance)

H. pylori

The antrum of the stomach

Neutrophils

Swelling/edema (no gastric pits)

T cells and B cells may be present in chronic infection

Acidic damage to the stomach mucosa

Transient mucosal inflammatory process (as long as you take away the cause- H.pylori or NSAIDs)

pH of the stomach is close to1

Protective mechanisms are disturbed

Replaced every 2-6 days

Chemotherapy suppresses mitosis (could cause acute gastritis)

NSAIDs

ETOH (damages the mucosa)

Severe burns

Severe burns can cause a curling ulcer

Patients with severe burns are in a state of hypovolemia

The stomach has a rich vascular supply which takes away acid

Hypovolemia = decreased blood supply > stomach can't sweep away acid

Prostaglandins lead to decreased acid and mucus production

Prostaglandins also stimulate bicarbonate secretions which neutralize acid

NSAIDs inhibit prostaglandins

Intracranial injury

Systemic acidosis

Hypoxia

Shock

Swelling in the brain (intracranial injury) leads to stimulation of vagal nuclei in the brain > Increases HCl

Vagal cells release Ach which binds to receptors on epithelial cells and stimulates HCl production

Systemic acidosis causes low pH inside the cells which can lead to acute gastritis

Decreased blood flow interferes with the removal of acid from the lamina propria which can lead to gastritis

PPI ulcer prophylaxis

Histamine, gastrin, and Ach all bind to receptors on the basolateral membrane of the parietal cell

The parietal cell brings in chloride

A proton pump (ATPase pump) pumps K into the cell in exchange for H > This leads to the opening of a Cl channel > H and Cl join to form HCl

They prevent histamine from binding to its receptor on the parietal cell which lowers HCl production

Swelling in the brain causes the vagal nuclei in the brain to tickled > Ach is produced > Increased HCl production

Superficial inflammation > Erosion (loss of superficial epithelium) > Ulcer (loss of mucosal layer)

H. pylori

Chronic autoimmune gastritis

Destruction of parietal cells because antibodies attack parietal cells and/or there are antibodies directed against intrinsic factor (needed to absorb B12)

Pathogenesis mediated by T cells (hypersensitivity type IV)

Parietal cells being attacked causes atrophy of the mucosa and persistent inflammation

Achlorhydria (low HCl production) is associated with autoimmune gastritis

G cells respond by producing more gastrin to compensate for low HCl > This causes G cell hyperplasia

Antibodies against intrinsic factor cause anemia (megaloblastic)

Spiral-shaped bacilli

Present in 90% of individuals with chronic gastritis (antrum)

Mode of transmission of understood

Humans are the only host

Intraepithelial neutrophils and plasma cells (Acute- neutrophils; Chronic- Neutrophils and plasma cells)

Duodenal ulcers are mostly caused by H. pylori

Gastric ulcers cause more pain on eating

Duodenal ulcers are associated with pain relief from eating (The duodenum prepares for acid coming from the stomach and releases things to neutralize acid like bicarbonate and secretin)

Duodenal ulcers almost never lead to malignancy

Gastric ulcers can lead to malignancy

Flagella

Adhesin proteins (attachment to epithelial cells)

Urease (produces ammonia which neutralizes acid because H. pylori likes a higher pH)

LPS (induces an inflammatory response)

VacA (formation of vacuoles which leads to apoptosis, disruption of epithelial junctions, blockage of T cell response)

CagA (alteration of signaling pathways, cytoesquelet rearrangement, alteration of tight junctions)

Production of urease neutralizes gastric acid

Mucosal damage occurs by mucinase which chews through the mucosa > Leads to inflammation and mucosal death

Ammonia also contributes to mucosal cell death

An increase in IL-6 and IL-8 occur

IL-6 is inflammatory and IL-8 leads to recruitment of neutrophils to the site which further exacerbates inflammation

A type of lymphoma that is caused by chronic H. pylori infection

B cells like to live in the germinal center of lymphoid tissue

Persistent H. pylori leads to B cell lymphoma

One of the few cancers that can be resolved just by removing the cause (H. pylori)

Because of malabsorption of the building blocks needed to make protein

Because iron is not being absorbed

Celiac disease

A connective tissue that wraps around each muscle fiber

No, because IgA is only present in mucus

Villi

Epithelial and goblet cells line the villi

Capillary network in each villus

Intestinal glands

Fibroblasts and immune cells

No villi

Columnar epithelium

More goblet cells than the small intestine

Enterocytes

Every 3-5 days

Enterocytes express enzymes on their surface called brush border enzymes

Brush border enzymes further help break down products within the intestine

Where small intestinal stem cells are located

Responsible for regeneration of cells

Lymphatics located in the villi

Absorb fat in the small intestine

Lactose intolerance occurs when there is no lactase (brush border enzyme) to break down lactose into glucose and galactose (monosaccharides)

The small intestine can only absorb monosaccharides (not disaccharides)

Disaccharides that are not broken down draw water into the lumen (sugar is osmotically active like salt) causing diarrhea

Large carbohydrates are broken down to disaccharides > disaccharides are broken down by brush border enzymes into monosaccharides

SGLT-1 transporter is a sodium glucose cotransporter the lines the lumen surface

In order to bring glucose and galactose into the cell, the enterocyte creates a sodium gradient (the enterocyte allows sodium to come into the cell) > higher levels of sodium in the enterocyte allows glucose and galactose to come into the cell (no energy required)

Exporting glucose and galactose out of the enterocyte ATP is needed

Sodium goes out of the cell and potassium comes into the cell

Glucose and galactose leave the cell via the GLUT-2 transporter (glucose cotransporter)

By passive/facilitated diffusion

They are taken to the liver

This is how we get our nutrients from the small intestine

Stomach agitation (stomach acid starts to break things down)

Bile salts synthesized in the liver are excreted into the duodenum along with pancreatic lipase (likes to chew up fat)

Lipase chews up triglycerides into monoglyceride and free fatty acids

Bile salts form micelles which collect monoglycerides and free fatty acids > Mixed micelle is formed

The enterocyte will take the mixed micelle inside and break it down into triglycerides > forms water soluble triglycerides (must be water soluble in order to travel back to the liver)

Chlyomicrons (water soluble triglycerides) will go to the lymphatics and to the liver where they will be further processed

Occasional intraepithelial lymphocytes

You do not want to see too many

Decreased absorption

Intraepithelial lymphocytes (CD8+ T cells)

Immune-mediated enteropathy triggered

More common in women and people 30-60 years old

Chronic diarrhea, anemia, bloating

T cell-mediated autoimmune disease

Results in villus shortening, crypt hyperplasia, and lymphocytic infiltration of the epithelium

Loss of immune tolerance (immune system attacks self)

Gluten is rich in proline and glutamine which protects is from being degraded by stomach acid

Brush border enzymes cleave gluten into peptides called gliadin > gliadin peptide comes through the epithelial cells > tTH deaminates the gliadin (removes amide group) and targets the peptide for degradation > Gliadin is a highly negatively charged peptide and HLA molecules (DQ2 or DQ8) like negatively charged peptides > Gliadin has a higher affinity for HLA molecule than peptide already sitting in HLA molecule, so Gliadin displaces peptide > Autoreacitve T cell (reactive to gliadin) gets out of the thymus and sees the gliadin in the HLA and releases IFNy > Causes epithelial cells to upregulate MIC-A (like a MHC class I molecule) > Autoreactive T cell (T helper cell) will tickle a B cell which will produce antibodies (Anti-gliadin, Anti-endomysium, and Anti-tTG

Gliadin can also bind to enterocytes and make them angry cause them to produce IL-15 which tickles CD8+ intraepithelial lymphocytes causing them to become activated

Because there is an increased expression of MIC-A, the CD8+ T cell will go and kill the enterocytes which leads to a loss of villi

Idiopathic

Chronic

Crohn's disease and Ulcerative colitis

More common in females in their teens and early 20's

Hygiene hypothesis (we are too clean)

SNPs

Genetic predisposition (Certain genes have been linked to these disease)

Environmental factors (possibly an infection with a virus or bacteria)

Gut microbiota

Host immune response (innate/adaptive)

Starts in the rectum and moves up

No skipped lesions

Confined to the large intestine

Pseudopolyps and ulcers in the mucosa and sometimes the submucosa

LLQ pain (location of rectum)

Skipped lesions

Lesions can be found anywhere from the mouth to the anus

Transmural inflammation (all layers affected)

Ulcerations and fissures can form

Ulcerative colitis

Crypt abscess

Crypts are full of neutrophils

Crypts may also be seen in Crohn's disease, but are not nearly as prevalent

Cancer

Smoking

Loss of haustra due to diffuse inflammation

Granulomas

Granulomas contain lymphocytes

Recurrent, granulomatous type of inflammatory response that can affect any area of the GI tract

Terminal ileum or cecum is the most common portion of the bowel where inflammation occurs

Transmural chronic inflammation

RLQ pain because that is where the ileum is

Knife-like fissures (like a stab wound in the ileum)

Damage to all the layers can damage stem cells

Knocking out the stem cells does not allow the tissue to restore to normal

Can cause granulation and fibrosis

Myofibroblasts are part of the healing process

Seen in Crohn's disease

Is a result of the gut trying to heal

Fat surrounds the intestines

Myofibroblasts contract the wound

The intestines contract and the fat is pulled closer to the intestine (creeping fat)

This is a part of the healing process when stem cells are knocked out

TH1 and TH17 (autoreactive) are predominant in Crohn's disease and mediate inflammation

T17 recruits neutrophils and causes inflammation

TH1 cells produce IFNy which makes macrophages angry causing them to secrete TNF-a

Treated with biologic agents like TNF-a antibodies

Alleviates symptoms

Patients must be tested for Tb every 6 months because TNF-a protects against Tb

TH2 (autoreactive) are predominant in UC

Patients with UC have elevated levels of IL-13 in their serum

Insulin

Digestive enzymes

Zymogen granules which contain inactive digestive enzymes

Inflammation and hemorrhage of the pancreas that results in autodigestion of the tissue (from enzymes, mainly trypsin)

May be acute or chronic (acute form is considered a medical emergency)

The pancreas lacks a fibrous capsule so destruction may progress into tissue surrounding the pancreas and substances released by necrotic tissue lead to widespread inflammation (hypovolemia and circulatory collapse may follow)

Trauma (Ex. MVA)

Hypercalcemia (Calcium activates enzymes, so if you have a lot of calcium you can activate enzymes and cause pancreatitis)

Hyperlipidemia

Scorpion stings

Mumps

Coxsackie B virus

Rupture of posterior duodenal ulcer (pancreas is right behind the duodenum)

Abdominal pain (cardinal symptom)

Anorexia

N/V

Edema (If the pancreas is unable to release enzymes then you get malabsorption > low albumin > edema)

10% can develop psudocysts

Native Americans

Duct obstruction

Acinar cell injury

Defective Intracellular transport

Cholelithiasis (ampullary obstruction) and Chronic alcoholism (ductal concretions) > Duct obstruction blocks enzymes from reaching the duodenum > edema and inflammation > impaired blood flow > ischemia > Acinar cell injury/death > activated enzymes > acute pancreatitis

Alcohol, Drugs, Trauma, Ischemia > Release of intracellular proenzymes and lysosomal hydrolases > activation of enzymes (intra or extracellular) > acinar cell injury/death > activated enzymes > acute pancreatitis

Alcohol and duct obstruction > Delivery of proenzymes to lysosomal compartment > intracellular activation of enzymes > acinar cell injury/death > activated enzymes > acute pancreatitis

Lipase and phospholipase (fat necrosis)

Elastase (hemorrhage from damage to elastic fibers of blood vessels)

Inflammation

Vascular injury

Acinar cell injury

Activation of proteolytic enzymes (trypsin)

Activation of clotting cascade (can lead to DIC)

Resolution

ETOH oxidative stress

Inflammation

Pancreatic fibrosis and acinar cell loss

Not usually

Pancreatitis affects the exocrine cells

When hemoglobin is under 8

The patient may require transfusion

Hepatocytes

In the bile duct

In the bile duct

ETOH

An obstruction

Lipase because amylase is also made by the salivary gland

Because bilirubin is in the urin

Diabetes

An issue with the endocrine cells of the pancreas

Bilirubin is not getting to the gut where it needs to go and so it is backing up into the liver and then into the blood

To compensate, the bilirubin is urinated out

Bilirubin is broken down into urobilinogen in the gut

Urobilinogen gives feces its characteristic brown color

Yes

Some urobilinogen is pooped out, some is reabsorbed and taken back to the liver to be reused, and any excess urobilinogen is removed by the kidney (normally a little is found in the urine)

This would cause clay colored stools

A blockage

Bilirubin is not getting to the gut and is not being broken down into urobilinogen

Gall stones and cancer

In the head

Symptoms from pancreatic cancer do not usually present until late in the disease

A scope goes to the duodenum, through the major papilla, and into the common bile duct

Contrast is injected to help visualize the common bile duct

Dilated bile duct from obstruction

Stricture of the bile duct caused by a mass

No, cancer from other sites is usually spread to the liver via the blood

through the bile ducts

The blood supply to the liver is dual (portal vein and hepatic artery)

The portal system is not heavily oxygenated

The portal vein brings things in to the liver from the intestines, stomach, pancreas, and spleen to be filtered

Contains a lot of lobules

Lobules gather together and a central vein exists in the center of them

Liver dysfunction

Like little capillaries

Come off the portal vein

Like macrophages in the liver

Surround the sinusoids

Filter the blood and make bile

Hepatocytes > canaliculus > bile duct > gall bladder

In a state of fasting, amino acids, glycerol, and lactic acid are used to make glucose (gluconeogenesis)

If there is too much glucose, the liver can store it as glycogen (glycogenesis)

When glucose is needed, glycogen can be broken down into glucose (glycogenolysis)

Fat

Goes to the bloodstream and/or is stored in adipose tissue

Dietary proteins are broken down into amino acids > Amino acids will be used in the liver to make tissue or plasma proteins

Amino acids can also undergo transamination (accepting of an amine group) or deamination (removal of an amine group)

Transamination occurs to make glucose and nonessential amino acids

Deamination occurs to make fatty acids, ammonia, and ketoacids

Ammonia goes through the urea cycle to make urea

Ketoacids generate ATP

Neurons

Dietary fats (triglycerides) are broken down into fatty acids > Fatty acids are broken down into 2 molecules of Acetyl-CoA by beta oxidation

Acteyl-CoA is used in the citric acid cycle to make ATP

HMG-CoA can convert Acetyl-CoA to cholesterol or bile salts, or lead to steroid synthesis

Statins inhibit the conversion of Acetyl-CoA to HMG-CoA which inhibits cholesterol formation

What is happening in the meat (bulk) of the liver

ALT

AST can also come from muscle, including the heart

AST is greater than ALT by two or three times

In alcoholics

AST > 300 indicates alcohol

In fatty liver disease

By 1000x in acute hepatitis, ischemia, toxins, autoimmune

Liver, bile duct, kidney, bone, placenta

The bile duct

Can also be found in the liver (in the ER of cells)

GGT and AP

120 days

Breakdown of the RBC

As the RBC travels through circulation it begins to breakdown and the macrophages recognize this the breakdown

This occurs on average at 120 days

Destruction of the RBC by macrophages in t he spleen > Heme and Globin > Globin is broken down into amino acids which are recycled and heme is broken down into iron and bilirubin (iron is recycled) > Bilirubin is made water soluble by pairing with albumin (bilirubin needs to be water soluble to get to the liver) > In the liver bilirubin is conjugated by the addition of glucuronic acid

Prehepatic or Hemolytic Jaundice (hemolytic anemia)

Intrahepatic Jaundice (hepatitis)

Posthepatic or Obstructive jaundice (gall stones)

Occurs before the liver (ex. hemolytic anemia)

Hemolytic anemia causes excessive breakdown of RBC which leads to increased levels of unconjugated bilirubin in the blood (the liver cannot keep up and conjugate the extra bilirubin)

Feces will be normal or darker in these patients

Something going on with the meat (bulk) of the liver (Ex. hepatitis)

Either:

Increased unconjugated bilirubin in the blood because hepatocellular damage will prevent conjugation

Or

Increased conjugated bilirubin in the blood from inflammation which obstructs flow to the hepatic duct

Feces color is variable

Ex. Gall stone

Obstructed flow to the intestine causes backup to the liver and blood which increases conjugated bilirubin in the blood

Stool will be a light color

Most common cause of liver disease

Initial change is a fatty liver > Alcoholic hepatitis (acute) > End-stage cirrhosis

End-stage cirrhosis occurs in 10-20% of alcoholics

AST > ALT

Alcohol can be directly absorbed from the stomach into the blood stream

Acetyl aldehyde and free radicals

Acetyl aldehyde is very toxic

The mitochondria (has a toxic affect on the electron transport chain)

Enlarged, soft, and yellow

Vacuoles that contain fat

Damaged electron transport chains cause increased levels of H ions which lead to a process of increased lipid synthesis inside the hepatocyte > accumulation of fat in vacuoles

Liver damage due to ETOH

Pink worms

Cirrhosis

Things can't enter the liver and get backed up

The fluid leaks out because there is a volume overload in the patient (increased hydrostatic pressure)

Increased hydrostatic pressure causes fluid to leave the vessels and lack of protein (albumin) causes the fluid to not be brought back in

Dilated capillaries (will blanch with pressure)

A result of cirrhosis

Portal hypertension

Rupture is a concern (especially from vomiting)

Cirrhosis > things get backed up > vessels dilate > varices

Granular

Granulation is caused by nodules which are hepatocytes trying to regenerate and repair the liver

Scar tissue forms between the nodules

Bilirubin likes to bind to elastin fibers and there are many elastin fibers in the sclera

Hepatic encephalopathy (due to elevated ammonia)

Telangiectasia, spider nevi, purpura, palmar erythema

Fibrotic liver changes

Ascites

Hemorrhoids

Muscle wasting

Edema

Esophageal varices

Gynecomastia (The liver breaks down hormones like estrogen so when the liver is not worked, estrogen is not broken down and results in gynecomastia)

Splenomegaly (Spleen becomes large because is is congested; the spleen can also become hyperactive)

Caput medusa

Testicular atrophy

Fetor hepaticus

Spleen is overactive

Macrophages eat RBC (Anemia)

The spleen gets congested and platelets get stuck (thrombocytopenia)

Thrombocytopenia leads to bleeding

WBC also get stuck (Leukopenia)

Ascites

Enlarged vessels (caput medusae, hemorrhoids, esophageal varices)

Ammonia can't be broken down to urea which results in increased ammonia which causes hepatic encephalopathy

Hepatic encephalopathy causes an altered mental status

Glucose > hypoglycemic events

Proteins > Hypoalbuminemia (ascites) and/or decreased coagulation factors (bleeding)

Lipoprotein and cholesterol > Decreased cholesterol

Bile salts > Impaired fat absorption > deficiency of fat-soluble vitamins and fatty stools

Amino acids > Impaired conversion of ammonia to urea > encephalopathy

Steroid hormones > Increased aldosterone (Edema/ascites) and/or increased androgens/estrogens (gynecomastia and testicular atrophy in men and menstrual irregularities in women)

Drugs > Drug interactions and toxicities

Bilirubin > Hyperbilirubinemia > jaundice

Aldosterone is a hormone made in the adrenal glands which causes your body to hold onto salt and water (causes swelling)

No