Download Pathology Test 2 Review

Pathology Test 2 Review
Pathology Chapter 6 Review: Neoplasia
1. Terminology
Knudson’s Two Hit Hypothesis: Both alleles of a tumor suppressor gene must be mutated for
loss of inhibitory function. A classic example of this is Retinoblastoma protein (RB) where
both of the normal alleles of the RB locus must be inactivated (two hits) for the development of
retinoblastoma.
Neoplasia: It literally means “new growth”. It is a loss of responsiveness to normal growth
controls.
Tumor: Swelling and often used to mean neoplasm. All tumors, benign and malignant, have
two basic components: Parenchyma (made up of neoplastic cells) and non-neoplastic stroma
(the connective tissue and blood vessels which supports it)
Oncology: The study of tumors
Benign Tumor: A localized mass that does not spread to other sites, grows slowly, and is
amenable to local surgical removal. Benign neoplasms are composed of well-differentiated
cells that closely resemble their normal counterparts. Mitoses are extremely scant in number
and are of normal configuration.
Malignant Tumor:
o Collectively referred to as cancers
o In terms of a neoplasm, it implies that the lesion can invade and destroy adjacent
structures and spread to distant sites (metastasis) and potentially causing death
Cancer:
o The book basically says that cancer is a malignant tumor (so see above )
Metastasis:
o Connotes the development of secondary implants (metastases) discontinuous with the
primary tumor, possibly in remote tissues
o The properties of invasiveness and, even more so, metastasis more unequivocally
identify a neoplasm as malignant than any of the other attributes
Adenoma:
o Benign epithelial neoplasms producing gland patterns and to neoplasms derived from
glands but not necessarily exhibiting gland patterns
Chondroma:
o A benign cartilaginous tumor
Papilloma- benign, epithelial neoplasms, growing on any surface that produce microscopic or
macroscopic finger-like fronds. (See fig. 6-1)
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Fibroma- a benign tumor arising in fibrous tissue.
Polyp- a mass that projects above a mucosal surface to form a macroscopically visible
structure. Generally used to describe benign tumors but sometimes used with malignant
tumors. Especially in the colon, the term is applied to non-neoplastic growths that form
polypoid masses.
Sarcoma- malignant neoplasm arising in mesenchymal tissues. It is designated by its
histogenesis. Ex. fibrosarcoma, chondrosarcoma
Carcinoma- malignant neoplasm derived from epithelial tissue. Ex. squamous cell
carcinoma. SN: Epithelia can be derived from all 3 germ layers so mesoderm can give rise to
both carcinomas (epithelial) and sarcomas (mesenchymal).
Adenocarcinoma: a subdivision of carcinoma; denotes a lesion in which the neoplastic
epithelium cells begin to grow in gland patterns (not new glands)
Differentiation: refers to the extent to which parenchymal cells resemble their normal
forebears both in morphology and function.
Teratoma: contains recognizable mature or immature cells or tissues representative of
more than one germ-cell layer and sometimes all 3; originates from
totipotential cells such as those present in the ovary/testis; have the capacity
to differentiate into any of the cell types found in the adult body (why it is
possible to see bone, epithelial, muscle, teeth, etc strange places;
A well differentiated teratoma is BENIGN
A less well differentiated teratoma is MALIGNANT
Mesothelioma: rare neoplasm of mesothelial cells, usually arising in the parietal
or visceral pleura (although can also occur in the peritoneum and
pericardium)-related to occupational exposure to asbestos in the air
Leiomyoma: benign tumor found in areas of smooth muscle; often associated with the
myometrium of the uterine wall
Rhabdomyosarcoma – a malignant mesenchymal neoplasm that exhibits skeletal muscle
differentiation. Has peak incidence in first decade of life and is the most common form of soft
tissue sarcoma in the pediatric patient.
Osteogenic sarcoma (Osteosarcoma) – malignant mesenchymal neoplasm in which the
neoplastic cells produce osteiod. Excluding multiple myeloma osteosarcoma is most common
primary malignant tumor of bone. Two types:
Primary forms: arise de novo. These conventional osteosarcomas occur most often in
the second decade of life and the most common site of origin is around the knee, the
distal femur, and the tibia.
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Secondary forms: usually arise as a complication of a known underlying process, like
Paget disease of bone or a history of radiation exposure.
Melanoma – a malignant tumor of melanocytes or the nevus-type cells. Tend to occur on sunexposed skin, although other less common sites include: the oral and anogenital mucosal
surfaces, the esophagus, the meninges, and the eye.
Seminoma – a malignant testicular tumor arising from the germ cell lines. Approximately 5%
of the time they arise from Sertoli or Leydig cells (although rarely) and these rare types are
benign.
Hamartoma – an excessive but focal overgrowth of cells and tissues native to the organ in
which it occurs. The cellular elements are mature and identical to those found in the remainder
of the organ, but they do not reproduce the normal architecture of the surrounding tissues. Ex/
may see mass of mature but disorganized hepatic cells, blood vessels, and bile ducts in the
liver.
Lymphoma: malignant lymphocytic neoplasm
Choristoma: a heterotopic rest of cells left behind as embryonic structures form; a congenital
anomaly; not a true neoplasm; for example, a small nodule of well-developed and normally
organized pancreatic substance may be found in the submucosa of the stomach, duodenum, or
small intestine. This heterotopic rest may be replete with islets of Langerhans and exocrine
glands.
Anaplasia: lack of differentiation; a hallmark of malignancy
Pleomorphism: variation in cell shape and size; signals malignancy
Dysplasia: disorderly, but non-neoplastic proliferation; loss in the uniformity of individual
cells and a loss in their architectural orientation; in dysplastic stratified squamous epithelium,
mitoses are not confines to the basal layers, where they normally occur, but may appear at all
levels and even in surface cells; dysplasias do not necessarily progress to cancer
Encapsulation—the coating or engulfing of particles within a continuous matrix
Oncogenes—mutated forms of proto-oncogenes (DNA), which no longer effectively
regulate cell replication, and promote autonomous cell growth in cancer cells; they have the
ability to promote cell growth in the absence of normal growth-promoting signals
Proto-oncogenes—genes which encode products that regulate cell division (growth
factors and growth factor receptors, nuclear regulatory proteins, etc.)
Oncoproteins—products of oncogenes which resemble the normal products of protooncogenes except that oncoproteins are devoid of important regulatory elements,
and their production in the transformed cell does not depend on growth factors or other external
signals
Promoters—non-carcinogenic chemicals that augment the actions of chemical
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carcinogens (however, many carcinogens do not require the actions of promoters)
Carcinogen - an agent or substance that causes cancer. There are three classes of carcinogenic
agents: chemicals, radiant energy, and oncogenic viruses. They can also be classified as
direct-acting (requiring no metabolic conversion to become carcinogenic) or indirect-acting
(require metabolic conversion before they become active).
Translocation – transfer of a part of one chromosome to another chromosome. The process is
usually reciprocal (i.e. fragments are exchanged between two chromosomes).
Philadelphia chromosome – translocation that causes genetic damage, characteristic of
chronic myeloid leukemia. A reciprocal translocation between chromosomes 9 and 22
relocates a truncated portion of the protooncogene c-abl (from chromosome 9) to the
breakpoint cluster (bcr) locus on chromosome 22. The hybrid c-abl-bcr gene encodes a
chimeric protein that, like several other oncoproteins, has potent tyrosine kinase activity.
Suppressor gene – also known as antioncogenes, these encode proteins that inhibit cell
proliferation. These are the genes related to Knudsen’s two-hit hypothesis (which is defined
earlier).
Paraneoplastic syndrome – a symptom complex other than cachexia (a general wasting away,
weakness, and anemia that is seen in cancer patients) that appears in patients with cancer and
that cannot be readily explained either by the local or distant spread of the tumor or by the
elaboration of hormones indigenous to the tissue of origin of the tumor.
2. Describe characteristics of benign vs. malignant neoplasmas (p. 168-174, Table 6.2)
Benign
Differentiation and
Anaplasia (refers to
parenchymal cells)
Rate of Growth
Local Invasion
Metastasis
Well differentiated; structure
may be typical of tissue of
origin
Usually progressive and slow;
may come to a standstill or
regress; mitotic figures are rare
and normal
Usually cohesive and expansile,
well-demarcated masses that do
not invade or infiltrate the
surrounding normal tissues
Absent
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Malignant
Some lack of differentiation
with anaplasia; structure is often
atypical; anaplastic cells display
pleopmorphism, the nuclei are
hyperchromatic and large
(nuclear-cytoplasmic ratio may
be 1:1 instead of 1:4 or 1:6)
Erratic and may be slow to
rapid; mitotic figures may be
numerous and abnormal
Locally invasive, infiltrating the
surrounding normal tissues;
sometimes may seem cohesive
and expansile but with
microscopic invasion
Frequently present; the larger
and less differentiated the
primary, the more likely are
metastases
-The better the differentiation of the cell, the more completely it retains the functional
capabilities of its normal counterparts.
-The more rapidly growing and anaplastic a tumor, the less likely it is to have specialized
functional activity.
-When dysplastic changes are marked and involve the entire thickness of the epithelium, the
lesion is referred to as carcinoma in situ, a preinvasive stage of cancer.
-The rate of growth of malignant tumors correlates with their level of differentiation.
-Most cancers take years to develop; very few, if any, develop suddenly (days to months).
-Rapidly growing malignant tumors often contain central areas of ischemic necrosis because
the tumor blood supply, derived from the host, fails to keep pace with the oxygen needs of the
expanding mass of cells.
-Some benign neoplasms have a fibrous capsule surrounding them but not all do. This capsule
involves the stroma when present.
-Next to the development of metastases, local invasiveness is the most reliable feature that
distinguishes malignant from benign tumors.
-Approximately 30% of new patients with solid tumors present with clinically evident
metastases. Another 20% have occult metastases at the time of diagnosis.
-In general, the more anaplastic and the larger the primary neoplasm, the more likely is
metastatic spread
-Cancers grow by progressive infiltration, invasion, destruction, and penetration of the
surrounding tissue
3. Describe the 3 pathways for metastatic spread of cancer (p. 172)
1. Seeding
-Neoplasms invade a natural body cavity
-Characteristic of cancers of the ovary, which often cover the peritoneal surfaces
-Can glaze all peritoneal surfaces yet not invade the underlying parenchyma
2. Lymphatic spread
-more typical of carcinomas
-may traverse all of the lymph nodes ultimately to reach the vascular compartment via
the thoracic duct
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-the necrotic products of the neoplasm and tumor antigens often evoke reactive changes
in the nodes, such as enlargement and hyperplasia of the follicles (lymphadenitis) and
proliferation of macrophages in the subcapsular sinuses (sinus histiocytosis)
3. Hematogenous spread
-more typical of sarcomas
-most feared consequence of a cancer
-arteries are penetrated less readily than veins
-liver and lungs are the most frequent secondary sites of hematogenous dissemination.
-Renal cell carcinoma often invades the renal vein up to the inferior vena cava reaching
the right side of the heart
-prostatic carcinoma preferentially spreads to bone
-bronchogenic carcinomas involve the adrenals and brain
-neuroblastomas spread to the liver and bones
-skeletal muscles are rarely the site of secondary deposits
4. Neoplasia Epidemiology (p. 174-178, Figure 6-13, 6-14)
A. Describe the most common cancers and cancer deaths in men and women.
 Top 3 cancers for men: Prostate (30%), Lung and bronchus (14%), and Colon and rectum
(11%)
 Top 3 cancers for women: Breast (31%), Lung and bronchus and colon and rectum (each 12%)
 Top 3 cancer deaths for men: Lung and Bronchus (31%), Prostate (11%), and Colon and
rectum (10%)
 Top 3 cancer deaths for women: Lung and Bronchus (25%), Breast (15%), and Colon and
rectum (11%)
B. Discuss the relative importance of age, occupation, environment, and heredity in the
development of cancer.
Age: The frequency of cancer increases with age. Most cancer mortality occurs between the ages
55 and 75 years; the rate declines, along with the population base, after age 75. The rising
incidence with age may be attributed to the accumulation of somatic mutations associated with the
emergence of malignant neoplasms. The decline in immune competence that accompanies aging
also is a factor.
Cancer causes slightly more than 10% of all deaths among children younger than 15 years. The
major lethal cancers in children are leukemia, tumors of the CNS, lymphomas, soft tissue
sarcomas, and bone sarcomas.
Occupation: Different occupations cause one to be exposed to various harmful agents. See
question 5 and table 6-3 for a complete list.
Environment: Environmental factors are the predominant determinant of the most common
sporadic cancers. There is no paucity of environmental carcinogens. They lurk in the
environment, workplace, food, and personal practices. They can be anything from sunlight, diet,
cigarette smoking, alcohol consumption, number of sex partners, etc. Some examples of
environmental/geographic cancers: Death rates from breast cancer are about fourfold higher in
America compared with Japan. The death rate for stomach carcinoma in men and women is about
seven times higher in Japan than in the United States.
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Heredity: Heredity forms of cancer can be divided into 3 categories which include the following:
Inherited Cancer Syndromes (autosomal dominant), Familial cancers, and Autosomal Recessive
Syndromes of Defective DNA Repair.
 Examples of Inherited Cancer Syndromes: Familial retinoblastoma, familial adenomatous
polyposis, multiple endocrine neoplasia, neurofibromatosis types 1 and 2, von Hippel-Lindau
syndrome
 Examples of Familial Cancers: Breast cancer, ovarian cancer, colon cancers
 Examples of Autosomal Recessive Syndromes of Defective DNA repair: Xeroderma
pigmentosom, ataxia telangiectasia, bloom syndrome, and fanconi anemia.
5. Discuss the role of occupation in development of specific types of cancer such as asbestosinduced (mesothelioma). Table 6-3.
Asbestos:
Human Cancer Site for Which Reasonable Evidence is Available: Lung, mesothelioma:
gastrointestinal tract (esophagus, stomach, large intestine).
Typical Use of Occurrence: Byproduct of metal smelting. Component of alloys, electrical and
semiconductor devices, medications and herbicides, fungicides, and animal dips.
See table 6-3 on page 176 for a complete list of every agent.
6. Understand genetic conditions that predispose to specific types of cancers. (Table 6-4)
Hereditary forms of cancer can be divided into 3 categories:
1. Inherited Cancer Syndromes (Autosomal Dominant)
-Occurs when inheritance of a single mutant gene greatly increases the risk of a
person developing a tumor. The best example of this is childhood
retinoblastoma (40% are familial).
-Carriers of this gene also have an increased risk of developing a secondary
cancer, usually osteogenic sarcoma. A cancer suppressor gene has been
implicated in the pathogenesis of this type.
-There may be multiple benign tumors in the affected tissue; sometimes, there
are abnormalities in non-targeted tissue (café-au-lait spots (available at Lucy’s)
in neurofibratosis)
2. Familial Cancers:
-Features that characterize this type include early onset age, tumors arising in 2
or more close relatives of the index case, and sometimes multiple or bilateral
tumors.
-Not associated with specific marker phenotypes, e.g. familial colonic cancers
do not arise in preexisting benign polyps.
-Transmission pattern isn’t clear, although certain familial cancers can linked to
the inheritance of mutant genes (e.g. ovarian and breast cancer).
3. Autosomal Recessive Syndromes of Defective DNA Repair:
-One of the best studied examples is xeroderma pigmentosum, in which DNA
repair is defective.
**In summary, no more than 5-10% of all human cancers fall into one of the 3 previous
categories.
7. Describe 6 preneoplastic disorders that may lead to development of cancer (p.177-178)
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-Certain clinical conditions are well-recognized predispositions to malignant neoplasia
and are called “preneoplastic disorders”.
1. Persistent regenerative cell replication (e.g. squamous cell carcinoma in the
margins of a chronic skin fistula or a long-unhealed skin wound; hepatocellular
carcinoma in cirrhosis of the liver)
2. Hyperplastic and dysplastic proliferations (e.g. endometrial carcinoma in
atypical endometrial hyperplasia; bronchogenic carcinoma in the dysplastic
bronchial mucosa of habitual cigarette smokers)
3. Chronic atrophic gastritis (e.g. gastric carcinoma in pernicious anemia)
4. Chronic ulcerative colitis (e.g. an increased incidence of colorectal carcinoma
in long-standing disease)
5. Leukoplakia of the oral cavity, vulva or penis (e.g. increased risk of
sqaumous cell carcinoma)
6. Villous adenomas of the colon (e.g. high risk of transformation to colorectal
carcinoma
**Are benign tumors cancerous? In general, NO. But it is better to say that
each type of benign tumor is associated with a particular level of risk, from
nonexistent to high. E.G. Adenomas of the colon can undergo malignant
transformation 50% of the time, contrasted with the extremely rare malignant
change of leiomyomas of the uterus.
8. What cancers are associated with smoking? Why does smoking cause cancer?
 LUNG CANCER
a. Smoking causes progressive alterations in the lining epithelium of the respiratory
tract. Changes begin with a rather innocuous basal cell hyperplasia and squamous
metaplasia and progress to squamous dysplasia and carcinoma in situ, before
culminating in invasive cancer.
b. 90% of lung cancers occur in active smokers or those who stopped recently
 RENAL CELL CARCINOMA
 BLADDER TUMORS
 ORAL CANCER
 CARCINOMA OF THE LARYNX
 ESOPHAGEAL CARCINOMA
 CARCINOMA OF THE PANCREAS
 VULVAR CARCINOMA
9. Carcinogenesis: The molecular basis for cancer. (see fig 6-16 pg.179)
 Non-lethal genetic damage lies at the heart of carcinogenesis
a. Mutation acquired by
i. Environmental agents: chemicals, radiation, viruses
ii. Inheritance through the germ line: a tumor mass results from the clonal
expansion of a single progenitor cell that has incurred genetic damage (i.e.,
tumors are monoclonal)
 Three classes of normal regulatory genes are the principal targets of genetic damage. They
are:
a. Growth-promoting protooncogenes
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i. Mutant alleles of protooncogenes are called oncogenes. They are considered
dominant because they transform cells despite the presence of their normal
counterpart.
b. Growth-inhibiting cancer suppressor genes
i. Both normal alleles of these tumor suppressor genes must be damaged for
transformation to occur (recessive oncogenes)
c. Genes that regulate apoptosis
i. May be dominant or recessive
 DNA repair genes are important in carcinogenesis.
a. They affect cell proliferation or survival indirectly by influencing the ability of the
organism to repair non-lethal damage in other genes, including protooncogenes,
tumor suppressor genes, and genes that regulate apoptosis.
b. A disability in these genes can predispose to wide-spread mutations in the genome
and to neoplastic transformation.
 Carcinogenesis is a multi-step process at both the phenotypic and genetic levels. (tumor
progression)
10. Describe how chemicals and radiation cause cancer.
Chemicals
- Extremely diverse structure, including natural and synthetic products
- Can be direct acting that require no chemical transformation and are usually weak carcinogens;
or procarcinogens, that act indirectly by being activated by promoters that augment their
carcinogenicity and turn them into the active unlimate carcinogens.
- Promoters by themselves have little, if any, transforming power
- All direct-reacting and ultimate chemical carcinogens are highly reactive electrophiles that
react with electron rich atoms in RNA, cellular proteins, and mainly DNA
- Chemical carcinogens usually target the RAS gene as well as the TP53 tumor suppressor genes.
Radiation
- Ionizing radiation can cause chromosome breakage, translocations, and less frequently point
mutations. The most important cause for carcinogenesis is the breakage of double stranded
DNA.
- The latent period of radiation-associated cancers is very long and the cancer emerges only after
the progeny of initially damaged cells accumulate additional mutations.
- Ex/ natural UV radiation derived from the sun can cause skin cancers, because UV light can
damage DNA by formation of pyrimidine dimmers. The DNA is usually repaired by a set of
proteins that effect nucleotide excision repair. With extensive UV exposure the protein repair
may be overwhelmed and skin cancers form.
11. Describe 5 types of cancer that have been related to infections and the proposed mechanisms by
which this occurs.
1. Human T-Cell Leukemia Virus Type 1 (HTLV-1)
- only known human RNA retrovirus associated with cancer
- Similar to AIDS, the HTLV-1 targets CD4+ T cells for neoplastic transformation
- stimulates the production of T cells by the TAX gene that encodes IL-2 and its receptor,
thereby setting up an autocrine system for proliferation
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- At the same time a paracrine pathway increases production of GM-CSF that acts to increase
the secretion of other T-cell mitogens, like IL-1.
- Along with these growth-promoting activities, there is also the inhibition of growthsuppressive pathways.
- human infection requires transmission of infected T-cells via sexual intercourse, blood
products or breast feeding
2. Human Papillomavirus (HPV)
- Definitely cause benign squamous papillomas (warts) and also can cause the genesis of
several cancers such as squamous cell carcinoma of the cervix and anal, perianal, vulvar, and
penile cancers.
- Oncogenic potential of HPV is related to products of two early viral genes, E6 and E7.
Together they act to simulate the loss of tumor suppressor genes, activate cyclins, inhibit
apoptosis, and combat cellular senescence.
- Infection of HPV alone is not sufficient for carcinogenesis. Cotransfection with mutated RAS
gene leads to full malignant transformation.
3. Epstein-Barr Virus (EBV)
- implicated in pathogenesis of Burkitt lymphoma, post-transplant lymphoproliferative disease,
primary central nervous system lymphoma in AIDS patients, a subset of other AIDS related
lymphomas, subset of Hodgkin lymphoma, and nasophyrngeal carcinoma
- all are B-cell tumors, except for nasopharyngeal carcinoma
- molecular basis by EBV-encoded gene LMP-1 acting as oncogene to promote B-cell
proliferation by activating signaling pathways that mimic B-cell activation by B-cell surface
molecule CD40.
4. Hepatitis B Virus (HBV)
- Strong evidence linking HBV infection with hepatocellular carcinoma (liver cancer), but
mode of tumor production is not fully known
- oncogenic effect seems to be multifactorial : 1) Causes chronic liver cell injury, followed by
regeneration that predisposes the cells to mutations, 2) HBV encoded regulatory element HBx
disrupts normal liver growth of infected liver by transcriptional activation of several growth
controlling genes, 3) cytosolic signal transduction pathways are turned on (ex/ RAS-MAP
kinases), 4) viral integration seems to cause secondary rearrangements of chromosomes,
including multiple deletions that may include tumor suppressor genes.
5. Human Herpesvirus 8 (HHV8)
- associated with rare group of tumors present as malignant effusions
- tumor cells infected with HHV-8 that encodes proteins homologous to several oncoproteins,
ex/ cyclin D1
- patients with these primary effusion lymphomas are usually immunosuppressed
12. Explain why persons with various types of immunodeficiency diseases are especially prone to
develop neoplasia. (p. 201-205)
Many factors in our immune systems have anti-tumor effects…
--Cytotoxic T-cells (CD8+) have been shown to provide a specific sensitivity
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toward some tumors, especially virus-associated tumors (ie. EBV-induced Burkitt lymphoma
and HPV-induced tumors). They recognized peptide antigens that are on the cell surface
latched into an MHC protein (MHC 1).
--Natural Killer (NK) cells are able to destroy tumor cells without prior
sensitization and they are possibly our first line of defense against tumors. Work
complementary to T-cells, but CD8+ T-cells cannot recognize tumors unless they show MHC 1
proteins, however, the NK cells can.
--Macrophages show selective cytotoxicity to tumor cells, and are activated by Tcells and NK cells (through their secretion of INF-gamma). They kill cells by the same way
they kill normal microbes (secretion of oxygen metabolites) or they can secrete tumor necrosis
factor (lyses many tumor cells).
--Humoral mechanisms function in two ways: (1) activation of complement, and (2) induction
of Ab-dependent cellular toxicity by NK cells
I believe what Dr. Waites is looking for in this question is that you have an idea of
how our immune system kills/reacts to tumors. Obviously if any of these mechanisms is
missing, the immune response is not near as strong. Another point worth noting is that
individuals with immunodeficiencies have a much higher rate of developing cancer (sometimes
up to 200x the average rate), and most of these cancers in immunocompromised individuals is
in the form of lymphomas.
13. Describe 4 ways cancers evade the immune system. (p. 204)
(1) Selective outgrowth of antigenic variants. During tumor progression, strongly
immunogenic subclones may be eliminated.
(2) Loss or reduced expression of histocompatibility antigens. Tumor cells can
hide MHC 1 molec…the result, CD8+ T-cells can’t find them. But remember that the NK cells
still can!
(3) Lack of co-stimulation. If the tumor cell does show the MHC 1 molec., it
might not have a co-stimulatory signal, which is the supplemental requirement for a T-cell to be
activated. When a T-cell recognizes an MHC 1 but has no co-stim. signal, it can render the Tcell anergic (no more function) or cause it to go through apoptosis.
(4) Immunosuppression. Many oncogenic agents (chemicals and ionizing
radiation) suppress immune responses. Also tumors and their products may be
immunosuppressive, see examples below:
--Transforming Growth Factor (TGF-beta) is very immunosuppressive
--Tumors can express Fas ligand (??? don’t know what it is) but it binds to
Fas on T-cells and this is a death signal for T-cells
14. Explain the term “paraneoplastic syndrome”, discuss its significance. (p.205-209)
These syndromes appear in 10% to 15% of patients with cancer. They are very important
because they may represent the earliest manifestation of a neoplasm, they may represent
significant clinical problems (some fatal), and they may also confuse treatment due to their
mimicking of metastatic diseases. Examples of common syndromes include hypercalcemia,
Cushing’s syndrome, and nonbacterial thrombotic endocarditis.
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15. Explain the pathogenesis of the “wasting syndrome” that occurs in persons with cancer. (p.205)
This “wasting syndrome” is referred to as cachexia and involves a progressive loss of body fat
and lean body mass, accompanied by profound weakness, anorexia, and anemia. The cause of
the cachexia is multifactorial and not completely understood. For example; anorexia is a
common problem in cancer patients, even those who do not have tumors of the GI tract. The
reduced food intake has been related to abnormalities in taste and in the central control of
appetite. Also TNF-a and IL-1 which are released from macrophages has been suspected of
being involved in suppression of appetite. Because of this wasting away, the body eventually
develops infection.
16.
Distinguish tumor grade and stage and how they relate to prognosis
o Methods to quantify the probable clinical aggressiveness of a given neoplasm and to
express its apparent extent and spread in the individual patient are necessary for
comparisons of end results of various forms of treatment
o Note: when compared to grading, staging is more important for prognosis clinically
a. Tumor Grade
 Grading of a cancer attempts to establish some estimate of its aggressiveness
or level of malignancy based on the cytologic differentiation of tumor cells
and the number of mitoses within the tumor
 May be classified as grade I, II, III, or IV, in order of increasing anaplasia
~ i.e. (1) is well differentiated and (4) is poorly differentiated
 Criteria for the individual grades vary with each form of neoplasia
b. Tumor Stage
 Staging of cancers is based on the size of the primary lesion, its extent of
spread to regional lymph nodes, and the presence or absence of metastases
 Two methods of staging:
~ TNM system {Tumor size (T1, T2, T3, T4), extent of spread to
regional Lymph Nodes (N0, N1, N2), and the absence or presence of
distant Metastases (M0, M1)}
~ AJC (American Joint Committee) system where cancers are divided
into stages 0-IV, incorporating the size of primary lesions and the
presence of nodal spread and of distant metastases.
17.
Explain how the following procedures are used in cancer diagnosis
a. Frozen Section
 the sample is quick frozen and sectioned, permitting histological evaluation
within minutes
 useful for determining the nature of a breast lesion or in evaluating the
margins of an excised cancer during surgery to see if the entire neoplasm has
been removed
b. Immunohistochemistry
 Powerful adjunct to routine histology
 Detection of cytokeratin by specific monoclonal antibodies labeled with
peroxidase points to a diagnosis of undifferentiated carcinoma rather than
large cell lymphoma
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c. Fine Needle Aspiration
 Aspiration of cells from a mass, followed by cytologic exam of the smear
 Commonly used with readily palpable lesions affecting the breast, thyroid,
lymph nodes, and salivary glands
d. Cytology ~ Papanicolaou Smear
 Used widely for the discovery of carcinoma of the cervix, often at an in situ
stage, but also used with endometrial carcinoma, bronchogenic carcinoma,
bladder and prostate tumors, and gastric carcinomas
 Neoplastic cells are less cohesive than others, and are shed into fluids and
secretions ; the shed cells are evaluated for features of anaplasia indicative of
their origin in cancer
e. Flow Cytometry
 Used routinely in the classification leukemias and lymphomas
 Fluorescent antibodies against cell surface molecules and differentiation
antigens are employed to obtain the phenotype of malignant cells
 Also useful in assessing DNA content (ploidy) of tumor cells
f. Tumor Markers ~ CEA, PSA
 Biochemical assays for tumor associated enzymes, hormones, and other tumor
markers in the blood cannot be construed as modalities for the diagnosis of
cancer, but can contribute to finding cases (screening) and in some instances
are useful in determining the effectiveness of therapy
 PSA
o prostatic carcinoma can be suspected with elevated blood levels
o PSA levels may also be elevated in benign prostatic hyperplasia
o Elevations in PSA are not diagnostic of an underlying cancer
 CEA
o Radioimmunoassay for circulating hormones may point to the presence
of tumors in the endocrine system
o CEA, normally produced in the embryonic tissue of the gut, pancreas,
and liver, is a complex glycoprotein that is elaborated by many
different neoplasm
o The level of elevation is correlated with the body burden of tumor so
that the highest levels are found in patients with advanced metastatic
disease
o CEA elevations have been reported in may benign disorders, thus CEA
assays lack specificity and sensitivity required for the detection of
early cancers
o Most useful in providing presumptive evidence of the possibility of
colorectal carcinoma because this tumor yields the highest levels and is
useful in the detection of recurrences after excision
g. Molecular Profiling
 DNA microarray analysis allows simultaneous measurements of the
expression levels of several thousand genes
 Process begins by extraction of mRNA from any two sources (ex. normal and
malignant, normal and preneoplastic, or of the same histological type) and
cDNA copies of the mRNA are synthesized in vitro with fluorescently labeled
nucleotides
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

For each sample, the expression level of thousands of genes is obtained, and
by using bioinformatics tools, the relative levels of gene expression in
different samples can be compared
Basically, a molecular profile is generated for each tissue analyzed
Chapter 9: Infectious Diseases
9.A. Laboratory Cases
1. Students should be familiar with all of the cases in the laboratory case studies for bacterial
diseases, viral diseases, fungal diseases, and parasitic diseases. This means understanding the
disease illustrated by each case, the microorganism causing it, and the characteristic
pathological findings as shown in the gross and microscopic illustrations.
Bacterial Diseases
1. Disease: Rocky Mountain Spotted Fever:
Microorganism: Rickettsia rickettsii
Disease pathology:
a. symptoms: headache, fever, morbilloform rash, and petechia: An eschar develops at the site
of the tick bite followed by a hemorrhagic rash that extends over the entire body, including the
palms of the hands and soles of the feet. The vascular lesions that underlie the rash often lead to
acute necrosis, fibrin extravasations, and thrombosis of the small blood vessels, including
arterioles. In severe RMSF, foci of necrotic skin can form on the fingers, toes, elbows, ears, and
scrotum.
b. transmission: rodent and dog tick bites
Characteristics:
a. gross: morbilloform rash and petechia
b. microscopic: hemorrhage in dermis, also a cellularity and thrombosis of small vessels in the
dermis, small vessels in dermis will display vasculitis (both mild and severe)
2. Disease: Bacterial Meningitis
Microorganism: This case is a Pseudomonas case (due to burn). Most common causes:
a. in neonates: the organisms include Escherichia coli and the group B streptococci;
b. in infants and children: S. pneumoniae and N. meningitidis pervade in immunized
children (H. influenzae type b (Hib) vaccine is routine in the U.S.), while Haemophilus
influenzae is more prominent in non-immunized children;
c. in adolescents and in young adults: Neisseria meningitidis;
d. in the elderly: Streptococcus pneumoniae and Listeria.
Disease pathology: This case: due to infection after 3rd degree burns: severe respiratory distress
and comatose, meninges containing thick, yellow, purulent exudate
Characteristics:
a. Gross: purulent exudates in meninges in brain
b. Microscopic: purulent exudates in meninges, congestion of vessels in the meninges with
inflammatory exudates with the vessels surrounded by neutrophils and the gram-negative
bacteria throughout the exudates. Also, microscopic images will show brain edema and
extravasations of fibrin.
3. Disease: Diphtheria
Microorganism: Corynebacterium diphtheriae
Disease:
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a. symptoms: upper respiratory infections, difficulty breathing, sore throat, membranous
exudates over tonsils, and even respiratory tract obstruction, maybe even pneumonia
b. transmission: This organism is passed from person to person by aerosols or by skin
shedding. It has one toxin that is encoded by a phage, so the phage must enter and give its
DNA for the toxin to work. The toxin is composed of fragment B that attaches to host cells
and fragment A which is linked to fragment B by a disulfide bridge. Bound diphtheria toxin
enters the acidic endosome of cells, fuses with the endosomal membrane, and then enters
the cell cytoplasm. There the disulfide bond of the toxin is broken, releasing the
enzymatically active fragment A which then catalyzes the covalent transfer of adenosine
diphosphate ribose (ADPR) from nicotinamide-adenine dinucleotide (NAD) to EF-2. EF-2,
a ribosomal elongation factor necessary for protein synthesis, is thus inactivated. One
molecule of diphtheria toxin can kill a cell by ADP-ribosylating more than a million EF-2
molecules.
Characteristics:
a. gross: membranous exudates (dense, grayish pink membrane) over tonsils to mid-trachea,
edematous lungs
b. microscopic: diphtheritic membrane over trachea, ulceration of the tracheal membranous
surface, with the only epithelial cells remaining on the glands. The diphtheritic membrane
consists of fibrin and inflammatory cells, most of which are dead. Most of the cells in the
inflammatory exudate are neutrophils.
4. Disease: Acute Rheumatic Myocarditis
Microorganism: Rheumatic fever is an acute, often recurrent, inflammatory disease that
principally affects children following a pharyngeal (but not skin) infection with group A betahemolytic streptococci. Evidence strongly suggests that rheumatic fever is the result of an
immune response to streptococcal antigens inciting either a cross-reaction to tissue antigens
or a streptococcal-induced autoimmune reaction to normal tissue antigens.
Disease Pathology: Acute rheumatic fever previously, mitral insufficiency and stenosis,
upper respiratory infection, acute migratory arthritis, rapid deterioration of cardiac function,
and death
Characteristics:
a. gross: enlarged heart, especially left atria, both aortic and mitral valves fibrosis, and fresh,
tiny verrucae characteristic of acute rheumatic fever. There is a thickening and fibrosis of
the valve leaflet. There are also numerous foci of fibrinoid necrosis within the cusps and
friable vegetations (verrucae) along the lines of closure (arrows). These irregular, warty
projections are found at sites of erosion on the inflamed endocardial surface. The verrucae
probably result from the precipitation of fibrin where the leaflets impinge on each other.
b. microscopic: The myocardium shows cellular accumulations called Aschoff bodies within
the interstitium of the myocardium. These are found especially around blood vessels.
Aschoff bodies are foci of fibrinoid necrosis surrounded by lymphocytes, macrophages, an
occasional plasma cell, and plump “activated” histiocytes called Anitschkow cells or
Aschoff cells (arrows). These distinctive cells have abundant amphophilic cytoplasm and
central round-to-ovoid nuclei in which the chromatin is disposed in a central, slender, wavy
ribbon resembling a caterpillar (hence the designation “caterpillar cells”). There are also
multinucleated Aschoff giant cells.
5. Disease: Clostridial Myonecrosis
Microorganism: Clostridium perfringens invades traumatic or surgical wounds and causes
an anaerobic cellulitis or myonecrosis (gas gangrene). Clostridium species are gram-positive
bacilli that grow under anaerobic conditions and produce spores which are frequently present
in the soil.
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Disease Pathology: chills and fever after a surgical wound (in this case passing a kidney
stone), redness and crepitance in extremities (legs), high white blood cell count and a low
packed red blood cell count, vomiting, aspiration of vomit, and death
Characteristics:
a. gross: swelling and hemorrhagic blebs in the skin, which are accumulations of gas being
discharged into the tissues from the Clostridium perfringens. This gas produces crepitance.
b. Microscopic: Muscle fascicles contain large gas bubbles. The muscle cells are
hypereosinophilic and most do not contain nuclei, indicating that these cells are dead or
dying. The round clear spaces in this tissue correspond to gas accumulations prior to death.
In between the bundles of muscle cells, accumulations of small dark blue-staining bacterial
organisms can be seen. There is no inflammatory response in this tissue. In other tissue
segments, there is a mild inflammatory response and thrombosed blood vessels, as well as
an accumulation of the rod shaped organisms.
6. Disease: Actinomycosis
Microorganism: Actinomyces
Disease Pathology: persistent and progressive skin rash and weight loss, about a month
before death, draining abscesses appear in the perirectal region
Characteristics:
a. gross: large abscess around the cecum and perirectal abscesses that are extensions from the
pericecal abscesses
b. microscopic: in the retroperitoneal abscesses, they’re multiple dark-staining foci that are
Actinomyces colonies. These colonies are known as "sulfur granules" because in gross
specimens they are visible to the naked eye as yellow grains, thus resembling grains of
sulfur. At higher magnification, these abscesses show a pocket of purulent exudates that
contains numerous actinomycotic colonies.
VIRAL INFECTIONS:
Herpes Simplex Glossitis
• 3 Types of Herpes Viruses: 1)Neurotropic alpha group, including HSV-1, and HSV-2
2)Lymphotropic beta group
3)Gamma group viruses
• Glossitis is caused by HSV-1(Herpes Simplex Virus-1). Viral proteins insert into the host cell’s
plasma membrane and damages the membrane integrity.
•Characterized by ulcerative epithelium with intranuclear inclusion bodies.
Herpes Encephalitis
•HSV-1 produces encephalitis in any age group but is common in children and young adults.
•Encephalits involves inferior and medial regions of the temporal lobes and the orbital gyri of the
frontal lobes. Infection is necrotizing and often hemorrgenic with inflammatory cells and
intranuclear inclusion bodies.
•Symptoms include alterations in mood, memory, and behavior.
Rabies
•Pathogenesis is transmitted by a bit of a rabid animal. The virus enters the CNS by ascending
along the peripheral nerves.
•Symptoms include headache, fever, and paresthesias around the site of the animal bite.
Symptoms can exhibit CNS excitability progressing to convulsions causing gagging and foaming
at the mouth.
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•Again, inclusion bodies are found around neurons microscopically.
Poliomyelitis
•Is an enterovirus usually acquired from contaminated water. Can be effectively controlled by
immunization.
•Causes gastroenteritis and can invade the nervous system.
•The Polio virus causes cell death by replicating inside neurons and causing cell lysis.
•Microscopically, inflammatory cellular infiltrate and tissue breakdown and a significant loss of
neurons and myelin are seen.
Hepatitis B
•Is an enveloped icosahedron
•Clinical/Pathologic Syndromes that can occur after infection are: 1)Acute Hepatitis, 2)Chronic
nonprogressive Hepatitis, 3)Progressive chronic disease ending in cirrhosis, 4)Fulminant hepatitis
with liver necrosis, 5)and Asymptomatic carrier state with or without progressive disease.
•Microscopically, hepatocytes containing accumulations of magenta staining in cytoplasm is
seen.
FUNGAL DISEASES (5 from the labs)
1) Candidisis of Kidney – Candida colonize kidney. Candida is the only fungus which grows as
1) a yeast form, 2) pseudohyphae, and
3) true hyphae with septa.
-Candida often infects neutropenic patients.
-Candida species--especially C. albicans--are part of the normal flora of the skin, mouth, and GI
tract, and are the most frequent cause of human fungal infections. These infections vary from
superficial lesions in healthy persons to disseminated infections in neutropenic patients.
-Severe disseminated candidiasis is associated with neutropenia secondary to chronic
granulomatous disease, leukemia, anticancer therapy, or immunosuppression after
transplantation.
-Candida can be introduced into the bloodstream by intravenous lines, catheters, peritoneal
dialysis, cardiac surgery, or intravenous drug abuse.
-Candida infections can occur in the oral cavity (thrush), vagina, and in the skin--especially in
warm moist areas (i.e., between the fingers and toes and in inguinal creases, inframammary folds,
and the anogenital region).
-Candida esophagitis can occur with nasogastric tube placement.
2) Histoplasmosis of the Adrenal Gland is characterized widespread enlargement of lymph
nodes, ulcers of the intestines, and enlarged adrenal glands exhibiting multifocal granulomas.
-Histoplasma capsulatum infection is usually acquired by inhalation of dust particles from soil
contaminated with bird or bat droppings. The droppings contain small spores (microconidia).
Types of infections Histoplasma produces:
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1) A self-limited primary pulmonary involvement which may result in coin lesions on chest xray;
2) chronic, progressive, lung disease, which often localizes to the lung apices and causes cough,
fever, and night sweats;
3) localized lesions in extrapulmonary sites, including mediastinum, adrenals, liver, or meninges;
and
4) a widely disseminated involvement, particularly in immunosuppressed patients.
-Histoplasma conidia and yeasts bind to the beta-chain of the integrins receptors LFA-1
(CD11a/CD18) and MAC-1 (CD11b/CD18).
-Histoplasma yeasts are phagocytosed by the unstimulated macrophages, multiply within the
phagolysosome, and lyse the host cells.
3) Cryptococcosis may be seen as a nodular mass on a chest x-ray.
-Cryptococcus neoformans is present in the soil and in bird (particularly pigeon) droppings. The
organism infects humans when it is inhaled.
-Normal healthy people can get cryptococcal meningoencephalitis but cryptococcal infections are
more common in individuals:
(1) who receive high-dose corticosteroids and/or
(2) who have AIDS, leukemia, lymphoma, systemic lupus erythematosus,
and Hodgkin ’s disease, sarcoidosis, or transplant patients.
-Three properties of Cryptococcus neoformans are associated with virulence:
(1) the capsular polysaccharide;
(2) resistance to killing by alveolar macrophages; and
(3) production of phenoloxidase an enzyme that consumes host epinephrine in the synthesis of
fungal melanin and thus protects the fungi from the epinephrine oxidative system present in the
host nervous system.
It is thought that one reason why Cryptococcus neoformans preferentially infects the brain may
be because the CSF lacks alternative pathway complement components (present in serum) that
bind to the carbohydrate capsule and facilitate phagocytosis and killing by polymorphonuclear
cells.
4) Lung Blastomycosis caused by Blastomyces dermatitides which may be identified in stained
smears of sputum.
-Blastomyces is acquired by inhalation of infectious spores from the soil.
-In the United States, infection is usually limited to areas along the Mississippi, Ohio, and St.
Lawrence Rivers, and along the Great Lakes.
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-Increase risk of Blastomyces exposure are those exposed to dust--construction workers exposed
to dust from construction sites, hunters and outdoors people who walk in dusty areas, and farm
workers.
-The clinical manifestation of Blastomyces infection is usually a pyogranulomatous pneumonia.
However, Blastomyces can spread outside the lungs to the skin, bones, and prostate.
5) Carotid Artery Mucormycosis may be characterized by severe emphysema, severe
widespread abscessiform and necrotizing pneumonia, and bacterial (Staphylococcus aureus)
endocarditis of the pulmonic valve. The right internal carotid artery may be occluded by a
thrombus and there may be areas of necrosis (due to CVAs) in the brain.
-The spores are widespread in dust and air and can be inhaled or ingested. They are ubiquitous
contaminants colonizing the normal human skin or gut without causing illness in
immunocompetent people.
Mucor commonly causes vasculitis and thrombosis.
-The three primary sites of Mucor invasion are the nasal sinuses, lungs, and gastrointestinal tract.
-In diabetics, the fungus may spread from nasal sinuses to the orbit, and subsequently the brain,
giving rise to rhinocerebral mucormycosis.
9.B. General aspects of infectious disease pathogenesis
1. Understand how abnormalities in genetic background, anatomy and physiology,
immunocompetence, circulatory and ventilatory status, and the presence of underlying diseases
affect the host’s ability to resist infection by microorganisms. To appreciate this concept it is
also necessary to understand how all of the natural anatomic and physiologic barriers protect
the host from infection (pg. 312-314).
The natural anatomic and physiologic barriers of the human body are the first line of defense
against microorganisms in the environment that can invade and cause disease:
- the skin is the first and most important anatomic barrier. Its low pH, dryness (wet skin is more
susceptible to penetration by microorganisms), and the presence of fatty acids protect it from
penetration by infectious microorganisms
- the mouth has saliva and lysozyme that have antibacterial properties
- the GI tract is protected by its motility, the normal flora, low pH of the acid gastric juice, the
viscous mucus layer covering the gut, and the presence of enzymes
- the respiratory tract has a thick mucocilliary ladder that prevents invasion. Smaller
microorganisms tend to travel farther, and are eventually phagocytosed by alveolar macrophages
or neutrophils recruited to the lung by cytokines
- the urinary tract is protected by the numerous daily flushings, the presence of anti-adhesins, and
a low pH
- the reproductive tract has a low pH and normal protective flora (mainly in females)
- the vascular system is protected by the immune system phagocytes, and the process of
inflammation
Abnormalities can affect the host’s ability to resist infection:
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- certain genetic disorders can make patients more susceptible to specific infections. Ex/ cystic
fibrosis causes defects in the ability to clear secretions in the lungs, so these patients tend to get
recurrent pulmonary infections and permanent lung damage. Another ex/ are diabetics that have
increased blood glucose levels. Some of the excess glucose can spill over into the lungs and
create a favorable environment for urinary infection
- defects with anatomy or physiology can lead to infections. Ex/ someone with respiratory failure
will need an endotracheal tube into their lungs, which will bypass the mucocilliary ladder. It can
allow a foreign object direct access to the lungs, thereby passing natural defenses.
- immunocompromised patients sometimes lack neutrophils or functional T-cells that obviously
will increase their susceptibility to infection
- circulatory or ventilatory (discussed above) status can lead to increased infections. If a patient
does not have good blood supply than infections won’t heal easily. Ex/ diabetics have peripheral
neuropathy, where they don’t feel pain in their feet, and the nerves are damaged. Wounds occur,
and they get infected due to the lack of feeling.
- anyone with a previous underlying disease is more susceptible to infection and it makes the
infection more difficult to manage. The management of a patient with an underlying disease is
usually very different from an otherwise healthy patient that normally would not be susceptible to
the same microorganism.
2. Explain the difference between colonization and infection.
Colonization refers to a bacteria or other microorganism populating itself in a certain area
of the body without prompting an immune response or damage to the host. These “colonizing
microorganisms” are adapted usually specifically to that area, and could possibly cause infection
if it migrated to another area of the body. These microorganisms can also have beneficial effects
to the host, such as bacteria in the gut which produce Vitamin K in humans. Think of
colonization as both the body and the microorganism “tolerating” each other, or either the
microorganism keeping its population to a level low enough to “slip under the radar,” and not
cause problems. Colonization does not disrupt normal body functions.
Infection refers to a microorganism either invading or opportunistically causing damage
to the human host. Infection can be caused by strict pathogens, which come in and disrupt things
to harm the host, or by opportunistic pathogens. Opportunistic pathogens can be microorganisms
that normally colonize the body, but when the body’s normal flora (bacterial levels) and function
is disrupted, these organisms are allowed to proliferate and cause damage or other problems.
Infection does disrupt normal body functions.
3. Explain the different mechanisms that are operative in diseases caused by exogenous
infections versus endogenous infections and be able to provide and recognize examples of
diseases that fit into each of these categories.
Viruses:
-may inhibit host cell DNA,RNA, or protein synthesis i.e. poliovirus
-may insert into the host cell’s plasma membrane and damage its integrity or promote cell fusion,
i.e. HIV, measles, Herpes
-replicate efficiently and lyse host cells, i.e. rhinovirus, influenzavirus, yellow fever virus, polio,
rabies
-viral proteins on the surface of the host cells may be recognized by the immune system, and the
host lymphocytes may attack the virus-infected cells, i.e. HBV infection, respiratory syncytial
virus
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-may damage cells involved in host antimicrobial defense , leading to secondary infxns,i.e.
damage to resp. epith. leads to pneumonia, HIV leads to many other opportunistic infxns
-viral killing of cells of one type may cause damage to other cells that depend on their integrity,
i.e. poliovirus attack of motor neurons=death of distal skeletal muscle
-slow viral infxns culminate in severe, progressive disease after a long latency period, i.e.
subacute sclerosing panencephalitis by measles virus
-can cause cell proliferation and transformation resulting in cancer,i.e. EBV, HPV, HBV, HTLV-I
Bacteria:
•damage to host cell depends on ability to adhere to and enter host cells or to deliver toxins
•adhesins bind bacteria to host cells, i.e. streptococci has lipoteichoic acids and protein F, grambac. have fimbriae or pili to mediate adherence
•Legionella, M. tuberculosis, Leishmania- all bind to CR3
•E. coli-secretes protein that inserts in target cell plasma membrane and is used by bac. as an
attachment site
•Shigella- secretes proteins that reorganize the cytoskeleton of epith. cells and enclose the bac.
•Shigella and E. coli- inhibit host cell protein synth., replicate, and lyse host cells
•Salmonella and Yersinia-replicate within phagolysosomes
•Mycobacterium and Legionella- inhibit the acidification that occurs after endosome fusion
w/lysosome
•Salmonella- secretes second set of proteins via type 3 apparatus, Legionella via type 4
•Endotoxin-LPS-made of Lipid A + core sugar chain + O antigen; cause fever, septic shock,
disseminated intravascular coagulation, acute respiratory distress syndrome, and effects on the
immune system i.e. Superantigens cause fever, shock, and organ failure by binding to MHC-II on
APC’s and stimulating T cells to secrete excess IL-2/TNF
•Exotoxin-secreted proteins that directly cause cell injury and disease, i.e. lethal factor in
anthrax; diptheria toxin causes neural and myocardial disfunction; enterotoxins of V. cholerae
and E. coli generate excess cAMP causing the squirts; Clostridium perfringens digests host
tissues using its alpha toxin, which disrupts plasma membranes; Clostridium tetani secretes the
exotoxin tetanospasmin which interferes w/ release of inhibitory transmitter substances causing
tetany; Clostridium botulinum toxins block the release of cholinergic NT at neuromusc. jxns.
resulting in limb, respiratory muscle, and cranial motor nerve paralysis
SN: this may not completely answer the question, but it followed the progression in the book.
Read back in your micro notes about endo vs. exo toxins
4. Compare extracellular versus facultative intracellular bacterial pathogens and obligate
intracellular pathogens in terms of the mechanisms by which they evade the host immune system
and cause disease and be able to recognize examples of each class of pathogens.
Microorganisms escape the immune system by (1) remaining inaccessible; (2) cleaving antibody,
resisting complement-mediated lysis, or surviving in phagocytotic cells; (3) varying or shedding
antigens; and (4) causing specific or nonspecific immuno-suppression.
The following microorganisms escape the immune system by remaining inaccessible.
Microbes that propagate in the lumen of the intestine (e.g., toxin-producing Clostridium difficle)
or gallbladder (e.g., S. typhi) are inaccessible to the host immune defenses including secretory
IgA. Viruses shed from the luminal surface of epithelial cells (e.g., CMV in urine or milk and
poliovirus in stool) or those that infect the keratinized epithelium (poxviruses that cause
molluscum contagiosum) are also inaccessible to the host humoral immune system. Some
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organisms establish infections by rapidly invading host cells before the humoral response
becomes effective (e.g., malaria sporozites enter liver cells). Also, some larger parasites (e.g.,
larvae of tapeworms) form cysts in host tissues that are covered by a dense fibrous capsule that
walls them off from host immune responses.
The carbohydrate capsule on the surface of all major pathogens that cause pneumonia or
meningitis (Strep. pneumoniae, N. meningitis, Haemophilus influenza, Klebsiella, and E. coli)
makes them more virulent by covering bacterial antigens and preventing phagocytosis of the
organisms by neutrophils. Pseudomonas bacteria secrete leukotoxin that kills neutrophils. Some
E. coli have K antigens that prevent activation of complement b the alternative pathway and lysis
of the cells. Some gram-negative bacteria, have very long polysaccharide O antigens that bind to
host antibody and activate complement at such a distance from bacterial cells that the organisms
fail to lyse. Staphylococci are covered with protein A molecules that bind the Fc portion of the
antibody and so inhibit phagocytosis.
Viral infection evokes neutralizing antibodies, which prevent viral attachment, penetration, or
uncoating. This highly specific immunity is the basis of antiviral vaccination, but it cannot
protect against viruses with many antigenic variants (e.g., rhinoviruses or influenzaviruses).
Pneumococci are capable of more than 80 permutations of their capsules, so that in repeated
infections the host is unlikely to recognize the new serotype. One species of Neisseria can take
up DNA from another species and is able to change its repetoir of attachment proteins in the
absence of mutation. The spirochete Borrelia recurrentis causes a relapsing fever by repeatedly
switching its surface antigens before the host exterminates each successive clone.
Finally, viruses that infect lymphocytes (HIV and EBV) directly damage the host immune
system and cause opportunistic infections (e.g., AIDS).
5. Understand 10 different mechanisms of transmission of infectious agents and examples of
diseases that fall into each category.
1. Direct spread- Neisseria gonorrheae
2. Droplets- Influenza virus
3. Water- Cryptosporidium parvum (acute and chronic diarrhea)
4. Food- Listeria monocytogenes (listeriosis)
5. Soil- Blastomyces dermatitidis (blastomycosis)
6. Fomites- Hepatitis B Virus
7. Transplacental- Cytomegalovirus
8. Perinatal- Herpes Simplex Virus
9. Animal reservoir- Rabies Virus
10. Arthropod/insect vector- Plasmodium vivax (benign tertian malaria)
9.C. Histopathological response to infection
1. Explain 5 different histopathological responses to infections using specific examples of each.
Suppurative Polymorphonuclear Inflammation- reaction to acute tissue damage marked by
increased vascular permeability and neutrophilic exudation. Neutrophils are attracted to the site
of infection by release of chemoattractants from rapidly dividing bacteria(mostly gram-positive
cocci and gram-negative rods). Bacteria also attract neutrophils indirectly by releasing
endotoxin. Massing of neutrophils results in pus formation. The magnitude of tissue destruction
depends on location and the organism involved.
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Example(s):
-pus-filled fallopian tubes caused by N. gonorrhoeae
-diffuse involvement of the meninges during H. influenzae infection.
Mononuclear Inflammation- acute response to intracellular parasites/bacteria,
viruses, spirochetes, and helminthes. Which mononuclear cell predominates
within the lesion depends on host immune response. Granulomatous inflammation
is a distinct form of mononuclear inflammation usually evoked by slowly dividing infectious
agents (M. tuberculosis) and by agents of relatively large size (schistosome
eggs)
Example(s):
-plasma cells seen in primary and secondary syphilis lesions
-lymphocytes predominate in viral infections of the brain
-macrophages filled with M. avium-intracellulare are present in many tissues of aids patients
Also, the book doesn’t mention it, but Dr. Waites (Patterson’s biological father) says that
mononuclear inflammation is seen in chronic conditions like myocarditis and hepatitis.
Cytopathic-Cytoproliferative Inflammation- damage to individual host cells with little or no
inflammatory response. These reactions are usually produced by viruses and are characterized by
viral inclusion bodies and giant cells.
Example(s):
-Cytomegalovirus and adenovirus replicate to form viral aggregates/inclusion
bodies
-Measles and herpes viruses induce cells to fuse and form polykaryons
-Chickenpox virus causes epithelial cells to become discohesive and form blisters
-Human papillomavirus (HPV) causes epithelial cells to proliferate and take unusual forms
Necrotizing Inflammation- characterized by rapid and severe tissue damage that
results in cell death. This type of inflammation is most often caused by the secretion of very
strong bacterial toxins. These lesions look like infarcts because very few inflammatory cells are
involved. Occasionally, viruses can also cause
necrotizing inflammation.
Example(s):
-gas gangrene caused by C. perfringens
-colonic ulcers and liver abscesses caused by E. histolytica
-destruction of the temporal lobes of the brain by herpes virus
-destruction of the liver by Hepatitis B
Chronic Inflammation and Scarring- Neither the book, nor Dr. Waites provides a clear
definition for chronic inflammation and scarring. There may be some discussion in the
transcript, but he didn’t have a slide for it like he did for the other four histopathological
responses, so I will just list some examples.
Example(s):
-cirrhosis caused by Hepatitis B
-“pipe-stem” fibrosis of the liver caused by schistosomal eggs
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-gummas of tertiary syphilis in the liver and CNS (scarring is the
major cause of disease for this and for “pipe-stem” fibrosis)
2. Understand use of appropriate descriptive pathological terms such as carbuncle, furuncle,
abscess, empyema, cellulites as they apply to the lesions (p. 320-322).
Carbuncle - a painful localized bacterial infection of the skin and subcutaneous tissue that
usually has several openings through which pus is discharged.
Furuncle - a painful, circumscribed (locally expanding) pus-filled inflammation of the skin and
subcutaneous tissue usually caused by a local staphylococcal infection.
Abscess – focal collections of pus that may be caused by deep seeding of pyogenic organisms
into a tissue or by secondary infections of necrotic foci. Abscesses typically have a central,
largely necrotic region rimmed by a layer of preserved neutrophils with a surrounding zone of
dilated vessels and fibroblastic proliferation indicative of early repair. In time, the abscess may
become completely walled off and eventually replaced by connective tissue.
Empyema – the presence of pus in a body cavity, especially the pleural cavity
Cellulitis – a spreading inflammation of subcutaneous or connective tissue
9.D. Pathogenesis of bacterial infections
1. Compare and contrast the types of disease, tissue reactions, and causative organisms involved
with infections mediated by exotoxins versus endotoxins (p. 317-318).
book:
1. Endotoxin – lipopolysaccharide (LPS) that is a structural component of the outer cell wall of
gram-negative bacteria.
- when these bacteria are destroyed (lysed), endotoxin is released and begins to affect the host
cells
-can result in fever, septic shock, DIC, acute respiratory distress, etc.
-effects are mediated by direct effects of endotoxin and the induction of cytokines like IL-1,
TNF, and others
2. Exotoxin – secreted proteins that directly cause cellular injury and determine disease
manifestations
- examples: Bacillus anthracis, Diptheria, C. perfringens, Tetanus, Botulism
powerpoint and transcript:
Produced by
Release
Nature
Location
Exotoxins
Gram (+) and Gram (-)
Secreted by living organisms
Protein
Cytoplasm
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Endotoxins
Gram (-) only
Autolysis of dead organisms
Lipopolysaccharide
Outer membrane of cell envelope
1.Exotoxin mediated diseases: tetanus, diphtheria, cholera, pertussis, staph., strep.
Example in transcript: Cholera - Cholera toxin can cause secretion of diarrhea because it acts on
cAMP. The diphtheria exotoxin interrupts protein synthesis in cells
2. Endotoxin – primary cause of septic shock due to bacteria in the blood stream which lead to a
variety of effects (fever, chemotaxis of WBC, shock because of increased vascular permeability
that results in hypotension, and disseminated intravascular coagulation because of the effects on
the clotting system)
Example: Meningococcus can cause gangrene of the digits due to DIC
2. Explain the biological basis for the clinical manifestations of endotoxin shock.
Bacterial endotoxin (LPS) is a structural component of the outer cell wall of gram-negative
bacteria. LPS is composed of a long-chain fatty acid anchor (lipid A) connected to a core sugar
chain, which are the same in all gram-negative bacteria. Attached to the core sugar is a variable O
antigen, used to serotype and distinguish different bacteria. Endotoxins are released into the
circulation when the bacterial cell walls are degraded, usually during an inflammatory response.
Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a
specific receptor on cells of the immune system. This activation leads to initiation of the cytokine
cascade (successive release waves of TNF, IL-1, and IL-6/IL-8 secretion) that enhances the local
acute inflammatory response and actually improves clearance of the infection at low doses.
Higher levels of LPS augment the cytokine cascade and cytokine-induced secondary effectors
(such as nitric oxide and platelet activating factor). In addition, systemic effects of the increased
levels of TNF and IL-1 may begin to be seen, including fever, increased synthesis of acute-phase
reactants, and increased production of neutrophils.
Finally, at very high levels, the classic signs of “septic shock” begin to manifest themselves.
Cytokines and secondary mediators are now at dangerously high levels resulting in:
-Systemic vasodilation (severe hypotension)
-Diminished myocardial contractility (low cardiac output)
-Widespread endothelial injury and activation, causing systemic leukocyte
Adhesion and diffuse alveolar capillary damage in the lung
-Activation of the coagulation system, ultimately leading to DIC
The summation of these effects causes multiorgan system failure that often
Affects the liver, kidneys, and central nervous system, resulting most often in death.
Apparently, though he said we didn’t have to know this picture, thought it would help:
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Biological Actions of Endotoxin
in Septic Shock
Endothelial
injury
Platelet
aggregation
Activation
of Hageman
Factor
Endotoxin
Mast cell
degranulation
Release
of tissue
factor
Complement
activation
C5a release
Macrophage
activation
Increased
vascular
permeabtility
Neutrophil
chemotaxis
& activation
DIC
Hypothalamus
Fever
Release of Il-1
Muscle
catabolism
Increased synthesis
of glucagon &
insulin secretion
3. Explain the basic steps involved in general terms for viral infection and replication and how
these steps differ from what occurs with bacterial infections.
My response is based on the things that are in the book. I could type pages 1-16 of Waites’
Pathology of Infectious Diseases Powerpoint, but you can read them. I highly recommend it.
Viral Infection + Replication
Viruses damage host cells by entering the cell and replicating at the host’s expense. They have
specific surface viral proteins (ligands) that bind to particular host proteins (receptors).
Examples: HIV binds to CD4, EBV binds to complement receptor on macrophages, rhinoviruses
bind to ICAM-1. Viral tropism is the tendency of certain viruses to infect specific cells but not
others. This tendency is fueled by the presence of absence of host cell proteins that allow the
virus to attach. Another cause of viral tropism is the ability of the virus to replicate inside some
cells but not in others.
The virion is the portion of the virus that contains the genome and essential polymerases. The
virion penetrates the cell cytoplasm by 1) translocating the entire virus across the plasma
membrane
2) fusing of the viral envelope with the cell membrane
3) receptor-mediated endocytosis and fusion with endosomal membranes.
Once inside the cell, the virus uncoats and separates its genome from its structural components
and loses it sinfectivity. They replicate using enzymes that are distinct for each virus family.
Viruses kill host cells and cause tissue damage in a number of ways:
1. Inhibit host cell DNA, RNA, or protein synthesis.
2. Viral proteins may insert into the host cell’s plasma membrane and directly damage its
integrity or promote cell fusion
3. Viruses replicate efficiently and lyse host cells.
4. Viral proteins on the surface of the host cells may be recognized by the immune system,
and the host lymphocytes may attack the virus-infected cells.
26
5. Viruses may also damage cells involved in host antimicrobial defense, leading to
secondary infections.
6. Viral killing of cells of one type may cause damage to other cells that are dependent on
their integrity.
Bacterial Infexn + Replication
Bacterial damage to host tissues depends on the ability of the bacteria to adhere to and enter host
cells or to deliver toxins. The coordination of bacterial adherence and toxin delivery is so
important to bacterial virulence that the genes encoding adherence proteins and toxins are
frequently co-regulated by specific environmental signals.
Bacterial adhesions are the molecules that bind bacteria to host cells. The surface of grampositive cocci (strep) is covered with two molecules that may mediate adherence of the bacteria
host cells. 1). Lipoteichoic aids are hydrophobic molecules that bind to the surface of all
eukaryotic ells but have a higher affinity to particular receptors on blood cells and oral epithelial
cells. 2.) Protein F binds to fibronectin, and extracellular matrix protein also found on most
host cells. 3.) M proteins form fibirillae on the surface of gram-positive bacteria and their
carbohydrate capsules prevent phagocytosis by host macrophages.
Produced by
Release
Nature
Location
Exotoxin
Grand (+) and Gram (-)
Secreted by living organisms
Protein
Cytoplasm
Endotoxin
Gram (-) only
Autolysis of dead organisms
LPS
Outer membrane of cell envelope
In Chronic bacterial infections, the intracellular location of the organism helps protect it from the
host immune system and may contribute to chronicity. The local tissue damage may ensure from
release of enzymes and byproducts of the acute inflammatory response generated in response to
acute bacterial infection. Autoimmune reactions may occur when antibodies against bacterial
pathogens cross react with host tissues.
4. Explain the role of autoimmune reactions in the pathogenesis and lesion development of
diseases such as rheumatic heart disease.
The pathogenesis of acute rheumatic fever is based on a hypersensitivity reaction induced by
group A streptococci. Antibodies are directed against the M-protein of group A. The
streptococcal antigens immunologically mimic heart antigens, such as cardiac myosin. The
cross-reaction of the antibodies against the M-protein and the heart antigens lead to the
development of the disease. The inflammatory infiltrates occur in the synovium, joints, skin, and
the heart. The response can result in fibrosis in cardiac tissue, sometimes involving all three
layers off the heart as well as the connective tissue.
5. What are the necessary steps that must take place in order for a bacterium to invade the body
and produce disease?
Bacterial damage to host tissues depends on the ability of the bacteria to adhere to and enter host
cells or to deliver toxins. The coordination of bacterial adherence and toxin delivery is so
important to bacterial virulence that the genes encoding adherence proteins and toxins are
27
frequently co-regulated (triggered) by specific environmental signals (temperature, osmolarity,
pH). Gram + bacteria: Lipoteichoic acids are hydrophobic molecules that bind to the surface of
eukaryotic cells and non-fibrillar adhesions (protein F) bind to fibronectin in the ECM. M
proteins, which form fibrillae on the surface of these bacteria and on the capsules prevent
phagocytosis by host macrophages. Exotoxins are secreted proteins that directly cause cellular
injury and determine disease manifestations. Gram – bacteria: Fimbriae, or pili on the surface
mediate adherence of bacteria to host cells. At the tips of the pili are minor protein components
that determine to which host cells the microbes will attach (bacterial tropism). A single
bacterium can express more than one type of pilus. LPS (endotoxin) and exotoxins aid in the
virulence of gram – bacteria.
6. What are fimbriae and what is their role in the pathogenesis of bacterial diseases?
Fimbria, aka pili, are on the surface of Gram (-) rods and cocci. They are non-flagellar
structures, made up of repeating sub-units. The base of the pili anchors it into the bacterial cell
wall, the tip of the pili has a protein that determines which host cell the bacteria will attach
to (e.g. Type I proteins bind mannose and cause UTI, Type S protins bind sialic acid and cause
meningitis). A single bacterium can have more than one type of pilus.
7. Explain the importance of cytadherance in the pathogenesis of mycoplasmal pneumonia.
Review: Mycoplasma pneumoniae is a bacterium with no cell wall, but it does have a
cell/cytoplasmic membrane present. Since they don’t have a cell wall, they don’t appear as cocci
or rods (bacilli); instead, they will appear as long, serpentine organisms. [serpentine =
resembling a serpent in form and movement; snake-like)
Mycoplasma pneumoniae is able to attach to adhesions and receptors on the host cell
surface b/c they have a specialized attachment organelle that consists of a P1 protein and some
other accessory proteins. When you ingest a Mycoplasma into the respiratory tract, it will seek
out the respiratory epithelium, where it will bind tightly to sialic acid conjugates in the receptors
of the host cell. It will then damage the cilia (ciliostasis, ciliolysis, and cytonecrosis) of the
respiratory epithelium host cells → causes the respiratory cells to die → release of peroxides
occurs → inflammation is induced → all of this is why we cough. So, this demonstrates the
importance of attachment tip of Mycoplasma pneumoniae in virulence.
Mycoplasma pneumoniae is also immunogenic in that many of the antibodies made
toward M. pneumoniae will be made against its P1 protein attachment tip. This is the way you
can tell if someone has had a recent Mycoplasma infection → you can measure the antibodies
(antibody response) in the serum.
9.E. Pathogenesis of viral infections
1. Explain the concept of antigenic shift and how it is responsible for influenza pandemics. (see
p 319-320 also see slide 40 on the Oct 6 lecture)
Viral infection evokes neutralizing antibodies, which prevent viral attachment, penetration, or
uncoating. This highly specific immunity is the basis of antiviral vaccination, but it cannot
protect against viruses with many antigenic variants such as Haemophilus influenza.
Pneumococci are capable of more than 80 per-mutations of their capsular polysaccharides, so that
in repeated infections the host is unlikely to recognize the new serotypes. This is known as
28
antigenic shift. The antigens change. That’s why the influenza we see this year may be different
from the influenza we saw last year. Antigenic shift makes it very difficult to make effective
influenza vaccines.
2. Describe 8 mechanisms by which viruses can kill host cells and provide an example of a
disease that is caused by each mechanism. (p. 316-317)
1) Viruses may inhibit host cell DNA, RNA, or protein synthesis. For example, the poliovirus
inactivates cap binding protein, which is essential for translation host cell mRNAs, but leaves
translation of poliovirus mRNAs unaffected.
2) Viral proteins may insert into the host cell’s plasma membrane and directly damage its
integrity or promote cell fusion (HIV, measles, and herpes viruses).
3) Viruses replicate efficiently and lyse host cells. For example, respiratory epithelial cells are
killed by explosive rhinovirus or influenza virus multiplication, liver cells by yellow fever virus,
and neurons by poliovirus or rabies viruses.
4) Viral proteins on the surface of the host cells may be recognized by the immune system, and
the host lymphocytes may attack the virus infected cells. For example, acute liver failure during
HBV infection may be accelerated by Fas ligands on cytotoxic T lymphocytes, which bind to Fas
receptors on the surface of hepatocytes and induce apoptosis in target cells. Respiratory syncytial
virus, a major cause of lower respiratory infections in infants, causes release of cytokines IL-4
and IL-5 from Th2-type helper T cells, which cause mast cell and eosinophil activation
respectively, inducing wheezing and asthma.
5) Viruses may also damage cells involved in host antimicrobial defense, leading to secondary
infections. For example, viral damage to respiratory epithelium predisposes to the subsequent
development of pneumonia caused by pneumococci or Haemophilus organisms, while HIV
depletes CD4+ helper lymphocytes and opens the floodgates for many opportunistic infections.
6) Viral killing of cells of one type may cause damage to other cells that are dependent on their
integrity. Denervation by the attack of poliovirus on motor neurons causes atrophy, and
sometimes death, of distal skeletal muscle cells.
7) Slow viral infections (e.g., subacute sclerosing panencephalitis caused by measles virus)
culminate in severe, progressive disease after a long latency period.
8) Viruses (e.g., EBV, HPV,HBV, and human T cell lymphotropic virus I) can cause cell
proliferation and transformation, resulting in cancer.
3. Compare and contrast the host inflammatory and immune response to viral versus bacterial
infections.
It is important to note that many of these responses overlap. Where the boxes are empty,
manifestations of the kind can still occur, but are not as common.
PMN
Inflammation
Bacterial Infections
- increased vascular
permeability and neutrophilic
exudates
- bacterial chemoattractants
contain N-formyl methionone
residues that are recognized by
receptors on neutrophils
29
Viral Infections
Mononuclear
Inflammation
Cytopathic –
cytoproliferative
Inflammation
Necrotizing
Inflammation
Chronic
Inflammation &
Scarring
-bacteria also attract neutrophils
by release of endotoxin that
stimulates macrophages to
secrete IL-1 or TNF
- massing of PMNs forms pus
- when occurring acutely, can
indicate an intracellular
bacterial invasion
- example: plasma cells in
syphilis
- granuloma formation is a
distinctive form of mononuclear
inflammation
- when occurring acutely, this
can indicate a viral response
- example: lymphocytes
predominate in HBV or viral
infections of the brain
- damage to individual host cell
with little or no host
inflammatory response
- some viruses form aggregates
intracellularly that are seen as
inclusion bodies
-some viruses induce cells to
fuse and form polykaryons
- can cause unusual epithelial
cell proliferation (ex. warts)
-can cause dysplastic changes
that lead to cancers
- bacteria secrete strong toxins
-occasionally, viruses can cause
that cause severe tissue damage necrotizing inflammation (ex.
and cell death
HBV and destruction of the
liver or destruction of the
temporal lobes by the herpes
virus)
- example: chronic gonnococcal - example: cirrhosis of the liver
salpingitis
by HBV
4. Explain the concept of viral latency and provide examples f diseases in which this occurs.
On page 309 in the discussion of viruses it mentions that some viruses are not eliminated from
the body but may remain in the body for years and continue to multiply and remain obvious for
years (example: chronic infection with hepatitis B virus). Viruses can also survive in the body
in some latent noninfectious disease form with the potential to be reactivated later. For
example, the herpes zoster virus, the cause of chicken pox, may persist in the dorsal root
ganglia and be periodically activated to cause the painful skin condition called shingles.
<this last part sums up the text’s point that different viruses behave differently so I included it.>
Different species of viruses can produce the same pathologic features (e.g.., upper respiratory
tract infections), and a single virus (eg., CMV-cytomegalovirus) can produce different clinical
manifestations depending on the host’s resistance and age.
30
5. Describe the difference between a virus and a prion and discuss transmission and
characteristics of the prion diseases including bovine spongiform encephalopathy and
Creutzfeldt-Jakob disease. (p. 309)
Viruses are obligate intracellular organisms that contain DNA or RNA w/in a capsid, which may
be surrounded by a lipid bilayer (envelope). Prions are composed only of a modified host protein
(PrPSc) and lack RNA or DNA (lack of nucleic acid distinguishes them from viruses). The PrP is
neuron protein material that undergoes conformational change to make it abnormal. The
infectious nature of PrP is that it can corrupt the integrity of normal host protein to change it from
a normal isoform to an abnormal isoform.
Prion diseases are known as Transmissible spongiform encephalopathies. They are
predominantly characterized by spongiform change caused by intracellular vacuoles in neural
cells associated w/abnormal PrP, that can be seen with a brain biopsy. Plaques form in the CNS
that are accumulations of this spongiform vacuolation.
Disease can be infectious or inherited. If inherited, mutations in the PrP gene favor spontaneous
conformational change to PrPSc. Infectious b/c introduction of exogenous PrPSc induces
conformation change of host PrP: infected beef, cannibalism, or iatrogenic via contaminated
surgical instruments (fomites). Transmission can be inoculation or oral.
Bovine Spongiform Encephalopathy: disease of cattle. Caused b/c cattle are fed contaminated
meat (aren’t cows herbivores?). Transmission of BSE from “mad cows” to humans causes the
human disease CJD.
Creutzfeld-Jakob disease: rare cause of rapidly progressive dementia, ataxia (cerebellar
symptoms: loss of coordination), myoclonia (involuntary muscle movement) and death
(ultimately fatal). Transmission via contaminated neural tissue (BSE) from cows and iatrogenic
cases (contaminated neural surgery instruments, transplanted corneas and administration of
cadaveric pituitary hormones).
6. What are interferons and why are they important in viral infections?
In class (it was not found in the book):
Interferons are produced naturally as a part of innate immunity to help destroy viral replications
in affected cells. They are one of several of the body’s mechanisms which respond to viral
infection. They do this by (1) Inhibiting translation of viral proteins, (2) Preventing viral
replication (3) Enhancing T cell and NK cell activity.
He also mentioned that you can take synthetic interferons to supplement your own in order to
counteract a viral infection more effectively.
In micro we also learned that they work only in the presence of double stranded RNA, therefore
RNA viruses are the best inducers of IFN. They also can cause fever when supplemented for
treatment of RRP.
I found in other sources:
An interferon is a protein that confers resistance to infection to other cells. It does not act directly
on the virus, rather it acts on the cells to make them resistant to infection. IFN is one of the first
lines of defense against viruses because it is induced early after virus infection before any of the
other defense mechanisms appear (e.g. antibody, Tc cells etc.). The time after which IFN begins
to be made will vary depending on the dose of virus. There are three types of interferon, IFNalpha (also known as leukocyte interferon), IFN-beta (also known as fibroblast interferon) and
31
IFN-gamma (also known as immune interferon). IFN-alpha and IFN-beta are also referred to as
Type I interferon and IFN-gamma as Type II. There are approximately 20 subtypes of IFN-alpha
but only one IFN-beta and IFN-gamma. IFN not only induces the production of antiviral proteins,
it also has other effects on cells, some of which indirectly contribute to the ability of the host to
resist or recover from a viral infection. IFN can help modulate immune responses by its effects
on Class I and Class II MHC molecules. IFN-alpha, IFN-beta and IFN-gamma increase
expression of Class I molecules on all cells thereby promoting recognition by Tc cells which can
destroy virus infected cells. IFN-gamma can also increase expression of Class II MHC molecules
on antigen presenting cells resulting in better presentation of viral antigens to CD4+ T helper
cells. Furthermore, IFN-gamma can activate NK cells which can kill virus infected cells. IFNs
also activate the intrinsic and extrinsic antiviral activities of macrophages. Intrinsic antiviral
activity is the ability of macrophages to resist infection with a virus and extrinsic antiviral
activity is the ability of macrophages to kill other cells infected with virus. The IFNs also have
anti-proliferative activity making them useful in the treatment of some malignancies.
9.F. Pathogenesis of fungal infections
1. Explain why a travel history is important in understanding causes of fungal diseases.
Okay this is kind of common sense but I’ll put what I found. A travel history may provide
information about exposures to certain organisms and the possibility of disease from them.
Travel to or residence in a geographic region that is endemic for one of the endemic fungi is a
strong determinant of the risk of exposure/infection and disease. Knowing the location of travel
can narrow down the possible fungal infections as help in the determination of possible treatment
and/or medications.
2. Describe 4 methods by which fungal diseases are transmitted? (lecture & book)
1. Respiratory inhalation
 Yeast forms of fungi produce spores which can be inhaled
 Ex: Histoplasma
 This is considered the major method for fungal disease transmission
2. Cutaneous inoculation
 Mainly inoculation of spores into skin
 This may involved the superficial as well as deep skin layers
 Ex: Sporothrix
3. Systemic invasion by opportunists
 Opportunists are ubiquitous contaminants colonizing normal human skin or gut without
causing illness
 Only in immunocompromised individuals do opportunistic fungi give rise to lifethreatening infections
 Opportunistic fungi infections are characterized by necrosis, hemorrhage, & vascular
occlusion with minimal or no inflammatory response
 AIDS patients are frequent victims of opportunistic fungus-like organisms
Pneumocystis carinii
 Ex of opportunists: Candida, Aspergillus, Mucor, Cryptococcus
32
4. Contact with infected hosts
 These fungal diseases are types that are spread person to person
 This is typified by Dermatophytes that cause “locker room” type infections
3. What is the difference between a yeast and a mold? Are any fungi considered in both of these
categories?
Fungi are classified as yeasts or molds according to their morphology. Yeasts are larger than
bacteria. They are budding organisms that stain gram positive due to their carbohydrate rich cell
wall. Molds look like the common bread mold and they produce spores. Some species of fungi
exhibit what is known as thermal dimorphism. Thermally dimorphic species exist as yeasts at
human body temperature and as molds at room/environmental temperature. (Thermally
dimorphic organisms are often in their mold form when they are transmitted.) Blastomyoces
and histoplasma are examples of thermally dimorphic fungi species. Aspergillus is a non
thermally dimorphic species that is always present in mold form.
4. Explain what is meant by thermal dimorphism and give examples of fungi that exhibit this
property.
Thermal Dimorphism: the ability of some fungi to alternate back and forth between a mold
form and a budding yeast form depending on the temperature at which they’re incubated. At
body temperature they will appear as a yeast, but at room temperature or in the environment
(which is how you contract them) they will appear as a mold with spores. Thermal Dimorphism
is common in many pathogenic fungi but absent in bacteria. Examples: Blastomyces and
Histoplasma
5. Describe 4 mechanisms by which disease can be caused by Aspergillus species.
1) Allergic-hypersensitivity to spores&#61664; (ex: asthma, wheezing)
2) Colonizing ?Fungus Ball?
3) Invasive-systemic infection in debilitated hosts&#61664; see this in transplant patients
4) Aflatoxin (A. flavus)&#61664; produces exotoxin that can destroy liver
6. Describe 6 histopathological responses that occur with fungal infections and provide
examples of fungi that produce each type of reaction.
1.
2.
3.
4.
5.
6.
Acute pyogenic abscess (Candida)
Chronic Granuloma (Histoplasma)
Chronic, localized dermal infiltration (Dermatophytes)
Mixed pyogenic and granuloma reaction (Blastomyces)
Blood vessel invasion with thrombosis & infarction (Mucor)
Hypersensitivity without tissue reaction (Aspergillus)
9.G. Pathogenesis of parasitic infestations
1. Describe 4 mechanisms by which eukaryotic parasites produce diseases in humans and
provide an example of a parasite that exhibits each mode.
33
1. Kill host cells by multiplying in them.
Ex. Toxoplasma gondii (causes brain cysts)
CNS manifestations and deficits result from the parasite growing in the brain
Pregnant women can catch toxoplasma from cat feces. It is then transmitted to their unborn child
resulting in problems in neonatal period with toxoplasma cysts in the brain
People beyond the neonatal period that get toxoplasma are people with T cell deficiencies, HIV
and AIDS patients
2. Eat Host cells
Ex. Ancylostoma duodenale (“Hookworm”)
Acquired from the hookworm larvae being present in the soil, which is often fecally
contaminated.
The hookworm burrows through the skin, gets into the circulation, and eventually attaches to the
intestinal mucosa.
The parasite feeds on blood, causing host to become iron deficient/anemic
3. Take up space in host
Ex. Taenia solium (“Tapeworm”)
Humans are the definitive T solium hosts and can carry an intestinal adult tapeworm (taeniasis),
often without symptoms. Intermittent fecal shedding of egg-containing proglottids or free T
solium eggs ensues, with the intention that the intermediate host (normally pigs) will ingest the
excreted eggs in contaminated food or water. When undercooked pork is consumed, an intestinal
tapeworm will again be formed, completing the life cycle of the worm.
The human can become the accidental intermediate host when T solium eggs are ingested via
fecal-oral transmission from a tapeworm host.
Cysticercosis is an infection caused by the pork tapeworm. Infection occurs when the tapeworm
larvae enter the body and form cysticerci. When cysticerci are found in the brain, the condition is
called neurocysticercosis
Tapeworm eggs are passed in the bowel movement of a person who is infected. These tapeworm
eggs are spread through food, water, or surfaces contaminated with feces. Once inside the
stomach, the tapeworm egg hatches, penetrates the intestine, travels through the bloodstream and
may develop into cysticerci in the muscles, brain, or eyes.
4. Induce destructive immune response
Ex. Schistosoma mansoni (“liver fluke”)
The larvae penetrate the skin, go into the bloodstream, go into the lungs, and eventually go into
the liver. They lay their eggs in the venules of the liver. Everywhere they lay an egg you get an
inflammatory reaction and a granuloma. When your liver fills up with these granulomas, it stops
the liver circulation and the processing of bile and you get cirrhosis.
9.H. Laboratory Diagnosis of infectious diseases
34
1. Understand the applications of various procedures in the diagnosis of infectious diseases,
including direct observation of body fluids or tissues, biopsy, special stains such as GMS,
culture, serology, antigen detection, and PCR. Be able to provide and recognize examples of
infections that may be best suited for diagnosis by each method.
1. Some infectious diseases can be directly observed in H & E stained sections. This includes the
inclusion bodies formed by CMV and herpes virus; bacterial clumps, which usually stain blue;
Candida and Mucor, among the fungi; most protozoans; and all the helminths.
2. Many infectious agents are best visualized after staining with special stains that identify
organisms based on particular characteristics of their cell walls or coat. This includes Gram stain
(most bacteria), Acid-fast stain ( Mycobacterium, Nocardia (modified)), Silver stain (Fungi,
Legionella, Pneumocystis), Periodic acid - Schiff (Fungi, amoebae), Mucicarmine (Cryptococci),
and Giemsa (Campylobacter , Leishmania, malaria plasmodium).
3. Antibody probes are used to detect viruses and rickettsiae.
4. Regardless of staining technique, organisms are usually best visualized at the advancing edge
of a lesion rather than at its center, particularly if there is necrosis. Because these morphologic
techniques cannot speciate organisms, determine drug sensitivity, or identify virulence
characteristics, cultures of lesional tissue must be performed. Culture can be used to detect all
classes of agents.
5. Polymerase chain reaction (PCR) based methods are used to identify microbes that grow
slowly in culture (Mycobacterium or CMV organisms) or cannot be cultured at all (HBV and
HCV).
6. DNA sequence analysis has been used to classify bacteria that have never been cultured. This
includes those that cause Whipple disease (Tropheryma whippelii) and hepatic peliosis and
bacillary angiomatosis (a rickettsia).
2. Describe 3 ways viral diseases can be detected in clinical specimens. How are these different
from methods used for bacterial diseases?
1. Bacterial Diagnosis
Direct examination of fluids/tissues:
Gram Stain
- CSF gram stain showing gram-negative intracellular cocci (meningitis due to
Neisseria meningitidis)
KOH
- often used to identify fungi in clinical specimens (oral thrush due to Candida albicans)
Stool Exam
- for parasites (Ascaris lumbricoides ova)
Darkfield Exam
- diagnosis of syphilis in lesion is present (Treponema pallidum)
Histology/Biopsy with special stains
- Periodic acid Schiff (CHO of fungi cell wall; Candida albicans)
- Gomori-methenamine silver (GMS) stain of Histoplasma capsulatum in lung tissue
35
- Silver stain (Helicobacter pylori, fungi, Legionella, Pnemosystis)
Culture
Selection Media
- mucoid lactose fermenting bacteria on MacConkey agar (Klebsiella pneumoniae)
Serology
Organisms not cultivable; slow growing
- Rickettsiae
- Hepatitis viruses
- Mycoplasma
PCR
microbes that grow slowly in culture (Mycobacterium; CMV organisms)
Other Methods
Ag detection
- Histoplasma, Aspergillus, Legionella, Cryptococcus
Skin Testing for Delayed Type Hypersensitivity/PPD
- Mycobacterium tuberculosis
2. Viral Diagnosis in clued methods that enable detection of uncultivable obligate
intracellular microbes.
PCR
Herpes CNS
Viral Load ( Hepatitis C, HIV)
Tissue Culture
- CMV
Histopathology
Serology
Hepatitis
HIV
(this was all I could find in the book and handout)
10. Atherosclerosis
A. Describe the steps in the process of atherosclerosis and understand the role of inflammation
in this process (p.334-338)
Atherosclerosis is a slowly progressing disease that is basically characterized by intimal plaques
called atheromas that protrude into the lumen, weaken the underlying media, and cause a series
of complications within the blood vessels. The cause of atherosclerosis is believed to be a
response to injury (chronic endothelial injury-could be caused by things such as toxins [ex:
smoking], endotoxins, viruses, and most commonly by hemodynamic disturbances [shear stress,
turbulent flow] and high cholesterol.
1. Development of focal areas of chronic endothelial injury result in increased endothelial
permeability or some other endothelial dysfunction.
2. Increased insudation of lipoproteins into the vessel wall (mainly LDL’s and VLDL’s).
3. Smooth muscle emigrates from media to intima and macrophages are activated, both of
which engulf the lipids.
4. Formation of ECM and build up of extracellular lipid debris.
36
These steps lead to a slowly progressing closure of the blood vessel. Inflammation plays an
important role because it is an inflammatory response that responds to the chronic injury and
brings the macrophages, monocytes, platelets into the area, which then uptake lipids and add to
the blockage of the blood vessel at the site of injury.
1. Specifically explain roles of smooth muscle cells, macrophages, monocytes, and platelets in
generation of atherosclerotic plaque.
Atherosclerotic plaques are lipid filled intimal lesions within an artery due to
biochemical changes in the endothelial cells and are caused most commonly by
hyperlipidemia, hypertension, and smoking. In a normal artery you have a single layer of
endothelium lining the vessel. Under it you have the intima. It is a potential space between
the endothelium and the internal elastic membrane (IEM). Under the IEM you have the media
which consists of smooth muscle cells.
When the endothelium is damaged they produce selectins that recruit inflammatory
cells. The formation of an intimal lesion occurs when this potential space is lifted up by
inflammatory cells. These cells release cytokines that recruit platelets to adhere to the area of
injury. The platelets release paracrine-type growth factors that stimulate the inflammatory
reaction and ADP which stimulates the clotting cascade (and thrombus formation). Some
platelets sit on the luminal surface of the lesion while others move into the subendothelial
space and continue to produce growth factors. These factors stimulate smooth muscle cells
(SMC’s) from the media to proliferate and migrate into the lesion. So now you have SMC’s
and inflammatory cells in the lesion. The SMC’s and macrophages (a.k.a. foam cells) begin
to phagocytize the excess lipids forming the fatty portion of the intimal lesion. SMC’s also
migrate to the top of the lesion forming a lesion similar to a granuloma. The SMC’s are
stimulated to produce fibrous connective tissue to form a fibrous cap over the lesion. This cap
however is not stable and can burst releasing its fibrous content (collagen) and causing
thrombus formation throughout the circulatory system.
B. Be able to list and explain the major clinical consequences of atherosclerosis (myocardial
infarction and chronic ischemic heart disease, cerebral infarction, aortic aneurysms, and
peripheral vascular disease) (Fig. 10-3, pp. 328-331)
Atherosclerosis primarily affects elastic arteries and large and medium-sized arteries, most
commonly the arteries supplying the heart, brain, kidneys, and lower extremities. Inside an
artery, a fibrofatty plaque develops, usually at a young age. As the plaque gets larger,
aneurysm/rupture or occlusion of the artery can occur. Major consequences include myocardial
infarction (heart attack), cerebral infarction (stroke), aortic aneurysms, and peripheral vascular
disease (gangrene of the legs). Chronic ischemic heart disease is a result of chronically
diminished arterial perfusion.
C. Explain why death rates from ischemic hear disease have decreased in the United States over
the past several years. (p. 329)
Between 1963 and 2000 there was an approximately 50% decrease in the death rate from
ischemic heart disease. Three factors have contributed to this improvement:
37
1. prevention of atherosclerosis through changes in life style, including reduced cigarette
smoking, altered dietary habits with reduce consumption of cholesterol and saturated animal fats,
and control of hypertension
2. improved methods of treatment of myocardial infarction and other complications of ischemic
heat disease
3. prevention of recurrences in patients who have previously suffered serious atherosclerosisrelated clinical events
D. Understand and explain the unchangeable and the changeable major risk factors for
development of atherosclerosis. (Table 10-2, p. 331-334)
Unchangeable major risk factors: increasing age, male gender, family history, genetic
abnormalities; Controllable major risk factors: Hyperlipidemia, hypertension, cigarette smoking,
and diabetes.
E. Understand the meaning of HDL and LDL and the role and relationship of these lipids with
development of atherosclerosis. (p. 332)
Hyperlipidemia is a major risk factor for ATH. Most of the evidence specifically implicates
hypercholesterolemia. The major component of the total serum cholesterol associated with
increased risk is low-density lipoprotein (LDL) cholesterol. In contrast, the higher the level of
high-density lipoprotein (HDL), the lower is the risk. HDL is believed to mobilize cholesterol
from developing an existing atheroma and transport it to the liver for excretion in the bile,
thereby earning its designation as the “good cholesterol.” There is thus great interest in dietary,
pharmacologic, and behavioral methods of lowering serum LDL and raising serum HDL. Both
exercise and moderate consumption of ethanol raise the HDL level, whereas obesity and smoking
lower it.
16. Viral Hepatitis
A. Compare and contrast the incubation period, clinical manifestations, potential for prolonged
carriage, development of chronic liver disease, and modes of transmission for hepatitis A, B, C,
D, E, and G.
Table 16-4 (p. 601) (Bold = Answer to question; Normal Font= book/resource,
Italics= handout)
Hepatitis A
Virus
1973
Hepatitis B
Virus
1965
Hepatitis C
Virus
1989
Hepatitis D
Virus
1977
Hepatitis E
Virus
1980
Hepatitis G
Virus
1995
Agent
27-nm
iscosahedral
capsid,
ssRNA
42-nm
enveloped
dsDNA
30- to 60-nm
enveloped
ssRNA
35-nm
enveloped
ssRNA:
replication
defective$
32- to 34-nm
un-enveloped
ssRNA
ssRNA virus
Classification
Picornavirus
Hepadnavirus
Flavivirus
Unknown
Caliciviridae
Flavivirus
Transmissio
n
Fecal-oral
(Daycare
transmission
common for
Parenteral:
close personal
contact, Sex,
perinatal
Parenteral:
close
personal
contact
Parenteral:
close
personal
contact
Waterborne
or fecal-oral
(endemic to
India with
Parenteral
Year of ID
38
children,
eating
shellfish from
contaminated
water)
(Serum
Hepatitis)
Incubation
Period (wks)
2-6
(Distaste for
cigarettes)
4-26
2-26
Fulminant
Hepatitis*
0.1% to 0.4%
(RARE)
<1.0%
RARE
Carrier State
None
0.1 to 1.0% of
blood donors in
the US and
Western World
Chronic
Hepatitis*
None
5 to 10% of
acute infections
0.2 to 1.0%
of blood
donors in the
US and
Western
World
> 70%
No
Yes
Hepatocellula
r Carcinoma*
Yes
(very high of
HBV carriers
2040%:middle
east, Africa,
southern
italy)
4-7
In
superinfectio
n with HBV
3 to 4% in coinfection
(7-10%)
1-10% in
drug addicts
and
hemophiliacs
< 5% with
co-infection;
80% with
superinfectio
n
No increase
above HBV
40%
seroprevalenc
e)
2-8
Unknown
0.3 to 3%;
20% in
pregnant
women
None
No
1 to 4% of
blood donors in
the US
(estimate)
None
None
No
No
Clinical Manifestations (p. 605-606):
Carrier State- without apparent disease or with sub-clinical chronic hepatitis
1) those who harbor one of the viruses but are suffering little or no adverse effects
2) those who have non-progressive liver damage but are essentially free of symptoms or
disability
Asymptomatic infection- serologic evidence only (elevated serum aminotransferases)
Acute Hepatitis- anicteric or icteric (not jaundice or jaundice, respectively)
1) Preicteric: Low grade fever, malaise, fatigue, headache, anorexia, nausea, vomiting, and
diarrhea are inconstant symptoms. Also pain in right upper quad., hepatosplenomegaly*.
Most often in HBV, serum sickness-like syndrome with fever, rash and arthralgias*
attributed to circulating immune complex.
2) Icteric: high fever, chills, headache, cholestasis*, distressing skin itching (pruritus) dark
urine, clay-colored stools, 1-5 days of jaundice, liver enlarged/tender, increase of liver
enzymes in blood levels. Usual in adults with HAV, half the cases of HBV and absent in
most cases of HCV.
Fulminant Hepatitis: sub-massive to massive hepatic necrosis
Chronic Hepatitis- with or without progression to cirrhosis; continuing or relapsing hepatic
disease for more than six months (very common in HCV). Clinical symptoms are highly variable
and are not a predictive outcome.
1) In some the only signs are elevated levels are serum aminotransferases
2) Fatigue (most common), malaise, loss of appetite, and bouts of mild jaundice
3) Sometimes spider angiomas, palmer erythema, mild hepatomegaly, hepatic
tenderness, and splenomegaly
4) With HBV and HCV sometimes, vasculitis and glomerulonephritis
5) Cirrhosis is the major cause of death thru liver failure, hepatic encephalopathy, or massive
hematemesis.
39
*Patients with long-standing HBV (especially neonate) or HCV infection are at substantially
increased risk for hepatocellular carcinoma
*Terms:
Fulminant Hepatitis is a severe and rapidly progressive form of hepatitis accompanied by
hepatocellular death and the signs and symptoms of hepatic failure.
Chronic Hepatitis is any of several types of hepatitis persisting for more than six months, often
progressing to cirrhosis.
Hepatocellular Carcinoma is a tumor of the liver. The most common primary malignant liver
tumor is hepatocellular carcinoma. Risk factors include chronic active hepatitis B and cirrhosis of
the liver (for example alcohol aetiology).
Hepatosplenomegaly is Abnormal enlargement of both the liver and the spleen, may be seen in
cases of leukemia, lymphoma, acute mononucleosis and others.
Cholestasis is an arrest of the normal flow of bile. This may occur due to a blockage of the bile
ducts resulting in an elevation of bilirubin in the bloodstream (jaundice).
Arthralgia is pain in a joint.
$- Because the replication is defective HDV can only cause infection if it is encapsulated with
HBsAg. Thus, HDV is dependent on HBV co-infection for its multiplication (p. 604).
There are two types of infection that arise:
(1) Acute Co-infection of HBV and HDV after exposure to serum that contains both
(2) Superinfection of a chronic carrier of HBV with a new inoculum of HDV
B. Explain how and why persons with viral hepatitis become jaundiced. What other symptoms
are prominent in acute viral hepatitis?
Jaundice is caused by hepatocyte damage or hepatocellular necrosis. Jaundice occurs in the
symptomatic icteric phase of acute viral hepatitis. Jaundiced is caused predominantly by
conjugated hyperbilirubinemia and hence is accompanied by dark colored urine related to the
presence of conjugated bilirubin. It can also be caused when the liver is damaged to the extent
that it can not conjugate bilirubin in a sufficient manner which results in a lot of circulating
bilirubin which is not water soluble and thus it is unable to be secreted.
Acute viral hepatitis is divided into 4 phases: incubation period, symptomatic preicteric phase,
symptomatic icteric phase, and convalescence. The preicteric phase is marked by malaise
followed by fatigability, nausea, and loss of appetite. Weight loss, fever, headaches, muscle and
joint aches, vomiting, diarrhea, and anorexia are inconstant symptoms. Around 10% of patients
mostly with HBV have serum sickness. Nonspecific symptoms include high fever, shaking
chills, and headache sometimes accompanied by right upper quadrant pain and tender liver
enlargement. The icteric phase is characterized by the appearance of jaundice.
Other morphological features include enlarged reddened liver. Parenchymal changes: hepatocyte
injure (swelling), cholestasis (canalicular bile plugs), HCV (fatty change of hepatocytes),
hepatocyte necrosis, lobular disarray, regenerative changes (hepatocyte proliferation), sinusoidal
cell reactive changes (accumulation of phagocytosed cellular debris in Kupffer cells and influx of
PMNs into sinusoids, and inflammation of portal tracts.
C. Which types of viral hepatitis can be prevented by vaccination? Who should receive these
vaccinations?
40
Hepatitis Virus
Hepatitis A
Vaccine? (Y/N)
YES
Hepatitis B
YES
Hepatitis C
Hepatitis D
Hepatitis E
Hepatitis G
No
No
No
No
If YES, who should receive the vaccination?
Anyone 2 years of age or older, planning to travel
to a foreign country (with poor sanitation)
All infants at birth, children 0-18 years of age that
have not been vaccinated, and people whose
behavior or jobs puts them at high risk for HBV
No vaccine
No vaccine
No vaccine
No vaccine
D. Blood for transfusions is routinely screened for which types of hepatitis?
The answer to this question is not in the transcripts, slides or book. I got it off the internet. HEP
B (risk of contraction 1/63,000 transfused) and C (risk of contraction 1/103,000 transfused) is
routinely screened for in blood intended for transfusion. The book said the blood borne
transmission of HEP A is rare, so it is not routinely screened for. The book also says that HEP D
is dependant on the presence of Chronic HEP B for multiplication, is detectable in serum, but
does not mention if it is routinely tested for. And the book does not mention the chances of HEP
E blood borne transmission. This question was asked by Dr. Waites to Dr. Benjamin in class and
Dr. Benjamin answered: “serologies include doing ELIZA and NAT to look for viral RNA; and
screening includes testing a “pool” of 20 bloods and if the “pool” reacts, they go back and find
out with one is positive.” Needless to say I don’t think that was the answer Kenny was looking
for, but yet it still shows up on our review
E. If a health care worker is vaccinated for hepatitis and has a needle stick injury, what is the
appropriate action to take? What is the likelihood of contracting hepatitis if the needle is
contaminated with hepatitis B or C?
If vaccinated for HBV then HBV will be prevented if exposed. HCV has no measures to reduce
transmission. 1.8-3% risk of transmission of HCV with a needle stick injury.
PER NANCY TOMLIN: ( I couldn’t locate a specific answer in the book, pp, or notes)
1- Report it
2- Blood to be drawn from you and the Pt. to be tested
Blood from PT. to check for HBV, HCV, HIV
Blood from you to check for your baseline numbers and to do a titer for HBV
3- From there depends on results as to what action to take
HBV- Needle stick transmission is common and it is 100 times more infectious than HIV. It is a
very tough virus that survives well on surfaces and again is very infectious. In the US there are
1.25 mil chronically infected with 73,000 new infections/yr.
HCV- Needle stick transmission is common and there is no vaccine or obvious immunity from a
natural infection. Occupational exposure to health care workers is around 4%. 60% of newly
acquired are IV drug users. 3 mil cases in US with 8-10,000 deaths/yr. New infections/yr reduced
from 180,000 in mid 80’s to 28,000 in mid 90’s.
There is a lot more info on HBV and HCV but not related to this question
41
F. Explain the methods by which hepatitis A, B, and C are diagnosed in the clinical laboratory.
Hepatitis A (HAV): Virus cannot be cultured in vitro from clinical material, and diagnosis is
made on the presence of HAV-specific IgM in the patient's blood.
Hepatitis B (HBV): Serology
 For HBV Acute Infection with resolution:
(a)Viral antigens:
1) Surface antigen (HBsAg) is secreted in excess into the blood as 22 nm spheres and tubules.
Its presence in serum indicates that virus replication is occurring in the liver
2) 'e' antigen (HBeAg) secreted protein is shed in small amounts into the blood. Its presence in
serum indicates that a high level of viral replication is occurring in the liver
3) core antigen (HBcAg) core protein is not found in blood
(b)Antibody response:
1) Surface antibody (anti-HBs) becomes detectable late in convalescence, and indicates
immunity following infection. It remains detectable for life and is not found in chronic carriers
(see below).
2) e antibody (anti-HBe) becomes detectable as viral replication falls. It indicates low infectivity
in a carrier.
3) Core IgM rises early in infection and indicates recent infection
4) Core IgG rises soon after IgM, and remains present for life in both chronic carriers as well as
those who clear the infection. Its presence indicates exposure to HBV.

Serology for HBV Chronic Carrier:
42
Hepatitis C (HCV): (a) Serology: HCV-specific IgG indicates exposure, not infectivity; (b)
PCR detects viral genome in patient's serum
G. Explain the use and diagnostic value of the following markers for hepatitis B: HBSAg,
HBeAg, HBcAg, IgM anti-HBc, IgG anti-HBs, IgG anti-HBc (p. 602-603).
Serum Marker
Present
HBs Ag
Before onset of
symptoms
Peaks
During onset overt
disease
Significance
Envelope glycoprotein
[Hepatitis B surface
antigen]
Immunogenic when in
blood
Nucleocapsid core
protein
Secreted in blood
HBe Ag
Before onset of
symptoms
During onset overt
disease
Immunogenic
indicates active viral
replication, infectivity,
and probable
progression to chronic
hepatitis
Hepatitis B core antigen
HBc Ag
Before onset of
symptoms
IgM anti HBc
Before onset of
symptoms
During onset overt
disease
Slowly replaced
with IgG anti-HBc
Prior to
43
Retained in infected
hepatocyte
rise together with IgG
anti-HBc,
convalescence
ultimately will decrease
while IgG increases
IgG anti-HB
IgG anti HBc
Once acute disease is
over
[convalescence]
Recovery phase
May persist for life
[convalescence]
Recovery phase
Basis for vaccination
strategies
Replaces IgM anti HBc
http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html
H. Describe the potential clinical outcomes of hepatitis B infection and the relative likelihood of
each occurrence.
Hepatitis B virus can produce
1) acute hepatitis with recovery and clearance of the virus
2) non-progressive chronic hepatitis
3) progressive chronic disease ending in cirrhosis
4) fulminant hepatitis with massive liver necrosis
5) an asymptomatic carrier state, with or without progressive sub-clinical disease
HBV also plays a role in the development of hepatocellular carcinoma
Figure 16-5
I. Describe the histopathological appearance of the liver with acute and chronic viral hepatitis
(Table 16-5 page 607).
44
Acute Hepatitis:
 Takes the form of diffuse swelling (ballooning degeneration), so that the cytoplasm looks
empty and contains only scattered wisps of cytoplasmic remnants.
 An inconstant finding is cholestasis, with bile plugs in canaliculi and brown pigmentation
of hepatocytes.
 Fatty change is mild and is unusual except with HCV infection.
 May generate “ground-glass” hepatocytes, which are a finely granular, eosinophilic
cytoplasm in the form of spheres and tubules.
 Two patterns of hepatocyte necrosis are seen: The first pattern is Cytolysis, which is the
rupture of cell membranes. The necrotic cells appear to have “dropped out”, with collapse
of the sinusoidal collagen reticulin framework. Macrophages aggregate into these mark
sites of dropout. The second pattern is apoptosis. Apoptotic hepatocytes shrink, become
eosinophilic, and have fragmented nuclei.
 Inflammation is present. Kupffer cells undergo hypertrophy and hyperplasia and are often
laden with lipofuscin pigment caused by phagocytosis.
 The portal tracts are usually infiltrated with a mixture of inflammatory cells.
 Bile duct epithelium may become reactive and may proliferate, forming poorly defined
ductular structures in the midst of the portal tract inflammation. Bile duct destruction,
however, does not occur.
Chronic Hepatitis
 Changes shared with acute hepatitis: hepatocyte injury, necrosis, and regeneration. Also
Sinusoidal cell reactive changes.
 Smoldering hepatocyte necrosis throughout the lobule may occur in all forms of chronic
hepatitis.
 In mild forms, inflammation is limited to portal tracts and consists of lymphocytes,
macrophages, and plasma cells, and rare neutrophils or eosinophils.
 Lymphoid aggregates in the portal tract are often seen in HCV infection
 Liver architecture is usually well preserved.
 Continued periportal necrosis and bridging necrosis are harbingers of progressive liver
damage.
 The hallmark of irreversible liver damage is the deposition of fibrous tissue.
 Continued loss of hepatocytes and fibrosis results in cirrhosis, with fibrous septa and
hepatocyte regenerative nodules. This pattern of cirrhosis is characterized by irregularly
sized nodules separated by variable broad scars.
45