Pathology: Medical School Crash Course

Pathology Medical School Crash Course™

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Quiz ........................................................................................................................................... 50 Chapter 6: Genetics/Pediatric & Developmental Pathology ................................................... 53 Genetic Disorders...................................................................................................................... 53 Basics of Genetic Inheritance ................................................................................................... 66 Fetal Pathology ......................................................................................................................... 66 Key Takeaways ......................................................................................................................... 68 Quiz ........................................................................................................................................... 68 Chapter 7: Hematopoietic System/Lymph Nodes & Spleen ................................................... 71 Hematopoietic System .............................................................................................................. 71 Red Blood Cell Evaluation ....................................................................................................... 72 White Blood Cell Evaluation .................................................................................................... 74 Platelet Evaluation .................................................................................................................... 76 Peripheral Smear Findings ........................................................................................................ 77 Lymphatic System Pathology ................................................................................................... 78 Spleen Pathology ...................................................................................................................... 78 Key Takeaways ......................................................................................................................... 79 Quiz ........................................................................................................................................... 79 Chapter 8: Cardiovascular System ........................................................................................... 82 Pathology of Acute Myocardial Infarction ............................................................................... 82 The Pathology of Myocarditis .................................................................................................. 84 Pathology of the Blood Vessels ................................................................................................ 86 Key Takeaways ......................................................................................................................... 89 Quiz ........................................................................................................................................... 90 Chapter 9: Respiratory System ................................................................................................. 93 Pathology of Lung Cancer ........................................................................................................ 93 Pathology of Chronic Obstructive Airway Disease .................................................................. 95 Pathology of Pneumonia ........................................................................................................... 99 Key Takeaways ....................................................................................................................... 101 Quiz ......................................................................................................................................... 101 Chapter 10: GI Disorders ......................................................................................................... 104 The Pathology of Celiac Disease ............................................................................................ 104 Pathology of Crohn’s Disease................................................................................................. 106 Pathology of Ulcerative Colitis............................................................................................... 108 Key Takeaways ....................................................................................................................... 110

Quiz ......................................................................................................................................... 111 Chapter 11: Hepatobiliary ....................................................................................................... 114 Pathology of Viral Hepatitis ................................................................................................... 114 Pathology of Non-Alcoholic Fatty Liver Disease................................................................... 117 Pathology of Liver Cirrhosis................................................................................................... 120 Key Takeaways ....................................................................................................................... 122 Quiz ......................................................................................................................................... 123 Chapter 12: Nutrition/Oral Cavity.......................................................................................... 126 Pathology of Malabsorption.................................................................................................... 126 Pathology of Mouth Diseases ................................................................................................. 129 Key Takeaways ....................................................................................................................... 131 Quiz ......................................................................................................................................... 131 Summary .................................................................................................................................... 134 Course Test Questions .............................................................................................................. 136 Course Test Answers ................................................................................................................ 153

Preface This course involves a discussion of the many different facets of the pathology of human diseases. The course starts with an overview of the cellular pathological response to injury or to an environmental insult. There can be a variety of cellular responses to insult, with the cellular response to a burn injury and an infectious disease being important aspects of cellular metabolism.

The second chapter of the course is all about the study of cellular pathology and anatomic pathology. Pathologies evaluate microscopy slides in order to identify diseases on a microscopic level. Autopsies of human remains are also performed in cases where the cause of death was unclear in cases where the cause of death was suspicious for homicide or suicide.

The third chapter in the course is a brief overview of the pathology of inflammation and tissue repair. Cells respond to injury by becoming inflamed and then repairing themselves, restoring homeostasis and decreasing the inflammatory response brought on by the acute injury.

The fourth chapter in the course talks about the pathology of the immune system. The normal response of the immune system will be covered as well as the wide variety of diseases that can be termed immune-related pathological disorders.

The fifth chapter in the course involves a discussion on various types of neoplasia in the human body. There are solid neoplasias that can be cancerous or benign. There can be neoplasias that do not form a solid mass but exist in cellular form, such as cases of human leukemia and lymphoma.

The sixth chapter of the course talks about the various genetic diseases that can affect individuals from the time of the prenatal period until adulthood. Genetic diseases can involve the entire chromosome, a single gene, or a cluster of genes. Disorders stemming from genetic diseases can be inherited in a variety of ways. Along with genetic diseases, the chapter will cover the pathology related to fetal demise in utero.

The seventh chapter of the course will talk about the pathology of the hematopoietic system, including diseases of the blood, diseases of the lymph nodes, and diseases of the spleen as it relates to its effect on the blood.

The eighth chapter of the course will cover the pathology of the cardiovascular system. This includes the pathology involved in the diagnosis of an acute myocardial infarction, myocarditis, and diseases of the blood vessels themselves.

The ninth chapter of the course will cover the pathology seen in diseases of the respiratory system. This includes diseases such as chronic obstructive pulmonary disease, acute pneumonia, and cancer of the lung.

The tenth chapter of the course is primarily associated with the pathology of the gastrointestinal tract. The main diseases a pathologist will encounter as part of gastrointestinal diseases will be covered, including celiac disease, Crohn’s disease, ulcerative colitis, and adenocarcinoma of the colon.

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The eleventh chapter in the course is a brief discussion of the pathology of hepatobiliary diseases. The main hepatobiliary diseases faced by the pathologist include viral hepatitis, nonalcoholic fatty liver disease, and cirrhosis of the liver.

The last chapter of the course will include a discussion of the pathology of the gastrointestinal tract, specifically at those pathological diseases resulting in nutritional deficiencies and malabsorption. Disorders of the mouth, including oral cancer will also be covered in this section.

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Chapter 1: Cell and Tissue Response to Injury/Environmental Pathology This chapter is about the pathological responses to certain environmental stressors. In particular, the chapter discusses the cellular and tissue changes that occur when an individual sustains a significant burn as well as what happens when burned tissue becomes infected. Tissues of the skin and other organs can become infected in the absence of a burn. Also discussed in this chapter is the pathology seen when a body tissue becomes infected.

Metabolic Response to Burns On a macroscopic scale, burns have a significant effect on the metabolism of the patient’s organs and tissues. There is a hyperdynamic circulatory system, physiologic adaptations to injury and rapid fluid loss, immune system responses, and total body catabolism, which increases the metabolic and nutritional needs of the burned patient.

Some of the hypermetabolic response can be moderated by early excision of burned tissue and grafting, which will decrease fluid losses. Nutrients are given to cover for the hypermetabolic state and growth factors promote healing.

After a burn, the body responds by increasing its metabolism. The blood pressure and heart rate increases, and there is an increase in insulin resistance, resulting in hyperglycemia. There is increased catabolism of both proteins and lipids, which leads to an increase in body temperature, high energy expenditures by the cells, loss of total body protein, wasting of the muscles, and stimulation of acute phase proteins. This response can be seen in other types of critically ill patients but it is enhanced when the individual has sustained a large burn.

The cause of this type of total body response is not completely understood. What is known is that there is an increase in glucocorticoids, catecholamines, glucagon, and dopamine that initiate a global response that leads to a hypermetabolic state and an overabundance of catabolism.

Multiple immune factors get stimulated as well as reactive oxygen species and coagulation factors. There is altered glucose metabolism in the cells which need managing in the acute care setting.

Histologically, there are three separate zones of tissue associated with a burn. The first zone is known as the zone of coagulation. This is where the maximal damage to tissue has happened.

The tissue loss is irreversible because of coagulation of proteins, which cause cellular death.

Around this is the zone of stasis. This is characterized by a reduction in the perfusion of the tissue that is potentially reversible with urgent resuscitation. Things like infection, swelling, and prolonged hypotension can cause tissue loss in this area, which is irreversible. Around this is the zone of hyperemia. There is an increase in tissue perfusion here and a strong possibility of tissue recovery unless there is prolonged hypotension or severe sepsis.

If a burn involves more than thirty percent of the total body surface area, there is a release of cytokines and other inflammatory mediators that have a systemic effect on the body. In the 3

cardiovascular system, there is an increase in capillary permeability and a loss of proteins from the intravascular space as they leak into the interstitial space. There is vasoconstriction of both the peripheral and splanchnic vessels. The contractility of the heart increases in response to tumor necrosis factor alpha release. There is a great deal of fluid loss in a major burn, which causes secondary hypotension and end-organ perfusion reduction.

Inflammatory mediators also result in bronchoconstriction in the lungs and can set up a situation that leads to acute respiratory distress syndrome. The basal metabolic rate can increase to as high as three times the normal rate. There is splanchnic hypoperfusion, which can affect nutrient absorption. Early and aggressive enteral feeding is necessary to maintain the integrity of the gut and to decrease the catabolic state. There is down regulation of the immune response that can adversely affect the way the immune system works.

Burns create a state of immunosuppression that increases the likelihood of secondary infectious complications. Even with maximal burn treatment, burn patients are at high risk for sepsis, inflammatory response syndrome, and multiple end organ dysfunction.

Immune Response to Burns The normal defense against infection involves both the innate and adaptive immune systems.

The innate immune system acts as soon as there is a breach in the skin. Cells of this system are activated to protect the broken and damaged skin from pathogens. The innate immune system takes longer to activate but is more efficient in killing pathogens in the long run. Unfortunately, the immunosuppression seen in burn victims adversely affects both these immune components.

Even though there is local inflammation and the beginning of wound healing after a burn, major burns lead to a systemic response. Systemic inflammatory response syndrome can occur, which can progress to septic shock. This leads to major end organ damage and cell death from hypoperfusion of tissues not involved in the burn itself. Initially, the response is proinflammatory but later the response is anti-inflammatory as the body tries to maintain homeostasis and to restore baseline physiology. These phases are mediated by cytokines and cellular responses.

In the inflammatory phase, there is an increase in the amount of proinflammatory cytokines in the bloodstream. Interleukin one beta and tumor necrosis factor alpha are made by the cells, particularly by leukocytes. This causes the fever seen in burn patients and the systemic state of catabolism. There is an increase in prostaglandin E production, interleukin six production, and platelet-activating factor production. Interleukin six is responsible for fever and the making of acute phase reactants that increase the activation of T cells. High levels of interleukin six are linked to an increased risk of morbidity and death in burn patients.

The anti-inflammatory phase of burn recovery occurs next. There is immunosuppression and a decrease in the activity of monocytes and macrophages. Macrophages produce high amounts prostaglandin E2 and decreased amounts of interleukin twelve, which promotes T cell differentiation. T helper cells evolve into Th two cells, which produce anti-inflammatory cytokines. Following a burn, the body produces high levels of vasopressin, growth hormone, aldosterone, glucagon, catecholamines, and cortisol. High levels of prostaglandin E two by 4

macrophages causes a decrease in the proliferation of lymphocytes and decreases the levels of proinflammatory cytokines. Natural killer cell activity is inhibited and the effectiveness of the adaptive immune system is diminished.

The innate immune system responds to a burn injury, providing a natural resistance to infection early in the course of the burn. They initiate a significant localized and systemic inflammatory response, providing the stimulus for the activation of the adaptive immune system.

Unfortunately, the overall effect is to decrease the patient’s ability to fight off pathogens that invade burned tissue. Besides the obvious penetration by pathogens in the burned skin, there is an increase in the chance of gastrointestinal pathogen infection because the barrier function of the gastrointestinal epithelium is impaired. There is decreased intestinal motility and decreased mucus secretion, which exposes the body to endotoxins. This derangement in intestinal permeability contributes to the end organ damage seen in burn victims.

At the site of the burn injury, there is a reduction in the ability of macrophages to phagocytize pathogens and a disruption in the normal immune response. High levels of prostaglandin E two are made, which suppresses the ability of B cells and T cells to react to pathogens. Overall, there is a suppression of the ability of the body to kill both bacterial and fungal organisms.

Alterations in the function of the innate immune system result in increasing the burn patient’s exposure to pathogens. The natural defenses for counteracting these organisms is decreased so infection risk increases. The anti-inflammatory phase of burn healing suppresses the natural killer cells, macrophages, and neutrophils, so infection is more likely to occur. Patients are at risk for wound infections and sepsis, with a high chance of end organ damage.

The adaptive immune system also responds in burn situations. There are changes in the T lymphocyte population with a reduction in numbers see in the first week after a burn. The function of the T cells is also decreased with a reduction in the amount of immunoglobulin G. After an initial stage of proinflammation, the anti-inflammation stage occurs, which is associated with an increase in septic events in burn patients.

In order to reduce the incidence of burn-related complications, the goal is to surgically resect the burn as soon as possible and graft it so there is an intact skin barrier. Aggressive nutritional support along with fluid resuscitation to maintain blood pressure and end organ perfusion can optimize the oxidative killing capacity of the neutrophils, which improves immune function.

Attention to nutritional support helps increase protein production and will help restore immune function.

Burn Infections The most serious complication in a burn injury is a wound infection in the early stages of the injury. The risk of infection is diminished by excising the burn early and replacing lost skin with grafted skin but there is still a high risk of infection. The use of topical antibiotics and preventative antibiotics plays a role in diminishing the chances of having a wound infection in a burn setting.

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Very young children and the elderly are at an increased risk of getting burned in the first place and have worsened clinical outcomes. Disabled people and people who deliberately burn themselves also have a worsened outcome. Obesity and diabetes contributes to an increase in mortality after a burn. Patients who are already immunosuppressed from an underlying disease process have an increased chance of complications related to burn infections.

There has been an ongoing decline in wound infections following burns after the protocols changed to involve early excision of burned tissues. Prior to these changes, the wound was left open, allowing for colonization of the wound by pathogens before the wound had a chance to heal secondarily. Patients were at risk of being colonized by pathogens coming from the outside as well as by pathogens entering the body through a highly permeable gut wall. Patients were at an increased risk of nosocomial infections from introduction of bacteria by the hands of healthcare workers before it was determined that these people needed strict isolation from bacteria brought to their skin surface by unclean hands. In the past, many patients with burns received hydrotherapy, which caused infection as the tanks were difficult to clean and there was cross-contamination from patient to patient through the use of these tanks. The current use of showering with hand-held sprayers has decreased the risk of this type of infection.

Wound factors that play a role in burn infections include loss of a protective skin barrier and suppression of both the local and systemic immune response. The surface of the burn is usually avascular and this provides a medium for the growth of organisms that can cause infection to tissues that aren’t adequately perfused. Toxic substances released by the dead tissue have an adverse reaction to the host’s immune response, increasing the infection risk.

In the beginning of burn recovery, the wound becomes colonized by Staphylococcal organisms that survived the thermal injury. They can, however, be suppressed by using topical antibiotic creams. After a week or so, however, organisms of every type can colonize the wound, including organisms that have invaded the body through the weakened abdominal wall. Upper respiratory tract flora can also colonize the wound. Yeast can be transmitted from staff workers’ hands to the wound. If the wound isn’t rapidly excised and grafted, there can be infectious involvement of viable tissue as well.

After a burn injury, bacteria quickly colonize any open wound. As mentioned, they come from the patient’s skin, gastrointestinal tract, and respiratory tract, as well as from contact with external sources in the environment. When broad-spectrum antibiotics are used for prevention or treatment of bacterial burn infections, the wounds can become colonized by fungi and yeast organisms. Externally-derived organisms in a hospital environment tend to be much more resistant to treatment than those acquired in the general community, compounding the treatment of these wounds.

Before antibiotics were used, most patients succumbed to Streptococcus pyogenes infections.

After penicillin came into use, patients succumbed primarily to Staphylococcus aureus wound infections. Now, the most common wound infection seen is one caused by Pseudomonas aeruginosa that comes from the gastrointestinal tract. Anaerobic infections are possible but less likely when occlusive dressings are used.

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The risk of burn infections depends on the extent and depth of the burn as well as host factors that influence the immune response. Both Staphylococcus aureus and Pseudomonas aeruginosa release virulence factors that cause invasive infections. These infectious organisms have antimicrobial resistance traits that make them less likely to be killed by the usual antibiotics given for the treatment of burn infections. Antibiotic resistance is likely in a hospital setting, which contributes to the difficulty in healing these types of wounds.

Wound infections in burn patients delay maturation of epidermal tissue and increase the incidence of scarring. Microorganisms can invade the deeper tissues and can reach the blood supply, leading to bacteremia, septicemia, and end organ damage. Because of this, burn patients need tissue cultures, blood cultures, and urine cultures as soon as it becomes apparent the wound has become infected. Antibiotics need to be given early and dressing changes need to happen often in order to prevent tissue damage and systemic complications.

Burn wound impetigo can happen in a burn situation. This involves a loss of the epithelium from intact skin or from the graft. It can happen any time there is incomplete excision of the burn, hematoma beneath the graft, or mechanical disruption of the graft. A surgical wound infection can happen to tissue that has not yet epithelialized. The wound will have a purulent exudate that will culture out the offending organism. There will be evidence of hyperemia around the burn and a change in the characteristic of the wound itself.

Burn wound cellulitis results from an infection that has extended from the injured area into the healthy area of skin. It is evident by the finding of increased swelling and redness around the wound along with increased pain and tenderness of the affected area. Lymphangitis or lymphadenitis can be seen as the infection spreads through the lymphatic system.

Invasive infection is always possible whenever there is burn tissue that has not been excised.

There is a change in the appearance of the burn and inflammation of the surrounding healthy skin. Swelling of the tissues is seen as well as warmth and tenderness. Histology will show invasion of healthy tissue by bacterial organisms and blood cultures are likely to be positive for bacteria. There will be systemic signs of sepsis and unexplainable hyperglycemia from insulin resistance. The best way to handle these wounds is to give appropriate antibiotics and to excise any burn tissue that is remaining.

Burn wound infections are usually a clinical diagnosis but sampling of the wound can be done to show a causative organism. Tissue biopsies can be done to show extension of infection into healthy tissue in invasive infections. As an alternative to tissue biopsy, the surface of the wound can be swabbed in order to find the organism responsible for the infection. In cases of suspected systemic infection, cultures need to be obtained from blood, tissue biopsy, wound culture, and urine sampling to find the causative organism. Tissue biopsies are necessary whenever there is a suspected fungal or virus infection of the wound.

Histologically, a tissue biopsy from an infected burn wound will show invasion of microbial organisms beneath the surface of the burn eschar. This tissue can also be cultured to show actual infection of the tissue and will identify the causative organism. Tissue biopsies showing deep invasion of normal tissue by bacteria need more aggressive intravenous antibiotic treatment. The 7

tissue biopsy can also tell the difference between wound colonization and a wound infection by the demonstration of inflammatory reactions seen in wound infections that are not seen with simple wound colonization. There will also not be any clinical symptoms when the wound is just colonized with bacteria.

Unfortunately, there has been an increasing trend toward antimicrobial resistance in many large burn units. Things like methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci have adversely impacted the care of burn patients even with modern day antibiotic use. Nosocomial infections are always possible in a hospital setting. These can be decreased by using strict hygiene measures when caring for the patient and appropriate use of empiric antimicrobial therapy as soon as infection is suspected.

Cellular Responses to Injury The immune system in humans has evolved to have several lines of defense against pathogens in the event of an injury or illness. Things that contribute to the development of infection include a lack of mechanical barriers, disturbance of fluid drainage from the body, infection of secretions, alteration in microbial flora, and some type of concurrent immunodeficiency.

Mechanical barriers include the skin that can be damaged in burns and open wounds. Skull fractures can open a mechanical barrier that may lead to secondary infection. Poor vascularization of tissue leads to a decreased ability of the immune system to function and an increased risk of tissue infection. If secretions are not drained adequately, the risk of infection to the affected area is high. This includes not only the drainage of wound secretions but the ongoing drainage of urine that could become a source of infection if not drained properly.

Patients with respiratory secretions need drainage of these secretions to decrease the rate of respiratory infections.

There are normal bacteria on the skin and other body areas that predominate so that infectious organisms can’t colonize. Loss of normal flora from skin, respiratory tract linings, and gastrointestinal tract linings can result in superinfection with pathogens. The injudicious use of antibiotics can cause a loss of normal flora so invading organisms can take hold.

Different types of pathogens can cause different ways of harming the host. There can be endotoxins that damage tissue, viruses that invade cells, and bacteria that gain access to the intracellular environment of the host. Parasites can take hold and encapsulated bacteria can be resistant to antibiotics. The immune response to the infection can be so significant that it kills the host rather than the pathogen.

In the acute phase of an infection, there is a release of both interleukin one and interleukin two by macrophages that enter the bloodstream. These molecules stimulate the liver to respond by increasing protein production and complement proteins. C-reactive protein is one protein made by the liver that acts like a type of antibody that can bind to certain bacteria. The presence of infection in a host can be identified by elevations in the C-reactive protein level.

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The interaction between T cells and B cells heralds an ongoing infection. Bacteria express proteins that are identified by B cells. The B cells make antibodies to the bacterial antigens, which sets up the humoral immune system, which is an antibody-antigen system. T helper cells become involved and the antibodies bound to bacteria get recognized by T cells so they can be destroyed by these cells. Different kinds of antibodies are produced by different cells in the body. For example, IgA is preferentially made by epithelial cells of the gastrointestinal tract.

Memory cells are made from B cells, which allows for rapid response any time the host is reexposed to the antigen.

In septicemia and septic shock, the neutrophils in the bloodstream are unable to remove the bacteria from the bloodstream and systemic infection ensues. The spleen is recruited to remove pathogens that are not coated with antibodies to be targeted for destruction. Because the spleen is so important in the prevention of systemic infection, patients who have had their spleen removed are at a higher risk for systemic infections.

The finding of endotoxic shock can be seen when toxins affect the blood flow to end organs, resulting in multi-organ system failure and eventual circulatory collapse. The cause of the collapse is an exaggerated release of inflammatory cells by immune cells, particularly macrophages. There is a fine line between mounting an adequate immune response to a pathogen and killing the host because of a hyperactive immune system.

Organisms that are particularly dangerous to humans include Neisseriae meningitidis, Pneumococcus, and Haemophilus. These bacteria are encapsulated, making them less able to be degraded by the human immune system. They can’t bring about an adequate T helper cell response. These types of infections are particularly dangerous to young children who don’t respond with an adequate antibody response to these types of bacteria.

Viral infections in humans can become uncontrolled by immunosuppression of T cells. Viruses that are particularly able to do this are herpes viruses, cytomegaloviruses, and Epstein Barr virus.

In order to fight these infections, natural killer cells have evolved in ways that can directly kill these organisms without an antibody response necessary.

Immunity to non-viral microbes is normally the responsibility of T cells. Unfortunately, several organisms have evolved that can evade the intracellular killing of these pathogens. Some organisms that are particularly resistant to cell mediated death include Mycobacterium tuberculosis, Salmonella, Listeria, and certain protozoal organisms. Immune response to these organisms depends on aggressively killing them by macrophages, which don’t need an antibody to kill them off.

Parasitic organisms can invade mucosal surfaces in the gastrointestinal tract or the skin.

Parasites have complex mechanisms for the evasion of the immune response and are highly effective in causing infection if not prevented from causing infection in the first place. The host response to parasitic infections is to generate IgE, which promotes an anaphylactic response from the release of histamine and other immune molecules. It takes the action of eosinophils in order to adequately kill off parasites.

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Key Takeaways • • • • • •

Burn patients can be better managed by rapidly excising the eschar and grafting the affected area.

Burn victims go through a pro-inflammatory period followed by an anti-inflammatory period.

The anti-inflammatory period puts a person at risk for infection because it involves a general suppression of the immune system.

Burn victims have infection from respiratory organisms, gastrointestinal organisms, and skinrelated organisms.

Systemic infections can be prevented by maintaining mechanical barriers, draining fluids, and draining secretions.

Certain pathogens have evolved in ways that make them difficult to kill off by conventional immune mechanisms.

Quiz 1. Why is feeding burn patients as early as possible a good idea in order to prevent tissue damage? a. It allows the liver to make more proteins necessary for the immune response. b. It provides adequate nutrition to compensate for the victim’s hypermetabolic state. c. It allows for enhanced antibody production. d. It gives immune cells the nutrition they need to fight off infection.

Answer: b. Burn patients need to be treated early with feeding in order to compensate for their hypermetabolic state that would otherwise use valuable resources necessary for fighting infection.

2. Which cell type is most active in the local innate immune response in burns and other open wounds? a. Neutrophils b. T cells c. B cells d. Macrophages Answer: d. Macrophages are the cells most active at the wound site and are the main cell used in the innate immune system.

3. If a patient is suspected of an invasive burn wound, what evaluation can best detect this? a. Wound culture of exudate b. Tissue biopsy of the wound c. Blood culture d. CBC Answer: b. A tissue biopsy can show evidence of invasive disease and can identify the offending organism before a culture can be obtained.

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