HIV, Environmental, and Nutritional Diseases Flashcards
1
Q
What are the three major routes of transmission for HIV?
A
- Sexual contact
- Parenteral inocculation
- Passage of virus from infected mothers to newborns
2
Q
What is the risk of HIV seroconversion for health care workers after needle-stick accidents?
A
- Believed to be about 0.3%, and antiretroviral therapy given w/in 24-48 hours of needle stick can reduce the risk of infection 8x
- By comparison, approximately 30% of those accidentally exposed to Hep-B-infected blood become seropositive
- Overall, an extremely small, but definite risk is present, and seroconversion has been documented after accidental needle-stick injury or exposure of non-intact skin to infected blood in laboratory incidents
3
Q
Explain why HIV infects memory and activated T cells, but is inefficient at productively infecting naive (unactivated) T cells.
A
- Naive T cells contain active form of enzyme that introduces mutations in HIV genome -> APOBEC3G, aka, apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G
- Cytidine deaminase that introduces cytosine-to-uracil mutations in viral DNA made by reverse transcription
- Mutations inhibit further DNA replication by mechs that are not fully defined
- Activation of T cells converts cellular APOBEC3G into an inactive, high-molecular-mass complex, which explains why the virus can replicate in previously activated (e.g., memory) T cells and T-cell lines
- HIV has also evolved to counteract this cellular defense mechanism; the viral protein Vif binds to APOBEC3G and promotes its degradation by cellular proteases
4
Q
What is Vif?
A
A viral protein that binds to APOBEC3G and promotes its degradation by cellular proteases
5
Q
Imagine you are a radiologist, looking at this chest x-ray with no history provided. This is classic. What is it? How did smoking cause it?
A
- This is a right middle lobe lobar pneumonia probably due to pneumococcus
- Toxins in cigarette smoke:
1. Injure the mucociliary apparatus used for escalating bacteria out of lungs
2. Cause inflammation, recruiting phagocytes that leak their proteases
3. Inhibit anti-proteases needed to protect against protease tissue injury
4. Cause mucus production and secretion yielding a place for bacteria to grow
5. Inhibit phagocytosis and bacterial killing by phagocytes
6. Cause squamous metaplasia, removing mucociliary clearance of bacteria
7. Kill respiratory epithelial cells, removing a barrier to bacterial invasion
6
Q
List some of the adverse effects of smoking.
A
- Pulmonary emphysema, chronic bronchitis, COPD, bacterial pneumonia
- Hypertension, tachycardia, atherosclerotic CVD (myocardial, cerebral, and extremity ischemia and infarction)
- Thromboangiitis obliterans (Buerger disease)
- Spontaneous abortion, intrauterine growth restriction, preterm birth and diseases of prematurity
- Cancer of lung, larynx, mouth, esophagus, stomach, colon, pancreas, liver, kidney, bladder, breast, uterine cervix, and other organs
7
Q
What is going on with this lung?
A
Pulmonary emphysema
8
Q
What is wrong with this lung?
A
- Pulmonary emphysema
- Abnormal, permanent enlargement of airspaces due to destruction of walls between alveoli
9
Q
Describe this lung.
A
Normal lung
10
Q
Explain how smoking and drinking are related.
A
Multiplicative increase in risk of laryngeal cancer from interaction between cigarette smoking and alcohol consumption -> synergistic toxicity
11
Q
What is this?
A
- This is a respiratory bronchiole with large numbers of macrophages loaded with “dusty,” finely granular brown and black pigment in the bronchiolar lumen and a few lymphocytes
- Respiratory bronchiolitis: characteristic of smoking injury to bronchioles
12
Q
A patient is about to drop over dead from the condition shown here, which is a trichrome stain of a coronary artery. What is the condition? How did smoking contribute to causing this early death?
A
- This is thrombosis of the coronary artery precipitated by the rupture of an atherosclerotic plaque
- Toxins in cigarette smoke get into bloodstream and:
1. Injure endothelial cells, increasing permeability of lipids into arteries
2. Induce a pro-coagulant state
3. Increase heart rate, blood pressure, and myocardial contractility, which increases heart need for blood
4. Decrease blood oxygen-carrying capacity (carbon monoxide)
5. Play a role in causing one-third of MI
13
Q
Compare electronic cigarettes to traditional cigarettes.
A
- Electronic cigarette vapor lacks most of the cancer-causing components of cigarette smoke
- However, nicotine is the component of cigarette smoke that causes most of the cardiovascular (CV) harm of smoking
- Electornic cigarettes have most, if not all, of the CV harm of tobacco cigarettes
14
Q
What is the toxic metal in these cells?
A
- Iron -> hemochromatosis: genetic disease causing excess iron absorption and injurious accumulation in hepatocytes and other cells
- Lead, mercury, arsenic, and cadmium, the heavy metals most commonly associated with harmful effects in humans are NOT visible as pigments in tissue
15
Q
What do you call these cells?
A
- Smoker’s macrophages
- Pigment in them is a very light brown, and is in such tiny granules they are not individually discernable
- Black pigment can also be mixed in
16
Q
What condition does this individual have?
A
Carbon monoxide poisoning: causes a red discoloration of skin and mucus membranes (code word: “cherry red”)
17
Q
What is the pathophysiology of carbon monoxide poisoning?
A
- Binds to hemoglobin 200x better than O2 and blocks O2 binding, transport, and delivery to tissues who need it
- Symptoms (headache and exertional dyspnea) appear when 20-30% of hemoglobin is bound to carbon monoxide, and coma and death when 60-70% is bound to it
18
Q
What is carbon monoxide?
A
- Systemic asphyxiant that is an important cause of accidental and suicidal death
- Non-irritating, colorless, tasteless, odorless gas
- Most important envo source of CO is burning of carbonaceous materials, i.e., automotive engines, furnaces, cigarettes -> in small, closed garage, average running car can produce sufficient CO to induce coma or death within 5 minutes
- CO concentrations can also rapidly rise to toxic levels with improper use of gasoline-powered generators, e.g., during power outages
19
Q
How does carbon monoxide affect the CNS?
A
CO kills in part by inducing CNS depression, which apears so insidiously that victims are often unaware of their plight
20
Q
Describe chronic poisoning by CO.
A
- Carboxyhemoglobin is very stable, so even with low-level, persistent exposure to CO, carboxyhemoglobin may rise to life-threatening levels in the blood
- Slowly-developing hypoxia can evoke widespread ischemic changes in the CNS, esp. in basal ganglia and lenticular nuclei
- Cessation of CO exposure will lead to recovery, but there may be permanent neurologic sequelae, i.e., impairment of memory, vision, hearing, and speech
- Dx made by carboxyhemoglobin levels in blood
21
Q
What RBC abnormality is shown here? Describe it, and its associated conditions.
A
- Basophilic stippling consisting of clumped ribosomes
- Associated with lead poisoning, but also other disorders of red cell maturation, e.g., megaloblastic anemia due to Vit B12 or folate deficiency
22
Q
What are the manifestations of lead toxicity in children at low vs. higher concentrations?
A
- Low concentrations: cognitive impairment (esp. memory), behavior problems (esp. hyperactivity), decreased verbal ability, hearing loss, irritability, lethargy, fatigue, myalgia, vomiting, and anemia
- High concentrations: colicky abdominal pain, arthralgia, renal insufficiency, constipation, tremor, headache, intellectual disability, seizures, coma and death
23
Q
What are the manifestations of lead toxicity in adults at low vs. high concentrations?
A
- Low concentrations: short-term memory loss, difficulty concentrating, anxiety, phobias, irritability, depression and hostility
- High concentrations: peripheral demyelinating neuropathy (especially motor, especially of hands, then feet), myalgia, arthralgia, diffuse severe abdominal pain (lead colic), constipation, renal insufficiency, anemia, headache, anorexia and decreased libido
24
Q
What is the pathophysiology of lead toxicity?
A
- Electropositivity (heme toxicity): electropositive metal w/high affinity for (-) charged sulfhydryl gps, leading to inhibition of sulfhydryl-dependent enzymes like delta-aminolevulinic acid dehydratase (δ-ALA-D) and ferro-chelatase in heme synthesis, leading to high free erythrocyte protoporphyrins. Inhibition of pyrimidine 5’ nucleotidase can cause degradation of ribosomal RNA in red cells, leading to basophilic stippling
- Neurotoxicity: divalent lead competes w/Ca in mito respiration and various nerve functions -> interference w/several Ca-dependent processes and activation of protein kinase C has been implicated as a contributing mechanism in neurotoxicity
25
Q
How can you differentiate the anemia of lead toxicity from iron deficiency?
A
Both are hypochromic and microcytic, but lead toxicity is associated with basophilic stippling of red cells and high red cell free protoporphyrin (or zinc protoporphyrin)
26
Q
Describe how the completion of the viral life cycle of HIV looks in latently infected cells.
A
- Occurs only after CD4+ T cell activation -> in most cases, virus activation results in T cell lysis
- T cell activation:
-> kinase phosphorylates I kappa B, targeting it for enzymatic degradation
-> NFKB released, and travels to nucleus
-> NFKB binds gene promoter sequences, incl. the long-terminal-repeat sequences flanking the HIV genome
27
Q
Describe how HIV “uses” the immune system to infect and persist inside the host.
A
- HIV enters the body through mucosal tissues and blood, first infecting CD4+ T cells, dendritic cells, and macrophages, which carry the infection to the lymphoid tissues, where the virus may remain latent for long periods
- Active viral replication is associated with more infection of cells and progression to AIDS, whose hallmark is profound immune deficiency, primarily affecting cell-mediated immunity -> loss of CD4+ T cells, and impaired function in T cell survivors
28
Q
How do macrophages act as portals of HIV infection?
A
- Initial infection of macros or dendritic cells may be important in the pathogenesis of HIV
- Blood monocytes may be vehicles for HIV to be transported to various parts of the body, including the nervous system
- In certain tissues, such as lungs and brain, as many as many as 10-50% of macrophages are infected
29
Q
How does HIV-1 infect macrophages?
A
- Can infect and multiply in terminally differentiated, non-dividing macrophages
- Dependent on viral vpr gen -> the vpr protein allows nuclear targeting of the HIV pre-integration complex through the nuclear pore
30
Q
How are HIV-infected macrophages different than HIV-infected T cells?
A
- Infected macros bud relatively small amounts of virus from the cell surface, but contain large numbers of virus particles in their IC vacuoles
- While macros allow viral replication, they are quite resistant to cytopathic effects of HIV, in contrast to CD4+ T cells -> may be RESERVOIRS OF INFECTION whose output remains largerly protected from host defenses
- In late stages of HIV infection, when CD4+ T cell #’s decline greatly, macros may be important site of continued viral replication
31
Q
What is this microscopic finding in the brain of an AIDS patient?
A
- A microglial nodule: brain equivalent of a granuloma
- Part of the explanation for this pt’s impaired cognition (dementia)
32
Q
What is this microscopic finding in the brain of an AIDS patient?
A
- Perivascular macrophages, some forming multinucleated giant cells
1. They have viral proteins in them, identifiable by immunostains - Part of explanation for this patient’s impaired cognition (dementia)
33
Q
What are the predominant cell types in the brain infected with HIV?
A
- Macrophages and microglia, cells in the central nervous system (CNS) that belong to the macrophage lineage
- It is believed that HIV is carried into the brain by infected monocytes
34
Q
What is the mechanism of HIV-induced damage of the brain?
A
- Remains obscure: b/c neurons not infected by HIV, and extent of neuropathologic changes often less than might be expected from severity of neurologic symptoms, most believe the neurologic deficit is caused indirectly by viral products and soluble factors produced by infected microglia
- Included among the soluble factors are the usuals, i.e., IL-1, TNF, and IL-6. NO induced in neuronal cells by gp41 has been implicated
- Direct damage of neurons by soluble HIV gp120 also postulated
35
Q
Briefly describe the clinical course of HIV infection.
A
- Early period after primary infection, virus disseminates, and immune response to HIV develops, which often produces an acute viral syndrome
- Clinical latency: viral replication continues, and CD4+ T-cell count gradually decreases until it reaches critical level, below which there is substantial risk of AIDS-associated diseases
36
Q
Briefly describe the immune response to HIV infection.
A
- CTL response to HIV is detectable by 2 to 3 weeks after the initial infection, and peaks by 9 to 12 weeks
- Marked expansion of virus-specific CD8+ T-cell clones occurs during this time, and up to 10% of a patient’s CTLs may be HIV specific at 12 weeks
- The humoral immune response to HIV peaks at about 12 weeks
37
Q
How does acute HIV infection involve mucosa?
A
- Acute infection is characterized by infection of memory CD4+ T cells (expressing CCR5) in mucosal lymphoid tissues -> death of many infected cells
- B/c mucosal tissues are largest reservoir of T cells in body, and major site of memory T cells, this local loss results in considerable depletion of lymphocytes
- Few infected cells are detectable in the blood and other tissues.
- Mucosal infection is often associated with damage to the epithelium, defects in mucosal barrier functions, and translocation of microbes across the epithelium.
38
Q
How do dendritic cells spread HIV inside the host?
A
- Dendritic cells participate in the dissemination of the virus and development of host immune responses post-acute infection by capturing the virus in epithelia at sites of virus entry
- Migrate into lymph nodes, and may pass HIV to CD4+ T cells via cell-cell contact in lymphoid tissues
- Viral replication be detected in the lymph nodes within days after first exposure to HIV
39
Q
Why is viremia important in HIV infection?
A
- High numbers of HIV particles are now present in the patient’s blood
- Virus disseminates throughout the body, infecting CD4+ T cells, macrophages, and dendritic cells in peripheral lymphoid tissues
- The extent of viremia, measured as HIV-1 RNA levels, in the blood is a useful surrogate marker of HIV disease progression and is of clinical value in the management of people with HIV infection.
40
Q
What is seroconversion? When does this happen in the HIV disease process?
A
- The period of time during which anti-HIV antibodies develop and become detectable
1. Infected individual mounts antiviral humoral and cell-mediated immune responses (developing virus-specific CD8+ CTLs) - Usually within 3-7 weeks of presumed exposure
41
Q
What is most likely responsible for the initial containment of HIV infection? Why do we suspect this?
A
-
CD8+ T cells detected in the blood at about the time viral titers begin to fall
1. This (and antiviral humoral) immune response partially control infection and viral production
2. Reflected by a drop in viremia to low, but detectable levels by about 12 weeks after primary exposure
42
Q
What is the acute retroviral syndrome?
A
- Clinical presentation of initial spread of the virus and host response -> estimated 40-90% of individuals who acquire primary infection develop this syndrome
- Typically occurs 3-6 weeks post-infection, and resolves spontaneously in 2-4 weeks
- Clinically associated w/self-limited illness w/nonspecific symptoms: sore throat, myalgias, fever, weight loss and fatigue -> flulike syndrome
1. Other clinical features, incl. rash, cervical adenopathy, diarrhea, and vomiting may also occur
43
Q
What is the HIV viral set point? Why is it significant?
A
- Level of steady-state viremia at the end of the acute phase; reflects equilibrium b/t virus and host response, and may remain fairly stable for many years
- Predictor of rate of decline of CD4+ T cells, and progression of HIV disease
1. EX: in one study, only 8% of pts with viral load 36,270 copies developed AIDS in same time frame
44
Q
How does the CDC classify HIV infection?
A
- Because loss of immune containment is associated with declining CD4+ T cell counts, the three categories are based on T cell count:
1. CD4+ cells >500 cells/uL
2. 200-499 cells/uL
3.
45
Q
For clinical management, what is the most reliable short-term indicator of disease progression?
A
Blood CD4+ T cell counts
46
Q
Where in the body is HIV during the chronic phase (clinical latency period)?
A
- Lymph nodes and spleen are sites of continuous HIV replication and cell destruction
- Few or no clinical manifestations of HIV infection present
47
Q
How many T cells does HIV destroy per day in the chronic phase of infection?
A
- Up to 2 billion CD4+ T cells killed per day
- While majority of peripheral T cells do not harbor the virus, destruction of CD4+ T cells in lymphoid tissues continues during this phase, and # of circulating CD4+ T cells steadily declines
48
Q
About what percentage of CD4+ T cells are infected with HIV during the chronic stage?
A
- Early in the course of disease, CD4+ T cells can be replaced almost as quickly as they are destroyed, but by the chronic stage, up to 10% of CD4+ T cells in lymphoid organs may be infected
- Frequency of circulating CD4+ T cells that are infected at any one time may be less than 0.1% of the total CD4+ T cells
49
Q
What are the symptoms of the chronic phase of HIV (in general)? Why?
A
- Patients are either asymptomatic, or develop minor opportunistic infections, like: oral candidiasis (thrush), vaginal candidiasis, herpes zoster, mycobacterial TB, or autoimmune thrombocytopenia
- Over a period of years, the continuous cycle of virus infection, T-cell death, and new infection leads to steady decline in # of CD4+ T cells throughout body, so host defenses begin to wane
- Proportion of surviving CD4+ cells infected with HIV increases, as does the viral burden per CD4+ cell. Not unexpectedly, HIV RNA levels increase as the host begins to lose the battle with the virus
50
Q
What is going on here?
A
- This is herpes simplex virus
- Can reactivate, most often around lips, and most often with vesicles
51
Q
What does this biopsy show?
A
- This is herpes simplex virus
- Can reactivate, most often around lips, and most often with vesicles
- Biopsy shows separation, usually at dermal-epidermal junction, w/3 M giant cells (Multinucleated, with Molded nuclei, and Marginated native chromatin)
52
Q
What is this cytology for?
A
- This is herpes simplex virus
- Can reactivate, most often around lips, and most often with vesicles
- Biopsy would show separation, usually at dermal-epidermal junction, w/3 M giant cells (Multinucleated, with Molded nuclei, and Marginated native chromatin)
53
Q
What is the crisis phase of HIV disease? How do these patients present?
A
- Final phase of this disease is progression to AIDS
- Characterized by breakdown of host defense, dramatic increase in plasma virus, and severe, life-threatening clinical disease -> after variable period, serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (and dx w/AIDS)
- Typically, patient presents with long-lasting fevere (>1 month), fatigue, weight loss, and diarrhea
- In the absence of TX, most patients with HIV progress to AIDS after chronic phase lasting 7-10 years
54
Q
What is the difference between rapid progressors, non-progressors, and elite responders?
A
Exceptions to standard HIV/AIDS disease progression:
- Rapid progressors: middle, chronic phase telescoped to 2 to 3 years after primary infection
- Long-term non-progressors: untreated HIV-1–infected individuals asymptomatic for 10 years or more, with stable CD4+ T-cell counts and low levels of plasma viremia (usually about 5% to 15% of infected individuals
- Elite responders: undetectable plasma virus ( about 1% of infected individuals
55
Q
What are 2 reasons the CDC recommends initiating antiretroviral therapy (ART)?
A
- To reduce the risk of disease progression
- To prevent transmission of HIV
56
Q
What accounts for the majority of deaths in untreated patients with AIDS?
A
- Opportunistic infections: many of these represent reactivation of latent infections
- The actual frequency of infections has been markedly reduced by the advent of highly active antiretroviral therapy (HAART), which relies on a combo of 3-4 drugs that block different steps in the HIV life cycle
57
Q
What is going on in this lung tissue? Describe its significance.
A
- Pneumocystis jiroveci (reactivation of prior infection): fungal pneumonia developed by 15-30% of untreated HIV-infected pts at some time during disease course
- Alveoli fill up w/foamy exudate of cysts containing sm. organisms, and interstitium expanded w/edema and inflammatory infiltrate of lymphocytes/macros, creating alveolar-capillary block impeding gas exchange
1. Most characteristic symptom is dyspnea (like PE)
2. “” blood test abnormality is hypoxemia
NOTE: clear space around exudate an artifact of tissue processing
58
Q
What are these? How are they stained?
A
- Pneumocystis cysts
- Some with closely apposed surfaces in the center (like red blood cells), creating dark areas; others are ruptured and collapsed
- Bronchoalveolar lavage fluid stained with methenamine silver stain
59
Q
What are the most common opportunistic infections in AIDS (9)?
A
- Candida (most common fungal infection)
- Cytomegalovirus
- Atypical and typical mycobacteria
- Cryptococcus neoformans
- Toxoplasma gondii
- Cryptosporidium
- Herpes simplex virus
- Papovaviruses
- Histoplasma capsulatum
60
Q
What is going on here?
A
- Candidiasis: most common fungal infect in pts w/AIDS
- Infection of oral cavity, vagina, and esophagus are the most common clinical manifestations
- Oral candidiasis (aka, thrush): white exudate that may resemble cottage cheese
- In asymptomatic HIV-infected individuals oral candidiasis is a sign of immunologic decompensation, and it often heralds the transition to AID
NOTE: invasive candidiasis is infrequent in patients with AIDS, and usually occurs when there is drug-induced neutropenia or use of indwelling catheters
61
Q
What is histoplasmosis?
A
- One of the most common opportunistic infections in Memphis b/c hyper-endemic in MS river valley
- Very similar to TB: caseating granulomatous infection if immunocompetent, but can be more diffuse pneumonia or disseminated if severely immunocompromised
62
Q
What do you think is going on in this lung tissue?
A
- Histoplasmosis: small yeast forms, often in macrophages
- Diffuse pattern pneumonia with numerous macrophages, but no discrete granulomas, and no necrosis
63
Q
What is going on in these cells in the lung?
A
- Histoplasmosis: small yeast forms, often in macrophages
- This high-power image shows many, small (3-5 micron) yeast forms in macrophages
64
Q
What is cytomegalovirus?
A
- A virus that may cause disseminated disease, but, more commonly, affects eye and GI tract
- Cytomegalovirus retinitis occurs almost exclusively in patients w/CD4+ T cell counts less than 50 per micro-L
- GI disease, seen in 5% to 10% of cases, manifests as esophagitis and colitis, the latter associated with multiple mucosal ulcerations
65
Q
What is this? What 4 kinds of cells do you see here?
A
Cytomegalovirus (CMV): simultaneous nuclear and cyto inclusions make the infected cells very large, hence name
- Red cells
- PNM’s
- Lymphocytes
- Lg cells + basophilic nuclear inclusions with halos + granular, basophilc cytoplasmic inclusions
66
Q
What is going on here? Hint: notice the type of stain.
A
- This is an acid-fast stain showing mycobacterium TB
- They tend to be dark red (evident here) and beaded (not evident here)
67
Q
What are the 2 types of mycobacterium that classically affect PLWH? When?
A
- Reactivation of latent pulmonary M tuberculosis, and outbreaks of primary infection, early in disease course
1. Infection may be confined to lung, or involve multiple organs - dissemination more common in pts w/very low CD4+ T-cell counts. Growing # of isolates resistant to multiple antimycobacterial drugs - Disseminated bac infection with atypical mycobacteria (chiefly, mycobacterium avium-intracellulare) late, in the setting of severe immunosuppression
68
Q
What is going on here? Hint: these are microscopic findings in meninges of an AIDS pt. with persistent headache.
A
- Cryptococcus neoformans meninges: reason for the headache
1. Lymphocytes and a few macros, and round, clear spaces containing faintly basophilic, round structures - Cryptococcus occurs in about 10% of AIDS pts. As in other settings with immunosuppression, meningitis is the major clinical manifestation of cryptococcus
69
Q
This is a cerebral biopsy. What is going on with the large, granular mass in the middle of the field? What about the dark circle right next to it? Describe the mechanism.
A
- This is (cerebral) toxoplasma gondii, a frequent protozoal invader of the CNS in AIDS
1. Causes encephalitis, and is responsible for 50% of all mass lesions in the CNS - The large, granular mass in middle of the field is a cyst (latent infection reactivation), containing bradyzoites, a motile, quickly multiplying form of the protozoa
1. Active infection has tachyzoites outside the cysts (seen in this image too - very small) - The dark circle is a glial cell responding, and necrotizing
70
Q
A starvin child has a liver with this microscopic finding. What is the pathologic condition, and pathogenesis?
A
- Kwashiorkor: protein starvation with less inadequate carbohydrate nutrition
- Lack of protein for lipoprotein synthesis causes lipid to accumulate in hepatocytes
71
Q
What is the fundamental difference between kwashiorkor and marasmus?
A
- In malnourished children, protein energy metabolism presents as range of clinical syndromes, all characterized by dietary intake of proteins and calories inadequate to meet body’s needs -> marasmus and kwashiorkor are the 2 ends of the spectrum (w/considerable overlap)
- Somatic protein compartment (skeletal muscle) affected more severely in marasmus
- Visceral protein compartment (visceral organs, esp. liver) affected more severely in kwashiorkor
72
Q
What is going on with this child?
A
- Kwashiorkor: protein depravation relatively more severe than total deficit in calories -> seen in African children who have been weaned too early, and subsequently fed almost exclusively carb diet
-
Hypoalbuminemia (severe depletion of the visceral protein compartment) causes generalized edema, masking weight loss with fluid retention
1. Relative sparing of subcu fat and muscle mass -
Signs/symptoms: flaky paint appearance, loss of hair color, enlarged, fatty liver (b/c reduced synthesis of carrier protein component of lipoproteins), and devo of apathy, loss of appetite, and listlessness
1. Vitamin deficiencies and secondary infections (immune deficiencies) also likely
73
Q
What is the cause of this chid’s pathologic skin appearance? Be specific.
A
- Kwashiorkor
- Flaky paint appearance: alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation
74
Q
Describe how less severe states of kwashiorkor can occur.
A
- Often with chronic diarrheal states in which protein is not absorbed
- Or in those with chronic protein loss due to conditions such as protein-losing enteropathies, the nephrotic syndrome
75
Q
What does this patient have?
A
Marasmus
76
Q
What does this patient have?
A
Cachexia (could also be anorexia - would need to know history)
77
Q
What does this patient have?
A
Anorexia
78
Q
What is marasmus?
A
- Weight falls to 60% of normal for height, sex, age
- Growth retardation, and loss of muscle (catabolism of somatic protein compartment)
1. S_erum albumin normal_ (or slightly reduced) b/c visceral protein (more critical for survival) only marginally depleted
2. Subcu fat also mobilized as fuel, so extremities emaciated and head appears too large
3. Leptin low, which may stimulate hypothalamic-pituitary-adrenal axis to make high cortisol, contributing to lipolysis - Anemia, multiple vitamin deficiencies, and evidence of immune deficiency (esp. T-cell mediated) and concurrent infections
79
Q
Compare the features of kwashiorkor and marasmus (11).
A
- Growth failure: both
- Wasting: both (marked in M)
- Edema: K (sometimes mild)
- Hair changes: K (common), M (less common)
- Mental changes: K (very common), M (uncommon)
- Dermatosis, flaky paint: K
- Appetite: K- poor, M- good
- Anemia: K (sometimes severe), M (less severe)
- Subcu fat: K (reduced, but present), M (absent)
- Face: K (may be edematous), M (drawn-in, monkey-like)
- Fatty infiltration of liver: K
80
Q
Describe marasmus, anorexia, and cachexia (each with one sentence).
A
- Marasmus: starvation w/depravation of all nutrients in proportion
- Anorexia nervosa: psychiatric disease with self-induced starvation due to obsession with thinness (and misperceived obesity)
- Cachexia: state of profound loss of lean body mass and fat due to cytokines, esp. TNF (cancer is most common cause)
81
Q
What is anorexia nervosa?
A
- Self-induced starvation -> marked weight loss
- Primarily in previously healthy young women who have devo’d obsession with body image and thinness
- Highest death rate of any psychiatric disorder
- Amenorrhea: result of less secretion of gonadotropin-releasing hormone, and less secretion of luteinizing hormone and follicle-stimulating hormone -> considered a diagnostic feature
- Major complication: increased susceptibility to cardiac arrhythmia and sudden death, from hypokalemia
- Other common findings due to decreased thyroid hormone release include cold intolerance, bradycardia, constipation, and changes in the skin (dry/scaly) and hair. Dehydration and electrolyte abnormalities freq present. Bone density decreased b/c low estrogen levels, like in postmenopausal osteoporosis. May also have anemia, lymphopenia, and hypoalbuminemia
82
Q
Define obesity, and list its criteria.
A
- Excess body fat; most often defined in terms of BMI (weight in kg/height in m)
- Recommended classification from NIH and WHO:
1. Normal weight: 18.5-24.9 kg/m(2)
2. Overweight: 25.0-29.9
3. Obesity: > or = 30
4. Morbid obesity: > or = 40 (aka, severe or extreme)
83
Q
Are the adverse effects of obesity influenced by race?
A
- Yes, the NIH and WHO cutoffs are derived from data collected on whites but in some populations, the level of risk in terms of body fat is reached at much lower BMI (South Asians) and in others a higher BMI (AA) when compared to whites
- Current cutoffs for (South) Asians:
1. Overweight: 23-24.9
2. Obesity: >25
86
Q
Can you describe the pathologic process in this coronary artery, and diagnose it?
A
- Eccentric thickening with loose atheroma containing cholesterol clefts and a fibrous cap producing severe stenosis (about 90%) of the lumen
- Diagnosis: atherosclerosis
89
Q
What is adiponectin?
A
- Anti-inflammatory cytokine produced exclusively by adipocytes
- Enhances insulin sensitivity, and inhibits many steps in the inflammatory process
- Reduced in the metabolic syndrome
- Very high levels in the blood (1,000x higher than other polypeptide hormones); lower in obese than lean people
94
Q
How might metabolic syndrome contribute to tumor growth? Refer to the table if you need to.
A
- Metabolic syndrome is associated with insulin resistance, T2D, and hormonal changes -> increases in insulin and insulin-like growth factor-1 (IGF-1) stimulate cell proliferation and inhibit apoptosis, which may contribute to tumor growth
- Hyperinsulinemia (HI) -> decreased IGFBP-1 and 2 (IGF binding protein), increasing the bioavailability IGF-1, which promotes cell proliferation, and decreases apoptosis (effect enhanced by decreased adiponectin)
1. HI also leads to increased estrogen bioavailability, decreased sex-hormone binding globulin, and increased ovarian androgen
95
Q
An obese person has a liver with the microscopic finding shown here. What is the pathological condition, and pathogenesis of this liver condition in obesity?
A
- Non-alcoholic fatty liver disease: consistently associated with insulin resistance and metabolic syndrome (having at least 2 of: HTN, dyslipidemia, abdominal obesity, T2D)
- Insulin resistance (T2D) results in the accumulation of triglycerides in hepatocytes by at least three mechanisms:
1. Impaired oxidation of fatty acids (FA)
2. Increased syn/uptake of FA
3. Decreased hepatic secretion of very-low-density lipoproteins (VLDL) cholesterol
96
Q
Can you identify this surgically removed body part and the pathological processes prompting its removal?
A
- Gall bladder with thickened, inflamed wall (cholecystitis), containing bile, pus, gallstone, and debris
- Two main types of gallstones:
1. Cholesterol stones - contain crystalline cholesterol monohydrate (80% of stones in the West)
2. Pigment stones - Bile formation is the ONLY significant pathway for the elimination of excess cholesterol from the body -> when cholesterol concentrations exceed solubilizing capacity of bile (supersaturation), cholesterol can no longer remain dispersed and crystallizes out of solution
99
Q
Can you describe the joint articular cartilage surface from this obese patient specimen, and diagnose this condition?
A
- Irregular-shaped areas of erosion
- Osteoarthritis
101
Q
Can you describe the microscopic pathology and pathophysiologic mechanism of this lesion in breast tissue?
A
- Clusters of tumor cells invading fibrous and adipose tissue -> diagnosis = breast cancer
- Possible mechanisms:
1. Fat tissue produces excess estrogen, associated with risk of breast, endometrial, and some other cancers
2. Obese people often have increased levels of insulin and IGF-1 in their blood
3. Fat cells produce hormones, adipokines, that may stimulate cell growth. Leptin, more abundant in obese people, seems to promote cell proliferation
4. Fat cells may also have direct and indirect effects on other tumor regulators, incl. mammalian target of rapamycin (mTOR) and AMP-activated protein kinase
5. Obese people often have chronic low-level inflammation
102
Q
Can you describe the gross pathology of this lesion from the breast?
A
- Stellate (star-shaped) tan-white lesion surrounded by yellow fat
- Breast resection (lumpectomy)
- Diagnosis: breast cancer
110
Q
What are two possible diagnoses considering this image of an HIV+ patient’s brain? How would you distinguish between the two of these?
A
- Cerebral toxoplasmosis or primary CNS lymphoma: accurate interpretation of CT and MRI is critical because the treatments are different
- In 50-80% of cases, these appear similar and require careful interpretation:
1. Primary CNS lymphoma: typically sub-ependymal spread, and more frequently is a solitary lesion
2. Toxoplasmosis: tends to be scattered throughout basal ganglia and at corticomedullary junction, and is multi-focal (86%) - Ependyma: thin epithelium-like lining of ventricular system of brain and central canal of spinal cord. One of four types of neuroglia in CNS, and is involved in the production of cerebrospinal fluid (CSF)
111
Q
This is an image of a CNS-infection in an HIV-positive individual. Describe the cells, and make a diagnosis.
A
- JC virus: a human papovavirus (assoc. with neoplasms in animals, and important cause of CNS infection in HIV+) -> causes:
1. Progressive, multifocal leukoencephalopathy: due to infection of oligodendrocytes (myelin-making cells of the CNS) - Large, circular, hyperbasophilic cell in upper right corner is an infected cell
- The larger, granular cells with long, pink tails are reactive glial cells
114
Q
Describe the microscopic pathology in this sample from an AIDS patient. What do you think is going on here?
A
- Proliferation of spindle-shaped cells, creating slit-like vascular spaces -> Kaposi Sarcoma (KS)
- Patients with AIDS have a high incidence of certain tumors, esp. Kaposi, B-cell lymphoma, cervical cancer in women, and anal cancer in men
- Estimated 25-40% of untreated HIV-infected individuals will eventually develop a malignancy
- Reversible, if immune function improved (so NOT really a malignant tumor)
115
Q
What is going on here?
A
Kaposi sarcoma
129
Q
Describe how tobacco damages the body at a molecular level. Use the table if you need to.
A
- Nicotine damages vascular endothelial cells, causing inflammation via IL-8, LTB4, and TNF, attracting neutrophils
- Inactivation of anti-proteases, i.e., alpha-1-antitrypsin, reduces efficacy in “cleaning up” ROS made by elastas from neutrophils -> tissue damage
- Increased alveolar macrophage elastase and metalloproteinases in lungs may cause emphysema
130
Q
What is going on here?
A
- Emphysema in lung tissue: abnormal, permanent enlargement of airspaces due to destruction of the walls between alveoli
133
Q
How is alcohol processed by the liver? Use the attached image, if needed.
A
- Oxidized to acetaldehyde by alcohol dehydrogenase, CYP 450 system, and catalase
- Acetaldehyde converted to acetate in mito, and utilized in respiratory chain
- Oxidation by alcohol dehydrogenase depletes NAD, leading to accumulation of fat in the liver and metabolic acidosis
135
Q
What do you see here? What is the pathology?
A
- Lead lines: excess lead interferes with normal remodeling of calcified cartilage and primary bone trabeculae in the epiphyses in children, causing increased bone density
- These may also occur in the gums, where excess lead causes hyperpigmentation
- Lead inhibits the healing of fractures by increasing chondrogenesis and delaying cartilage mineralization
140
Q
What is going on with this liver?
A
- Tan-yellow color instead of the typical red-brown
- Steatosis
141
Q
What is going on here? What are some of the common causes?
A
- Hepatocytes distended with clear cytoplasm due to lipid dissolved out during processing
-
Steatosis
1. Common causes: alcohol, obesity, uncontrolled diabetes
142
Q
What is this?
A
Normal liver
144
Q
Can you describe what is wrong with this liver, and name the condition?
A
- In addition to steatosis, there is acute neutrophilic inflammation, and some dying or dead hepatocytes with pyknotic nuclei
- Steatohepatitis
145
Q
What is this?
A
Normal liver
147
Q
What are the hypereosinophilic clumps seen in some of these cells?
A
-
Mallory-Denk bodies: tangled skins of deranged cytoskeletal cytokeratin intermediate filaments
1. Inclusion found in cytoplasm of liver cells
2. Damaged intermediate filaments
3. Most common in alcoholic hepatitis (65% prevalence) and alcoholic cirrhosis (51% prevalence)
148
Q
What is going on with this liver? Define it.
A
- Abnormal, nodular architecture -> cirrhosis
- Cirrhosis is a distinctive form of liver fibrosis w/regenerative nodules of hepatocytes, not properly connected to hepatic arterial supply, portal veinous circulation or biliary system, and surrounded by fibrous tissue
149
Q
What are these?
A
- Round-oval nodules of regenerative hepatocytes completely surrounded by fibrous tissue, characteristic of cirrhosis
151
Q
What is going on here?
A
- Trabeculae (right side) and glandular structures of cells that look like hepatocytes, but with bigger nuclei, less cytoplasm, and bile in some of the glandular structure lumens
- Hepatocellular carcinoma (liver cancer; complication of alcoholic liver disease): cause of death in 3-6% of cases of alcoholic liver disease
152
Q
What is going on here?
A
- Rounded, variegated, green, brown, and tan mass with background cirrhosis
- Hepatocellular carcinoma
153
Q
What are the characteristics of fetal alcohol syndrome? Use the image, if needed.
A
- Specific dysmorphic facial features
- Growth retardation
- CNS abnormalities: wide range of neurobehavioral problems, incl. impairment of self-regulation, cognition, and adaptive functioning
159
Q
How is acetaminophen metabolized?
A
- Metabolized to NAPQI (N-acetyl-p-benzoquinoneimine) via hepatic P450 system
- With very large doses, excess NAPQI leads to hepatic centrilobular necrosis
162
Q
Describe the molecular mechanism of cocaine.
A
- Can induce myocardial ischemia via coronary artery vasoconstriction + enhancing platelet aggregation and thrombus formation (Norepi/dopa reuptake inhibitor)
- Cigarette smoking potentiates cocaine-induced coronary vasospasm -> dual effect of cocaine, causing increased myocardial O2 demand by sympathomimetic action, and, decreasing coronary blood flow, sets stage for myocardial ischemia that may lead to MI
- Cocaine can also precipitate lethal arrhythmias by enhanced sympathetic activity, disrupting normal ion (K+, Ca 2+, Na+) transport in myocardium
- Toxic effects are not necessarily dose related, and fatal event may occur in first time user w/typical mood-altering dose
168
Q
What is going on here, especially at 1, 2, and 3?
A
- Low power view of ileum resected for obstruction caused by radiation therapy for uterine cervical squamous cell carcinoma
- Note the sharp border between the normal ileum (arrow 1) and the injured ileum
- The radiation-injured part is totally replaced by fibrous scar tissue (even the muscle layer above arrow 2)
- The epithelium is gone (arrow 3)
169
Q
What is up with the cells indicated by black arrows? Why is their appearance troubling for pathologists?
A
- Abnormal, pleomorphic, radiation-injured cells
- Radiant energy may induce cytoplasmic swelling, mito distortion, and degeneration of ER; plasma membrane breaks and focal defects may be seen
- Histologic constellation of cellular pleomorphism, giant-cell formation, conformational changes in nuclei, abnormal mitotic figures creates similarity b/t radiation-injured cells and cancer cells, a problem plaguing the pathologist when evaluating irradiated tissues for the possible persistence of tumor cells
170
Q
What is going on here?
A
- Artery (former) obliterated by radiation injury (junction of what used to be tunica intima and media arrowed)
- Vascular changes and interstitial fibrosis prominent in irradiated tissues. In immediate postirradiation period, vessels may show only dilation
- With time, or higher doses, a variety of degenerative changes appear, including endo cell swelling and vacuolation, or even necrosis and dissolution of walls of small vessels (e.g., venules or capillaries) -> affected vessels may rupture or thrombose
- Still later, endo cell proliferation and collagenous hyalinization and thickening of intima seen, resulting in marked narrowing or even obliteration of vascular lumens. At this time, increase in interstitial collagen in irradiated field becomes evident, leading to scarring
173
Q
What are the molecular mediators of cachexia? What is the mechanism?
A
- Mediators secreted by tumors and during chronic inflammation reactions contribute to devo:
1. Proteolysis-inducing factor: glycosylated polypeptide excreted in urine of weight-losing pts w/pancreatic, breast, colon, & o/cancers
2. Lipid-mobilizing factor: increases FA oxidation, and pro-inflammatory cytokines like TNF (aka, cachectin) and IL-6 - Proteolysis-inducing factor + pro-inflammatory cytokines cause skeletal muscle breakdown via NFKB-induced activation of ubiquitin proteasome pathway, promoting degradation of skeletal muscle structural proteins like myosin heavy chain by upregulating the expression of several muscle-specific ubiquitin ligases
- Other data implicate acquired abnormalities of the myofibril dystrophin-glycoprotein complex (figure), the same membrane complex that is defective in several forms of muscular dystrophy
177
Q
Describe the entry of retinol into the body, from its ingestion to its storage.
A
- Generally ingested as retinol ester or β-carotene (which is converted to retinol) and absorbed in intestine
- Transported in chylomicrons to liver for esterification & storage; uptake in liver via apolipoprotein E receptor
- >90% of body’s vitamin A reserves stored liver, mainly in perisinusoidal stellate (Ito) cells
- In healthy persons who consume an adequate diet, reserves are sufficient to meet body’s demands for at least 6 months
186
Q
Describe the effects of vitamin A deficiency?
A
- One of the earliest manifestations is impaired vision, esp. in reduced light (night blindness)
- EYE: Xerophthalmia (dry eye), buildup of keratin debris in small opaque plaques (Bitot spots), then destruction of cornea (keratomalacia), and blindness
- EPITHELIUM: upper respiratory passage and urinary tract undergoes squamous metaplasia. Loss of mucociliary epi of airways predisposes to secondary pulmonary infections, and desquamation of keratin debris in urinary tract predisposes to renal/urinary bladder stone
- IMMUNE deficiency
188
Q
What are the major sources of vitamin D for humans?
A
- Primary source: endogenous syn from precursor, 7-dehydrocholesterol, in photochemical rxn that requires solar or artificial UV light in range of 290-315 nm (UVB radiation) -> syn of cholecalciferol (aka, vitamin D)
- Under usual conditions of sun exposure, about 90% of required vit D endogenously synthesized in skin. Ppl with dark skin generally have lower level of vitamin D production b/c of melanin pigmentation
- Dietary sources, like deep-sea fish, plants, and grains, contribute the remaining required vit D, and depend on adequate intestinal fat absorption. In plants, vit D is present in a precursor form (ergosterol), which is converted to vitamin D in the body
197
Q
How does PTH compensate during periods of vitamin D deficiency? What major deficiency persists?
A
- When hypocalcemia occurs due to vit D deficiency, PTH production is elevated, causing:
1. Activation of renal 1α-hydroxylase, increasing the amount of active vitamin D and calcium absorption
2. INC resorption of Ca from bone by osteoclasts
3. Decreased renal Ca excretion
4. INC renal excretion of phosphate (by increased synthesis in bone of fibroblast growth factor 23 (FGF-23), a phosphatonin (gp of agents that block phosphate absorption in the intestine and phosphate reabsorption in the kidney) - While a normal serum level of Ca may be restored, hypophosphatemia persists, impairing mineralization of bone. INC production of FGF-23 may be responsible for tumor-induced osteomalacia and some forms of hypophosphatemic rickets
201
Q
Explain the details of this image.
A
Think back to first semester.
202
Q
This is lung. Can you describe and diagnose it? What symptoms might this patient have?
A
- Alveoli are filling up with a foamy (more foamy than PE fluid, for example) exudate of cysts that contain small organisms and interstitium is inflamed
- Alveolar exudate and interstitial inflammation create an alveolar-capillary block impeding gas exchange, causing dyspnea and hypoxemia
- Pneumocystis jiroveci pneumonia
- NOTE: this is an HIV+ patient
203
Q
What is pneumocystis jiroveci pneumonia?
A
- Symptoms: insidious onset of dyspnea, fever, & non-productive cough
- Signs: tachypnea with no rales or rhonchi (can be striking, up to 30 RR -> pt. will have difficulty defining exactly when started)
- Chest x-ray: symmetric bilateral hazy interstitial (this is important) infiltrates, which become dense alveolar infiltrates; may initially come back clear
-
Dr. Cross comments:
1. Can be sick week or 2 before coming to clinic, so not a sudden onset illness (fatal, if not treated)
2. Known AIDS patient: if CD4 if hypoxemic, you put them in the hospital
204
Q
What do you see in this sample from the lung of an AIDS patient? What are some associated problems this pt may have?
A
- Large cells with basophilic nuclear inclusions and granular cytoplasmic inclusions (and halos)
- Cytomegalovirus (CMV): there are immunostains for confirming dx of CMV and pneumocystis (unrelated -> common for these pts to have more than one type of infection)
- CMV in AIDS patients usually disseminated
- CMV enteritis common in AIDS patients -> diarrhea
- CMV retinitis common in AIDS patients -> visual impairment
