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Flashcards in HIV, Environmental, and Nutritional Diseases Deck (208)
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What are the three major routes of transmission for HIV?

- Sexual contact 

- Parenteral inocculation 

- Passage of virus from infected mothers to newborns 


What is the risk of HIV seroconversion for health care workers after needle-stick accidents?

- 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


Explain why HIV infects memory and activated T cells, but is inefficient at productively infecting naive (unactivated) T cells.

- 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


What is Vif?

A viral protein that binds to APOBEC3G and promotes its degradation by cellular proteases


 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?

- 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 


List some of the adverse effects of smoking.

- 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 


What is going on with this lung?

Pulmonary emphysema


What is wrong with this lung?

- Pulmonary emphysema 

- Abnormal, permanent enlargement of airspaces due to destruction of walls between alveoli 


Describe this lung.

Normal lung


Explain how smoking and drinking are related.

Multiplicative increase in risk of laryngeal cancer from interaction between cigarette smoking and alcohol consumption -> synergistic toxicity


What is this?

- 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 


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?

- 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


Compare electronic cigarettes to traditional cigarettes.

- 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 


What is the toxic metal in these cells?

- 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


What do you call these cells?

- 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 


What condition does this individual have?

Carbon monoxide poisoning: causes a red discoloration of skin and mucus membranes (code word: "cherry red")


What is the pathophysiology of carbon monoxide poisoning?

- 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


What is carbon monoxide?


- 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 


How does carbon monoxide affect the CNS?

CO kills in part by inducing CNS depression, which apears so insidiously that victims are often unaware of their plight


Describe chronic poisoning by CO.

- 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


What RBC abnormality is shown here? Describe it, and its associated conditions.

- 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


What are the manifestations of lead toxicity in children at low vs. higher concentrations?

- 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


What are the manifestations of lead toxicity in adults at low vs. high concentrations?

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


What is the pathophysiology of lead toxicity?

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


How can you differentiate the anemia of lead toxicity from iron deficiency?

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)


Describe how the completion of the viral life cycle of HIV looks in latently infected cells.

- 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


Describe how HIV "uses" the immune system to infect and persist inside the host.

- 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



How do macrophages act as portals of HIV infection?

- 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


How does HIV-1 infect macrophages?

- 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


How are HIV-infected macrophages different than HIV-infected T cells?

- 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 


What is this microscopic finding in the brain of an AIDS patient?

- A microglial nodule: brain equivalent of a granuloma 

- Part of the explanation for this pt's impaired cognition (dementia) 


What is this microscopic finding in the brain of an AIDS patient?

- 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) 


What are the predominant cell types in the brain infected with HIV?

- 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



What is the mechanism of HIV-induced damage of the brain?

- 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


Briefly describe the clinical course of HIV infection.

- 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 


Briefly describe the immune response to HIV infection.

- 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


How does acute HIV infection involve mucosa?

- 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.


How do dendritic cells spread HIV inside the host?

- 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


Why is viremia important in HIV infection?

- 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. 


What is seroconversion? When does this happen in the HIV disease process?

- 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 


What is most likely responsible for the initial containment of HIV infection? Why do we suspect this?

- 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 


What is the acute retroviral syndrome?

- 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


What is the HIV viral set point? Why is it significant?

- 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


How does the CDC classify HIV infection?

- 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




For clinical management, what is the most reliable short-term indicator of disease progression?

Blood CD4+ T cell counts 


Where in the body is HIV during the chronic phase (clinical latency period)?

- Lymph nodes and spleen are sites of continuous HIV replication and cell destruction

- Few or no clinical manifestations of HIV infection present



How many T cells does HIV destroy per day in the chronic phase of infection?

- 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 


About what percentage of CD4+ T cells are infected with HIV during the chronic stage?

- 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


What are the symptoms of the chronic phase of HIV (in general)? Why?

- 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


What is going on here?

- This is herpes simplex virus

- Can reactivate, most often around lips, and most often with vesicles



What does this biopsy show?

- 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)


What is this cytology for?

- 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)


What is the crisis phase of HIV disease? How do these patients present?

- 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 


What is the difference between rapid progressors, non-progressors, and elite responders?

Exceptions to standard HIV/AIDS disease progression:

1. Rapid progressors: middle, chronic phase telescoped to 2 to 3 years after primary infection

2. 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 

3. Elite responders: undetectable plasma virus ( about 1% of infected individuals


What are 2 reasons the CDC recommends initiating antiretroviral therapy (ART)?

- To reduce the risk of disease progression 

- To prevent transmission of HIV


What accounts for the majority of deaths in untreated patients with AIDS?

- 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 


What is going on in this lung tissue? Describe its significance.

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


What are these? How are they stained?

- 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


What are the most common opportunistic infections in AIDS (9)? 

1. Candida (most common fungal infection)

2. Cytomegalovirus

3. Atypical and typical mycobacteria

4. Cryptococcus neoformans

5. Toxoplasma gondii

6. Cryptosporidium

7. Herpes simplex virus

8. Papovaviruses

9. Histoplasma capsulatum


What is going on here?

- 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


What is histoplasmosis?

- 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


What do you think is going on in this lung tissue?

- Histoplasmosis: small yeast forms, often in macrophages

- Diffuse pattern pneumonia with numerous macrophages, but no discrete granulomas, and no necrosis


What is going on in these cells in the lung?

- Histoplasmosis: small yeast forms, often in macrophages

- This high-power image shows many, small (3-5 micron) yeast forms in macrophages


What is cytomegalovirus?




- 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


What is this? What 4 kinds of cells do you see here?

Cytomegalovirus (CMV): simultaneous nuclear and cyto inclusions make the infected cells very large, hence name

1. Red cells 

2. PNM's 

3. Lymphocytes 

4. Lg cells + basophilic nuclear inclusions with halos + granular, basophilc cytoplasmic inclusions 


What is going on here? Hint: notice the type of stain.

- This is an acid-fast stain showing mycobacterium TB

- They tend to be dark red (evident here) and beaded (not evident here) 


What are the 2 types of mycobacterium that classically affect PLWH? When?

- 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 


What is going on here? Hint: these are microscopic findings in meninges of an AIDS pt. with persistent headache.

- 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 


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.

- 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 


A starvin child has a liver with this microscopic finding. What is the pathologic condition, and pathogenesis?



- Kwashiorkor: protein starvation with less inadequate carbohydrate nutrition 

- Lack of protein for lipoprotein synthesis causes lipid to accumulate in hepatocytes 


What is the fundamental difference between kwashiorkor and marasmus?

- 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


What is going on with this child?

- 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


What is the cause of this chid's pathologic skin appearance? Be specific.

- Kwashiorkor 

- Flaky paint appearance: alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation 


Describe how less severe states of kwashiorkor can occur.

- 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


What does this patient have?



What does this patient have?

Cachexia (could also be anorexia - would need to know history)


What does this patient have?



What is marasmus?

- Weight falls to 60% of normal for height, sex, age 

- Growth retardation, and loss of muscle (catabolism of somatic protein compartment)

1. Serum 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


Compare the features of kwashiorkor and marasmus (11).

1. Growth failure: both 

2. Wasting: both (marked in M) 

3. Edema: K (sometimes mild) 

4. Hair changes: K (common), M (less common) 

5. Mental changes: K (very common), M (uncommon) 

6. Dermatosis, flaky paint: K 

7. Appetite: K- poor, M- good 

8. Anemia: K (sometimes severe), M (less severe) 

9. Subcu fat: K (reduced, but present), M (absent) 

10. Face: K (may be edematous), M (drawn-in, monkey-like)

11. Fatty infiltration of liver: K


Describe marasmus, anorexia, and cachexia (each with one sentence).

- 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)


What is anorexia nervosa?

- 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 


Define obesity, and list its criteria.

- 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)


Are the adverse effects of obesity influenced by race?

- 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 


Are there any important differences between "apple" and "pear" obesity?

- Increasing central adiposity is associated with increased risk of morbidity and mortality -> waist circumference should also be measured (+BMI) to assess abdominal obesity 

- Pts. with abdominal obesity (aka, central adiposity, visceral android, or male-type obesity) are at increased risk for heart disease, diabetes, HTN, and dyslipidemia 


List some of the adverse effects of obesity.

- T2D, HTN, dyslipidemia, accelerated atherosclerotic CVD

- Non-alcoholic fatty liver disease (steatohepatitis, steatosis, and cirrhosis), cholelithiasis (gallstones), cholecystitis (inflammation of gall bladder)

- Osteoarthritis, obstructive sleep apnea, GERD, urinary stress incontinence, hypoventilation syndrome, depression, infertility 

- DVT, thromboembolus, chronic pro-inflammatory state

- Cancers of colon, breast, esophagus, thyroid, kidney endometrium and gallbladder


Can you describe the pathologic process in this coronary artery, and diagnose it?

- Eccentric thickening with loose atheroma containing cholesterol clefts and a fibrous cap producing severe stenosis (about 90%) of the lumen 

- Diagnosis: atherosclerosis


What is the metabolic syndrome? In which populations is it most prevalent?

1. Diabetes mellitus 

2. HTN 

3. Dyslipidemia 

4. Abdominal (male-pattern) obesity 

- Each of these speeds patient toward death via heart disease -> increases with age 

- Aka, obesity dyslipidemia syndrome, insulin resistance syndrome, or deadly quartet 

- Most prevalent in: Native Americans, Hispanics, AA, and European Americans 


What is the relationship between the metabolic syndrome and inflammation? What molecular mediators are involved?

- Pro-inflammatory and pro-thrombotic 

- Associated with elevated levels of: 

1. C-reactive protein (CRP) 

2. IL-1 

3. IL-6

4. IL-18

5. TNF 

6. Plasminogen activator inhibitor-1


What is adiponectin? 

- 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


Describe the molecular effects of adiponectin.

1. Directs fatty acids (FA) to muscle for their oxidation

2. Decreases influx of FA to liver & total hepatic TG content

3. Decreases glucose production in liver, causing increase in insulin sensitivity and protection against metabolic syndrome 



What is the molecular structure of adiponectin? Describe its activity at the cellular level.

- Circulates as complex of 3, 6, or more aggregates of  monomeric form

- Binds two receptors, AdipoR1 and AdipoR2, found in many tissues, including the brain, but most highly expressed in skeletal muscle and liver, respectively

- Binding of adiponectin to its receptors triggers signals that activate cAMP-dependent protein kinase (protein kinase A), phosphorylating and inactivating acetyl coenzyme A carboxylase, a key enzyme required for FA synthesis


Would the metabolic syndrome respond to dietary therapy? What sort of diets, especially?

- Metabolic syndrome responds to diet, leading to weight loss, with additional benefit from specific diets:

1. Mediterranean: high in fruits, veggies, nuts, whole grains, and olive oil 

2. Dash diet: low in sodium 

3. Diet of foods with lower glycemic index, replacing refined grains with whole grains, etc. 


Would the metabolic syndrome respond to exercise? What about liposuction?

- Yes: practical, regular, moderate daily minimum of 30 minutes, like brisk walking 

- May be beneficial beyond its effect on weight loss by more selectively removing abdominal fat, at least in women 

- Liposuction reduces amt of subcutaneous fat, which changes abdominal - superficial adipose tissue ratio and might affect potential of metabolic syndrome by means of its separate parameters and clinical manifestations (from PubMed)


How might metabolic syndrome contribute to tumor growth? Refer to the table if you need to.

- 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


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?

- 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


Can you identify this surgically removed body part and the pathological processes prompting its removal?

- 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 


What are the 4 risk factors for cholelithiasis?

1. Female

2. 40's 

3. Fertile 

4. Overweight (fat, if it helps you remember) 


A 25-year-old Panamanian female music tourist visits Memphis, TN, in January 2014. She arrives at the Sun Studio too early and while waiting for it to open, standing outdoors with the temperature 10 degrees F, she experiences the sudden onset of well demarcated pallor of multiple fingertips (shown below), associated with numbness. She is frightened by this experience and has her husband drive her to the Methodist hospital ER.  On the way to the hospital, in the car, her fingertips become bluish and then bright red. What is the condition, cause, epidemiology, treatment, and prognosis?

- Condition: Raynaud phenomenon 

- Cause: exaggerated vascular response to cold with abnormal vasoconstriction of digital arteries 

1. Vasoconstriction (white), deoxygenation causing cyanosis (blue), reperfusion causing hyperemia (red); doesn't always have to have all of these phases 

-  Epi: very common (5% of US population), but more common in females and young adults 

- Treatment: warm hands 

- Prognosis: usually benign, except in minority of patient who have scleroderma with it 


Can you describe the joint articular cartilage surface from this obese patient specimen, and diagnose this condition?

- Irregular-shaped areas of erosion

- Osteoarthritis 



Describe the evolution of osteoarthritis. Why is the knee the joint typically affected by osteoarthritis in obese patients?

- Continually increased pressure on cartilage in weight-bearing joints causes pressure atrophy, progressing to injury and necrosis 

- The knee suffers a concentration of pressure per unit area higher than any other weight-bearing joint 



Can you describe the microscopic pathology and pathophysiologic mechanism of this lesion in breast tissue?

- 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


Can you describe the gross pathology of this lesion from the breast?

- Stellate (star-shaped) tan-white lesion surrounded by yellow fat 

- Breast resection (lumpectomy) 

- Diagnosis: breast cancer 


In 2007 in the US, about how many new cases of cancer in men and women were due to obesity?

- One study estimated: 

1. 34,000 new cases of cancer in men (4%) and 

2. 50,500 in women (7%) were due to obesity

- The percentage attributed to obesity was as high as 40% for some cancers, particularly endometrial cancer and esophageal adenocarcinoma


What is PYY?

- Secreted from endocrine cells in the ileum and colon 

- Acts centrally by stimulating POMC/CART neurons in the hypothalamus, causing decrease in food intake (similar to amylin)

- Plasma levels are low during fasting, and increase shortly after food intake 

1. IV administration reduces energy intake, and its levels generally increase after gastric bypass 

2. By contrast, levels of PYY generally decrease in ppl w/Prader-Willi syndrome (loss of imprinted genes on chromosome 15q11-q13), disorder marked by hyperphagia and obesity

- These observations have led to ongoing work to produce PYYs for the treatment of obesity


How is normal flora implicated in obesity?

- Alterations in the gut microbiome are the focus of new research b/c diet has marked effects on the bacterial makeup of the colon

- Bacterial flora can have large effects on the ability of the host to break down certain dietary constituents (e.g., fiber) and absorb nutrients, as well as on epithelial integrity and inflammation

- In response to these changes, expression of gut factors such as PYY that feedback on central appetite centers may also be altered


What is amylin?

- A peptide secreted with insulin from pancreatic beta cells that reduces food intake and weight gain 

- Being evaluated for treatment of obesity and diabetes 

- Acts centrally by stimulating POMC/CART neurons in the hypothalamus, causing decrease in food intake (similar to PYY)


How do the number of adipocytes create a set-point for body weight? Explain their importance.

- Total # of adipocytes established in childhood and adolescence (childhood obesity important), and is higher in obese than lean individuals 

- In adults, estimated 10% of adipocytes are renewed annually, regardless of level of individual's body mass, but # remains constant -> #'s are tightly controlled, and loss of fat mass occurs through shrinking of existing adipocytes 

- Difficulty maintaining weight loss from dieting not well understood, but appears to be related to homeostatic mechanisms keeping body fat constant w/time -> unless lowered caloric intake and/or energy expenditure maintained, body weight returns to pre-diet levels 


What are "good fats?"

- Omega-3-FA's, which may be protective against atherosclerosis (ex: eskimos who eat high fat diet, but have low incidence of atherosclerosis) 

- Avg. US adult consumes 3:1 ratio of saturated to polyunstaruated FA's. But, lowering this ratio to 1:1 causes 10-15% reduction in serum cholesterol level within weeks 

- Given strong association of hypercholesterolemia and atherosclerosis, low fat diet might lower risk (or substitution of "good fats") 

1. Note: recent studies have shown that omega-3 supplements do not lower risk of CVD


Why is obesity a pro-inflammatory state?

- In addition to leptin and adiponectin, adipose tissue produces cytokines like:

1. TNF, IL-6, IL-1, and IL-18, chemokines, and steroid hormones 

2. Increased production creates chronic pro-inflammatory state marked by high levels of circulating C-reactive protein

- May be more than a one-way street -> emerging evidence suggests immune cells, esp. tissue macros, have important roles in regulating adipocyte function

- Adipose tissue participates in control of energy balance and metabolism, functioning as a link between lipid metabolism, nutrition, and inflammatory responses


What are two possible diagnoses considering this image of an HIV+ patient's brain? How would you distinguish between the two of these?

- 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)


This is an image of a CNS-infection in an HIV-positive individual. Describe the cells, and make a diagnosis.

- 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 


How does herpes infection typically manifest itself in HIV+ patients?

Mucocutaneous ulcerations involving the mouth, esophagus, external genitalia, and perianal region



Name some common causes of persistent diarrhea in untreated patients with advanced AIDS.

- Persistent diarrhea, which is common in untreated patients with advanced AIDS, is often caused by infections with protozoans such as: 

1. Cryptosporidium, isospora belli, or microsporidia

- These patients have chronic, profuse, watery diarrhea with massive fluid loss

- Diarrhea may also result from infection with enteric bacteria, such as: 

1. Salmonella, shigella, and M. avium-intracellulare


Describe the microscopic pathology in this sample from an AIDS patient. What do you think is going on here?

- 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)


What is going on here?

Kaposi sarcoma


What is the immune reconstitution inflammatory syndrome?

- Some pts. w/advanced disease given ART devo a paradoxical clinical deterioration during recovery period of the immune system, despite increasing CD4+ T-cell counts and decreasing viral load 

-  Basis not understood, but postulated to be a poorly regulated host response to high antigenic burden of persistent microbes

- One of several new complications assoc. w/HIV-infection and tx that have emerged 



What are some of the adverse side-effects of long-term HAART?

- Include:

1. Lipoatrophy: loss of facial fat

2 Lipoaccumulation: excess fat deposition centrally

3. Elevated lipids 

4. Insulin resistance

5. Peripheral neuropathy

6. Premature cardiovascular kidney and liver disease


What are the major causes of morbidity in HAART-treated patients?

- Non-AIDS morbidity far more common than classic AIDS-related morbidity

- Major causes are: cancer, and accelerated CV, kidney, and liver disease

- Mechanism for these non-AIDS related complications is not known, but persistent inflammation and T-cell dysfunction may play a role


Which heavy metals are most commonly associated with toxic effects in humans?

Lead, mercury, arsenic, and cadmium


Briefly describe the primary effects of lead poisoning - are these different for adults and children?

- Children: CNS defects (b/c more permeable blood-brain barrier)

1. Absorb more than 50% of lead ingested from food, while adults absorb about 15%; main source of exposure is lead-based paint in older homes

- Adults: Peripheral neuropathy

- Both: Interferes with remodeling of cartilage, and causes anemia by interfering with hemoglobin synthesis 



What is the major source of exposure to mercury? How does it affect the fetus in utero?

- Major source of exposure is contaminated fish

- Developing brain highly sensitive to methyl mercury, which accumulates in the CNS 

- Exposure of fetus to high levels of mercury in utero may lead to Minamata disease: characterized by cerebral palsy, deafness, and blindness 


Where is arsenic usually found? Describe its pathological effects.

- Naturally found in soil and water, and is a component of some wood preservatives and herbicides 

- Excess arsenic interferes with mito ox phos, and the function of a variety of proteins 

- Also causes toxic effects in the GI tract, CNS, and CV system; long-term exposure causes skin lesions and carcinomas 



How might one be exposed to cadmium? What are some of its pathologic effects?

- Nickel-cadmium batteries and chemical fertilizers can contaminate soil

- Excess cadmium causes obstructive lung disease and kidney damage


What is the most preventable cause of human death?




Briefly describe the contents of tobacco smoke.

- Contains more than 2000 compounds

- Among these are nicotine, responsible for tobacco addiction, and potent carcinogens: 

1. Polycyclic aromatic hydrocarbons

2. Nitrosamines

3. Aromatic amines



What % of lung cancers occurs in smokers? What other cancers are associated with smoking?

- About 90% of lung cancers occur in smokers; smoking cessation reduces the risk of lung cancer.

- Smoking is also associated with an increased risk of cancers of the:

1. Oral cavity, larynx, esophagus

2. Stomach

3. Bladder, and kidney

4. Some forms of leukemia



What type of cancer is most associated with smokeless tobacco? How does tobacco consumption interact with alcohol and oxxupational exposures?

- Smokeless tobacco use is an important cause of oral cancers (tobacco companies moving into this business perceived as a continued public health threat)

- Tobacco consumption interacts with alcohol in multiplying the risk of oral, laryngeal, and esophageal cancer

- Tobacco consumption increases the risk of lung cancers from occupational exposures to asbestos, uranium, and other agents


In addition to increasing cancer risk, what other health risks does tobacco pose?

- Tobacco use is an important risk factor for development of: atherosclerosis and MI, peripheral vascular disease, cerebrovascular disease

- In the lungs, in addition to cancer, it predisposes to emphysema, chronic bronchitis, and chronic obstructive disease (COPD)

- Maternal smoking increases the risk of abortion, premature birth, and intrauterine growth retardation


Describe how tobacco damages the body at a molecular level. Use the table if you need to.

- 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 


What is going on here?

- Emphysema in lung tissue: abnormal, permanent enlargement of airspaces due to destruction of the walls between alveoli



List some of the adverse effects of alcohol.

- Intoxication, accidents, murder, suicide

- Pancreatitis, gastritis (erosive, hemorrhagic and ulcerative)

- Liver disease (steatosis, hepatitis, cirrhosis)

- Alcoholic cardiomyopathy, peripheral neuropathy

- Fetal alcohol syndrome

- Cerebral atrophy, cerebellar degeneration

- Cancer of the mouth, larynx, esophagus, breast, liver


At what blood levels does alcohol cause drowsiness? Is this affected by the rate of metabolism?

- Drowsiness at 200 mg/dL. Stupor (300 mg/dL) and coma, with possible respiratory arrest, at higher levels

- Yes: rate of metabolism affects the blood alcohol level 

1. Chronic alcoholics can tolerate levels up to 700 mg/dL, partially explained by accelerated ethanol metabolism caused by 5- to 10-fold induction of liver CYPs 


How is alcohol processed by the liver? Use the attached image, if needed.

- 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


Where is most absorbed lead taken up?

- Most (80-85%) is taken up in bone and developing teeth; competes with Ca, and binds phosphates, w/half-life in bone of 20-30 years 

- 5-10% remains in the blood, and the rest is distributed in the soft tissues


What do you see here? What is the pathology?

- 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 


How is lead excreted? How might this cause damage?

- Excreted via the kidneys 

- Acute exposures may cause damage to the proximal tubules 


What are the effects of chronic alcoholism?

- Main effects: fatty liver, alcoholic hepatitis, and cirrhosis (which leads to portal hypertension and increases risk for devo of hepatocellular carcinoma) 

- Can cause bleeding from gastritis and gastric ulcers, peripheral neuropathy (thiamine deficiency), alcoholic cardiomyopathy, and acute/chronic pancreatitis 

- Major risk factor for cancers of oral cavity, larynx, and esophagus -> risk is greatly increased by concurrent smoking or use of smokeles tobacco 


How many annual deaths in the US are caused by alcohol consumption? Describe this statistic a bit.

- Estimated more than 10 million chronic alcoholics live in US, and alcohol consumption is responsible for more than 100,000 deaths annually

- >50% from accidents involving drunk driving and alcohol-related homicides and suicides 

- About 15,000 (15%) a consequence of cirrhosis of the liver 


What blood alcohol concentration constitutes the legal definition of drunk driving in the US? How many drinks does it take to get there?

- After consumption, ethanol absorbed unaltered in the stomach and small intestine, and distributed to all of the tissues and fluids of the body in direct proportion to blood level 

- Concentration of 80 mg/dL in blood constitutes legal definition of drunk driving in US

1. For avg person, this is about three standard drinks, i.e., about three (12 ounce) bottles of beer, 15 ounces of wine, or 4 to 5 ounces of 80 proof distilled spirits 


What is going on with this liver?

- Tan-yellow color instead of the typical red-brown 

- Steatosis 


What is going on here? What are some of the common causes?

- Hepatocytes distended with clear cytoplasm due to lipid dissolved out during processing 

- Steatosis 

1. Common causes: alcohol, obesity, uncontrolled diabetes 


What is this?

Normal liver


How does alcohol cause hepatic steatosis?

1. Shunting of substrates away from catabolism and toward lipid biosynthesis b/c generation of excess reduced nicotinamide-adenine dinucleotide (NADH) from metabolism of ethanol by alcohol dehydrogenase and acetaldehyde dehydrogenase 

2. Impaired assembly and secretion of lipoproteins 

3. Increased peripheral catabolism of fat 


Can you describe what is wrong with this liver, and name the condition?

- In addition to steatosis, there is acute neutrophilic inflammation, and some dying or dead hepatocytes with pyknotic nuclei 

- Steatohepatitis 


What is this?

Normal liver 


By what pathophysiologic mechanisms does alcohol cause hepatitis?

- Acetaldehyde (major metabolite of ethanol) induces lipid peroxidation and acetaldehyde-protein adduct formation, which may disrupt cytoskeleton and membrane function

- Alcohol directly affects cytoskeleton organization (e.g., Mallory-Denk bodies), mito function and membrane fluidity

- ROS generated via oxidation of ethanol by microsomal ethanol oxidizing system react w/and damage proteins and membranes 

- Cytokine-mediated inflammation & cell injury major feature of alcoholic hepatitis & alcoholic liver disease 

- TNF considered to be main effector of injury; IL-1, IL-6 and IL-8 may also contribute.


What are the hypereosinophilic clumps seen in some of these cells?

- 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)


What is going on with this liver? Define it.

- 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 


What are these?

- Round-oval nodules of regenerative hepatocytes completely surrounded by fibrous tissue, characteristic of cirrhosis


How long does it take to get cirrhosis from chronic alcoholism? How can you differentiate it form non-alcoholic fatty liver disease (NAFLD)?

- 15 years (but only about 15% of alcoholics get it)

- Differentiate based on HISTORY


What is going on here?

- 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 


What is going on here?

- Rounded, variegated, green, brown, and tan mass with background cirrhosis 

- Hepatocellular carcinoma


What are the characteristics of fetal alcohol syndrome? Use the image, if needed.

1. Specific dysmorphic facial features

2. Growth retardation

3. CNS abnormalities: wide range of neurobehavioral problems, incl. impairment of self-regulation, cognition, and adaptive functioning


Describe the scope of substance abuse during pregnancy.

- 2011 US survey (pregnant women 15-44): 

1. Cigarette use: 17.6%

2. Alcohol use: 9.4% (2.6% binge drinking, 0.4% heavy drinking) 

3. Ilicit drug use 5%


What are the therapeutic drugs most frequently involved in drug injury?

- Antineoplastic agents 

- Anticoagulants 

- Menopausal hormone therapy preparations and oral contraceptives 

- Acetaminophen

- Aspirin 


How do menopausal hormone therapy and oral contraceptives cause drug injury?

- Menopausal hormone therapy increases risk of breast and endometrial cancers and thromboembolism, and does not appear to protect against ischemic heart disease 

- Oral contraceptives have protective effect against endometrial and ovarian cancers, but increase the risk of thromboembolism and hepatic adenomas (adenoma is a benign tumor of epithelial tissue with glandular origin)


How can acetaminophen and aspirin cause drug injury?

- Overdose of acetaminophen may cause centrilobular liver necrosis, leading to liver failure -> early treatment with agents that restore GSH (glutathione) levels may limit toxicity 

- Aspirin blocks production of thromboxane A2, which may produce gastric ulceration and bleeding 


What are the common drugs of abuse?

- Sedative-hypnotics (barbiturates, ethanol)

- Psychomotor stimulants (cocaine, meth, ecstasy)

- Opioid narcotics (heroin, oxycodone)

- Hallucinogens

- Cannabinoids (marijuana) 


How is acetaminophen metabolized?

- Metabolized to NAPQI (N-acetyl-p-benzoquinoneimine) via hepatic P450 system 

- With very large doses, excess NAPQI leads to hepatic centrilobular necrosis


Describe the epidemiology of acetaminophen toxicity.

- Most commonly used analgesic in the US -> toxicity is common, and responsible for >50,000 ED visits/year 

- In US, it is the cause of about 50% of acute liver failure cases, with 30% mortality 

- Intentional overdose is the most common cause of acetaminophen toxicity in UK, but unintentional OD most common in US, representing almost 50% of total intoxication cases 


Describe acetaminophen therapeutic window, and toxicity AE's and treatment.

- Window between usual dose (0.5gm) and toxic dose (15-25gm) large, and drug is ordinarily very safe 

- Toxicity begins with: nausea, vomiting, diarrhea, and sometimes shock, w/evidence of jaundice in a few days 

- Overdoses can be treated in early stages (w/in 12 hrs) by admin of N-acetylcysteine, restoring GSH levels 

1. If serious overdose liver failure ensues, starting w/centrilobular necrosis that may extend into entire lobules, liver transplant only hope for survival


Describe the molecular mechanism of cocaine.

- 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


What is the psychoactive substance in marijuana? Describe its effects.

- Delta-9-tetrahydrocannabinol: distorts sensory perception and impairs motor coordination, with acute effects generally clear in 4-5 hours

- With continued use, these changes may progress to cognitive and psychomotor impairments, such as inability to judge time, speed, and distance, a potential cause of automobile accidents



How does chronic marijuana smoking affect the respiratory system?

- Laryngitis, pharyngitis, bronchitis, cough and hoarseness, and asthma-like symptoms have all been described, along with mild, but significant airway obstruction

- Marijuana cigarettes also contain a large number of carcinogens that are also present in tobacco



Describe the endogenous cannabinoid system.

- A large number of studies have characterized the endogenous cannabinoid system, which consists of the cannabinoid receptors CB1 and CB2, and the endogenous lipid ligands known as endocannabinoids

- This system participates in the regulation of the hypothalamic-pituitary-adrenal axis, and modulates the control of appetite, food intake, and energy balance, as well as fertility and sexual behavior


How does ionizing radiation damage cells and vasculature?

- May injure cells directly or indirectly by generating free radicals from water or molecular oxygen

- Damages DNA -> rapidly dividing cells like germ cells, and those in bone marrow and GI tract very sensitive to radiation injury

- DNA damage that is not adequately repaired may result in mutations that predispose affected cells to neoplastic transformation

- May cause vascular damage and sclerosis, resulting in ischemic necrosis of parenchymal cells, & replacement by fibrous tissue 


Describe the damage exhibited by cells that survive radiant energy damage.

- Wide range of structural changes in chromosomes related to double-stranded DNA breaks, incl. deletions, translocations, and fragmentation

- Mitotic spindle often becomes disorderly; there may be polyploidy & aneuploidy, or apoptosis 

- Nuclear swelling, condensation/clumping of chromatin  and disruption of nuclear membrane may be noted

- Giant cells w/pleomorphic nuclei, or >1 nucleus may appear, and persist for years after exposure

- At extremely high doses of radiant energy, markers of cell death, i.e., nuclear pyknosis & lysis, appear quickly


What is going on here, especially at 1, 2, and 3?

- 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)


What is up with the cells indicated by black arrows? Why is their appearance troubling for pathologists?

- 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


What is going on here?

- 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


What is bulimia?

- A condition in which the patient binges on food, then induces vomiting 

- More common than anorexia nervosa, and generally has a better prognosis -> estimated to occur in 1-2% of women and 0.1% of men, w/avg. onset at 20 y/o 

- Primarily in previously healthy young women who have developed an obsession with body image and thinness 

- Major complication an increased susceptibility to cardiac arrhythmia and sudden death from hypokalemia


What is cachexia?

- Extreme weight loss, fatigue, muscle atrophy, anemia, anorexia, and edema -> mortality generally a result of atrophy of diaphragm and o/respiratory muscles 

- 50% of cancer pts, most commonly GI, pancreatic and lung, and responsible for 30% of cancer deaths 


What are the molecular mediators of cachexia? What is the mechanism?

- 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


How many vitamins are necessary for health? What are the two types? Which ones can be synthesized endogenously?

- Thirteen vitamins are necessary for health; distinction between fat- and water-soluble vitamins is important

1. Fat soluble: A, D, E, K -> more readily stored in the body, but may be poorly absorbed in fat malabsorption disorders, caused by disturbances of digestive functions

2. Water-soluble: all the others 

- Can be synthesized endogenously: 1) vitamin D from precursor steroids, 2) vitamin K and biotin by the intestinal microflora, and 3) niacin from tryptophan, an essential amino acid


What are the major functions of vitamin A?

- Maintenance of normal vision (esp. in reduced light)

- Regulation of cell growth and differentiation (esp. epithelial mucus -secreting cells) 

- Regulation of lipid metabolism

- Enhancing immunity to infection, esp in kids w/measles

- Vitamin A is the name given to a group of related compounds that include retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (vitamin A acid), which have similar biologic activities


What 3 things are required for vitamin A absorption?

- Bile 

- Pancreatic enzymes 

- Some level of antioxidant activity in the food



Describe the entry of retinol into the body, from its ingestion to its storage.

- 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


How are retinol esters stored in the liver mobilized?

- Before release, retinol binds to specific retinol-binding protein (RBP), synthesized in the liver

- Uptake of retinol/RBP in peripheral tissues dependent on cell surface receptors specific for RBP

- After uptake, retinol binds cellular RBP, and RBP is released back into the blood

- Retinol may also be stored in peripheral tissues as retinol ester or may be oxidized to form retinoic acid, which has important effects on epithelial differentiation and growth


How is rhodopsin synthesized? What is its role in vision?

- Synthesis of rhodopsin from retinol: 1) oxidation to all-trans-retinol, 2) isomerization to 11-cis-retinal, 3) covalent association w/7-transmembrane rod protein opsin

- Photon of light causes isomerization of 11-cis-retinal to all-trans-retinal, which dissociates from rhodopsin, and induces conformational change in opsin, triggering nerve impulse via neurons from retina to brain

- During dark adaptation, some of the all-trans-retinal is reconverted to 11-cis-retinal, but most is reduced to retinol and lost to the retina


How many forms of vitamin A-containing pigments are involved in the visual process?

- Four: rhodopsin in the rods, the most light-sensitive pigment and therefore important in reduced light, and three iodopsins in cone cells, each responsive to specific colors in bright light


How does vitamin A deficiency affect mucus-secreting epithelium?

Squamous metaplasia of mucus-secreting epithelium into a keratinizing epithelium


Explain how retinoic acid is involved in gene transcription.

- Activation of retinoic acid receptors (RARs) by their ligands (retinoic acid) causes the release of corepressors and the obligatory formation of heterodimers with another retinoid receptor, known as the retinoic X receptor (RXR)

- Both RAR and RXR have three isoforms, α, β, and γ. The RAR/RXR heterodimers bind to retinoic acid response elements located in the regulatory regions of genes that encode receptors for growth factors, tumor suppressor genes, and secreted proteins


Explain the metabolic effects of retinoids on adipogenesis.

- Retinoic X receptor (RXR), believed to be activated by 9-cis retinoic acid, can form heterodimers with other nuclear receptors, such as nuclear receptors involved in drug metabolism, the peroxisome proliferator-activated receptors (PPARs), and vitamin D receptors

- PPARs are key regulators of fatty acid metabolism, including fatty acid oxidation in fat tissue and muscle, adipo­genesis, and lipoprotein metabolism -> PPAR + RXR are ligand-activated transcription factors that decrease triglycerides and increase HDLs


How can Vitamin A supplementation reduce morbidity and mortality from some forms of diarrhea, and in preschool children with measles?

- Beneficial effect of vitamin A in diarrheal diseases may be related to the maintenance and restoration of the integrity of the epithelium of the gut

- The effects of vitamin A on infections also derive in part from its ability to stimulate the immune system

- Infections may reduce the bioavailability of vitamin A by inhibiting retinol binding protein (RBP) synthesis in the liver through the acute-phase response


How are retinoids used clinically for the treatment of cancer?

- Tx of acute promyelocytic leukemia: all-trans-retinoic acid induces differentiation and apoptosis of acute promyelocytic leukemia cells by binding a PML-RARα fusion protein that characterizes this form of cancer

- A different isomer, 13-cis retinoic acid, has been used with some success in the tx of childhood neuroblastoma

- NOTE: retinoids also used clinically for the tx of skin disorders like severe acne and some forms of psoriasis


Describe the effects of vitamin A deficiency?

- 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 


What is the major function of vitamin D?

- Maintenance of adequate plasma levels of Ca and phosphorus to support metabolic functions, bone mineralization, and neuromuscular transmission

- Required for prevention of bone diseases, i.e., rickets (in children whose epiphyses have not already closed), osteomalacia (in adults), and hypocalcemic tetany (a convulsive state caused by insufficient EC concentration of ionized Ca, which is required for normal neural excitation and the relaxation of muscles)


What are the major sources of vitamin D for humans?

- 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


What are the main steps in vitamin D metabolism (4)?

1. Photochemical syn from 7-dehydrocholesterol in skin and absorption from foods/supplements in gut

2. Vit D binding to plasma α 1 -globulin (D-binding protein or DBP), and transport into the liver

3. Conversion of vit D into 25-hydroxycholecalciferol (25-OH-D) in the liver via action of 25-hydroxylases, including CYP27A1 and other CYPs

4. Conversion of 25-OH-D into 1,25-dihydroxyvitamin D, [1α,25(OH) 2 D 3 ], the most active form of vitamin D, by the enzyme 1α-hydroxylase in the kidney


How is the production of 1,25-dihydroxyvitamin D in the kidney regulated (3)?

1. Hypocalcemia stimulates secretion of parathyroid hormone (PTH), augmenting the conversion of 25-OH-D into 1,25-dihydroxyvitamin D by activating 1α-hydroxylase

2. Hypophosphatemia directly activates 1α -hydroxylase , increasing the production of 1,25-dihydroxyvitamin D

3. Through a negative feedback mechanism, increased levels of 1,25-dihydroxyvitamin D down-regulate its own synthesis through inhibition of 1α-hydroxylase activity


How does 1,25-dihydroxyvitamin D mediate its effects (2)?

- Binds a high-affinity nuclear receptor that associates w/RXR -> heterodimeric complex binds vit D response elements in regulatory sequences of vit D target genes

- Receptors for 1,25-dihydroxyvitamin D are present in most cells of the body -> in small intestine, kidneys, and bones, signals transduced via these receptors regulate plasma levels of Ca and phosphorus

- Also appears to act through mechanisms that don't require transcription of target genes. Alternative mechanisms involve binding of 1,25-dihydroxyvitamin D to membrane-associated vit D receptor (mVDR), leading to activation of protein kinase C & opening Ca channels


How does vitamin D contribute to bone devo?

- Contributes to the mineralization of osteoid matrix and epiphyseal cartilage in both flat and long bones

- Stimulates osteoblasts to synthesize Ca-binding protein, osteocalcin, involved in the deposition of Ca during bone devo


What are the main functions of 1,25-dihydroxyvitamin D on calcium and phosphorus (3)?

1. Stimulation of intestinal calcium absorption

2. Stimulation of calcium reabsorption in the kidney

3. Interaction with PTH in the regulation of blood calcium. 


Explain how 1,25-dihydroxyvitamin D stimulates intestinal calcium absorption.

- Stimulates intestinal absorption of Ca in the duodenum through the interaction of 1,25-dihydroxyvitamin D with nuclear vitamin D receptor and the formation of a complex with RXR

- Complex binds to vit D response elements, activating the transcription of TRPV6 (a member of the transient receptor potential vanilloid family), which encodes a critical calcium transport channel



How does 1,25-dihydroxyvitamin D stimulate calcium reabsorption in the kidney?

- Increases calcium influx in distal tubules of the kidney via increased expression of TRPV5, a member of the transient receptor potential vanilloid family

- TRPV5 expression also regulated by PTH in response to hypocalcemia



How does 1,25-dihydroxyvitamin D interact with PTH in the regulation of blood calcium?

- Vit D maintains Ca and phosphorus at supersaturated levels in plasma

- Parathyroid glands have a key role in the regulation of EC Ca concentrations -> they have a Ca receptor that senses even small changes in blood Ca concentrations

- In addition to effects on Ca absorption in intestine and kidneys, both 1,25-dihydroxyvit D and PTH enhance expression of RANKL (receptor activator of NF-κB ligand) on osteoblasts: 

1. RANKL binds its receptor (RANK) in prosteoclasts, inducing differentiation of these cells into mature osteoclasts -> via secretion of HCl and activation of proteases like cathepsin K, osteoclasts dissolve bone and release Ca and phosphorus into circulation


How does PTH compensate during periods of vitamin D deficiency? What major deficiency persists?

- 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


In addition to the liver and kidney, what other organs/cells can produce 1,25-dihydroxyvitamin D?

- Macrophages

- Keratinocytes

- Tissues like breast, prostate, and colon

- NOTE: low levels of 1,25-dihydroxyvitamin D (<20 ng/mL) are associated with a 30%-50% INC in the incidence of colon, prostate, and breast cancers



How does 1,25-dihydroxyvitamin D synthesis occur in macrophages?

- Activity of CYP27B located in the mitochondria

- Pathogen-induced activation of TLRs in macros causes INC expression of vit D receptor and CYP27B, leading to local syn of 1,25-dihydroxyvit D and activation of vit-D-dependent gene expression in macros

- Recent clinical trial: vit D supplements INC lymphocyte counts, altered circulating levels of multiple cytokines and chemokines, and enhanced clearance of Mycobacterium tuberculosis from sputum


What is hypervitaminosis D?

- Megadoses of orally administered vitamin can lead to hypervitaminosis

- Children: may take the form of metastatic calcifications of soft tissues such as the kidney 

- Adults: causes bone pain and hypercalcemia

- Toxic potential of vitamin D is so great that in sufficiently large doses it is a potent rodenticide


Explain the details of this image.

Think back to first semester.


This is lung. Can you describe and diagnose it? What symptoms might this patient have?

- 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 


What is pneumocystis jiroveci pneumonia?

- 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 


What do you see in this sample from the lung of an AIDS patient? What are some associated problems this pt may have?

- 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 


Briefly describe the pathology of CMV in AIDS patients.

- MCV is a reactivation agent (pt. already has it), not a primary infection: 80-90% of people have had it, and not gotten that sick with it b/c it is an opportunistic infection that makes those that are immunosuppressed ill

- CMV pneumonia very rare (but exists in cancer & AIDS pts) -> in bronchoscopy/respiratory specimens to dx, there may be CMV reactivating, but doesn't mean it's causing the pneumonia

- CMV colitis/retinitis much more common than PNA when AIDS is very advanced, and CD4+ counts are very low

- CMV treatment pretty toxic for these pts (and can cause many terrible symptoms, including bone marrow suppression), and these pts are already bone marrow suppressed


The opportunistic infections AIDS patients get are typically those for which our prime effector cell defenses are...? Why?

- Macrophages

- Macros bind microbes coated w/Abs or complement and phagocytose and destroy them, serving as effector cells of humoral immunity 

- They also respond to signals from CD4 T cells, improving their ability to destroy these phagocytosed microbes, serving as effector cells of cellular immunity, which is depressed in patients with HIV/AIDS 

- NOTE: this was a clicker question, so there clearly could be better responses, but this was the best of those he listed 


55 y/o unemployed white male former injecting drug user comes to your ER with the insidious onset of gradually progressive dyspnea and a dry cough over 2 months, along with fever, chills, malaise, fatigue and a 20-pound weight loss. 

His temperature is 39.4, pulse 110, blood pressure 110/60 and respirations 24. His lungs are clear to auscultation. 

What is the dx?


- Note: there is now an opt-out test, so no longer have to ask for permission -> tell them you are going to do the test, unless they refuse

1. You can say: "We test everyone for HIV b/t the ages of 15 and 64; we are going to test you today, unless you refuse" 




55-year-old black male from South Africa has been living in New York city for 5 years and working as a dish- washer. He has been losing weight.  He has chronic diarrhea.  He frequently feels feverish.  He is finding it harder and harder to do his job.  He has a chronic cough and is now coughing up a small amount of blood. His HIV plasma viral load, CD4 count and duration of HIV infection is most likely to be virions/ml, cells/cu mm, years of HIV infection...?

A.  10 thousand, 1000, 10
B.  100 thousand, 200, 5
C.  1 million, 1000, 20
D.  10 million, 10, 10
E.  10 billion, 100, 30

- D = 10 million virions/mL, 10 cells/cu mm, 10 years of infection

- Dr. Cross comments

1. Key is CD4 count: at 200, pts are still pretty healthy, but this guy is sick, so his CD4 must be really low (i.e., 10, in this case)

2. Goal of treatment to get viral load undetectable 

3. Viral load hard to use to tell how long pt. has had HIV: may not always be as high as 10 million, but rather only be 50,000; can kind of fizzle out with advanced states