08-25-2007, 10:29 AM
1. ACID-BASE AND ELECTROLYTES
1. How do you analyze arterial blood gas values?
Remember three basic points:
1. pH tells you whether you are dealing with acidosis or alkalosis as the primary event. The
body will compensate as much as it can (secondary event).
2. Look at the carbon dioxide (CO 2) value. If it is high, the patient either has respiratory aci-
dosis (pH: < 7.4) or is compensating for metabolic alkalosis (pH: > 7.4). If CO2 is low, the patient
either has respiratory alkalosis (pH: > 7.4) or is compensating for metabolic acidosis (pH: < 7.4).
3. Look at the bicarbonate value. If it is high, the patient either has metabolic alkalosis (pH:
> 7.4) or is compensating for respiratory acidosis (pH: < 7.4). If bicarbonate is low, the patient
either has metabolic acidosis (pH: < 7.4) or is compensating for respiratory alkalosis (pH: > 7.4).
2. True or false: The body does not compensate beyond a normal pH.
True. For example, a patient with metabolic acidosis will eliminate CO, to help restore a
normal pH. However, if respiratory alkalosis is a compensatory mechanism (and not a rare, sep-
arate primary disturbance), the pH will not correct to > 7.4 . Overcorrection does not occur.
3. List the common causes of acidosis.
Respiratory acidosis: chronic obstructive pulmonary disease, asthma, drugs ( e.g., opioids,
benzodiazepines, barbiturates, alcohol, other respiratory depressants), chest wall problems
(paralysis, pain), and sleep apnea.
Metabolic acidosis: ethanol, diabetic ketoacidosis, uremia, lactic acidosis ( e.g., sepsis,
shock, bowel ischemia), methanol/ethylene glycol, aspirin/salicylate overdose, diarrhea, and car-
bonic anhydrase inhibitors.
4. List the common causes of alkalosis.
Respiratory alkalosis: anxiety/hyperventilation and aspirin/salicylate overdose.
Metabolic alkalosis: diuretics (except carbonic anhydrase inhibitors), vomiting, volume
contraction, antacid abuse/milk-alkali syndrome, and hyperaldosteronism.
5. What type of acid-base disturbance does aspirin overdose cause?
Respiratory alkalosis and metabolic acidosis (two different primary disturbances). Look for
coexisting tinnitus, hypoglycemia, vomiting, and a history of "swallowing several pills." Alka-
linization of the urine (with bicarbonate) speeds excretion.
6. What happens to the blood gas of patients with chronic lung conditions?
In certain people with chronic lung conditions (especially those with sleep apnea), pH may
be alkaline during the day because they breathe better when awake. In addition, just after an
episode of bronchitis or other respiratory disorder, the metabolic alkalosis that usually compen-
sates for respiratory acidosis is no longer a compensatory mechanism and becomes the primary
disturbance (elevated pH and bicarbonate). As a side note, remember that sleep apnea, like other
chronic lung diseases, can cause right-sided heart failure (cor pulmonale).
7. Should you give bicarbonate to a patient with acidosis?
For purposes of the Step 2 boards, almost never. First try intravenous fluids and correction
of the underlying disorder. If all other measures fail and the pH remains < 7.0, bicarbonate may
be given.
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3. BIOSTATISTICS
1. How is the sensitivity of a test defined? What are highly sensitive tests used for clinically?
Sensitivity is defined as the ability of a test to detect disease”mathematically, the number
of true positives divided by the number of people with the disease. Tests with high sensitivity are
used for disease screening. False positives occur, but the test does not miss many people with the
disease (low false-negative rate).
2. How is the specificity of a test defined? What are highly specific tests used for clinically?
Specificity is defined as the ability of a test to detect health (or nondisease)”mathematically,
the number of true negatives divided by the number of people without the disease. Tests with high
specificity are used for disease confirmation. False negatives occur, but the test does not call anyone
sick who is actually healthy (low false-positive rate). The ideal confirmatory test must have high
sensitivity and high specificity; otherwise, people with the disease may be called healthy.
3. Explain the concept of a trade-off between sensitivity and specificity.
The trade-off between sensitivity and specificity is a classic statistics question. For example,
you should understand how changing the cut-off glucose value in screening for diabetes (or chang-
ing the value of any of several screening tests) will change the number of true- and false-negative
as well as true- and false-positive results. If the cut-off glucose value is raised, fewer people will
be called diabetic (more false negatives, fewer false positives), whereas if the cut-off glucose value
is lowered, more people will be called diabetic (fewer false negatives, more false positives).
If the cut-off serum glucose value for a
Normal Diabetic diagnosis of diabetes mellitus is set at
subjects patients point A, no cases of diabetes will be
missed, but many people without dia-
betes will be mislabeled as diabetics (i.e.,
higher sensitivity, lower specificity,
lower positive predictive value, higher
negative predictive value). If the cut-off
is set at B, the diagnosis of diabetes will
not be made in healthy people, but many
cases of true diabetes will go undiag-
nosed (i.e., lower sensitivity, higher
A B
specificity, higher positive predictive
value, lower negative predictive value).
Glucose levels The optimal diagnostic value lies some-
where between points A and B.
4. Define positive predictive value (PPV). On what does it depend?
When a test is positive for disease, the PPV measures how likely it is that the patient has the
disease (probability of having a condition, given a positive test). PPV is calculated mathemati-
cally by dividing the number of true positives by the total number of people with a positive test.
PPV depends on the prevalence of a disease (the higher the prevalence, the higher the PPV) and
the sensitivity and specificity of the test ( e.g., an overly sensitive test that gives more false posi-
tives has a lower PPV).
5. Define negative predictive value (NPV). On what does it depend?
When a test comes back negative for disease, the NPV measures how likely it is that the
patient is healthy and does not have the disease (probability of not having a condition, given a
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100 Hematology
7. What are reticulocytes? Why is a reticulocyte count routinely ordered in an anemia
work-up?
Reticulocytes are immature red blood cells. If their count is abnormally decreased in the setting
of anemia, the marrow is not responding properly and is the problem. A high reticulocyte count
should make you think of hemolysis or blood loss as the cause (the marrow is responding prop-
erly and is not the problem).
8. Which test comes next?
At this point, it depends. If you have a complete history and results of the other three tests,
most possibilities will be eliminated and you can order a confirmatory test. If the answer is still
not clear, consider a bone marrow biopsy. For the Step 2 exam biopsy is unlikely to be necessary
unless malignancy is the cause of the anemia.
9. What are the classic causes of microcytic, normocytic, and macrocytic anemia? Which
of these tends to have an inappropriately low reticulocyte count?
Microcytic Normocytic
With normal or elevated reticulocyte count With normal or elevated reticulocyte count
Thalassemia/hemoglobinopathy Acute blood loss
(e.g., sickle cell disease) Hemolytic (multiple causes)
Medications (antibody-causing)
With low reticulocyte count With low reticulocyte count
Lead poisoning Cancer/dysplasia (e.g., myelophthisic,
Sideroblastic anemia acute leukemia)
Anemia of chronic disease (some cases) Anemia of chronic disease (some cases)
Iron deficiency Aplastic anemia/medications causing
bone marrow suppression
Endocrine failure (thyroid, pituitary)
Renal failure
Macrocytic (all types have low reticulocyte count)
Folate deficiency Cirrhosis, liver disease
Vitamin B12 deficiency Alcohol abuse (interferes with folate use)
Medications (methotrexate, phenytoin)
10. What clues point to hemolysis as the cause for anemia?
¢ Elevated lactate dehydrogenase (LDH)
¢ Elevated bilirubin (unconjugated as well as conjugated if the liver is functioning)
¢ Jaundice
¢ Low or absent haptoglobin (intravascular hemolysis only)
¢ Urobilinogen, bilirubin, and hemoglobin in urine (only conjugated bilirubin shows up in
the urine, and hemoglobin shows up in the urine only when haptoglobin has been satu-
rated, as in brisk intravascular hemolysis)
¢ Pigmented gallstones or history of cholecystectomy (usually at a young age)
11. What is the most common cause of anemia in the U.S.?
Iron deficiency anemia.
12. Why do people get iron deficiency?
Iron deficiency is common in women of reproductive age because of menstrual blood loss.
In all patients over age 40 (men and especially postmenopausal women), it is important to rule
out colon cancer as a cause of chronic, asymptomatic blood loss. Increased requirements also
may lead to iron deficiency in children and pregnant or breast-feeding women. Give iron sup-
plements or iron-containing formula to all infants except full-term infants who are exclusively
breast-fed. Giving cow's milk before 1 year of age may lead to anemia by causing GI bleeding.
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Hematology 101
Start iron supplementation at 4-6 months for full-term infants and at 2 months for preterm
infants. Iron supplements also are commonly given during pregnancy and lactation (because of
the increased demand).
13. What are the classic laboratory abnormalities in iron deficiency anemia? What weird
cravings may occur with iron deficiency?
Look for low iron and low ferritin levels, elevated total iron-binding capacity (TIBC; also
known as transferrin), and low TIBC saturation. Rare patients may develop a craving for ice or
dirt (pica).
14. What is Plummer-Vinson syndrome?
A triad of unknown etiology: esophageal web resulting in dysphagia; iron deficiency anemia;
and glossitis.
15. How is iron deficiency treated?
First you must determine the cause. In a menstruating woman, a presumptive diagnosis of
menstrual blood loss is often made. In patients over 40, be sure to test the stool for occult blood
and strongly consider colonoscopy to detect occult colon cancer. Postmenopausal vaginal bleed-
ing may also cause anemia and warrants screening for gynecologic cancer. Treat with iron sup-
plements for 3-6 months in uncomplicated cases to replete body iron stores.
16. What causes folate deficiency? In what patient populations is it commonly seen?
Folate deficiency is commonly seen in alcoholics (poor intake) and pregnant women
(increased need). All women of reproductive age should take folate supplements to prevent neural
tube defects in their offspring. Rare causes of folate deficiency include poor diet (e.g., tea and
toast), methotrexate, prolonged therapy with trimethoprim-sulfamethoxazole, anticonvulsant
therapy (especially phenytoin), and malabsorption. Look for macrocytes and hypersegmented
neutrophils (either one should make you think of the diagnosis) with no neurologic symptoms
or signs and low folate levels in serum or red blood cells. Treat with oral folate,
17. What is the most common cause of vitamin B 12 deficiency?
Pernicious anemia. This megaloblastic anemia is caused by antiparietal cell antibodies.
Remember the physiology of B, 2 absorption with intrinsic factor secretion by parietal cells and
absorption of the B 12”intrinsic factor complex in the ileum. Achlorhydria (no stomach acid
secretion and elevated stomach pH) and antibodies to parietal cells are generally present in per-
nicious anemia.
18. What else may cause vitamin B, 2 deficiency? How is B,2 deficiency diagnosed?
Gastrectomy, terminal ileum resection or disease ( e.g., Crohn's disease), strict vegan diet,
chronic pancreatitis, and the infamous Diphyilobothrium latum (fish tapeworm) infection. The
peripheral smear looks the same as in folate deficiency (macrocytes, hypersegmented neu-
trophils), but patients have neurologic deficiencies (e.g., loss of sensation and position sense,
paresthesias, ataxia, spasticity, hyperreflexia, positive Babinski sign, dementia). Diagnosis is
clinched by a low serum B, 2 level. A Schilling test usually determines the etiology.
19. How is vitamin B 12 deficiency treated?
Vitamin B 12 supplements are given. The usual replacement is via parenteral (intramuscular)
injection, because most patients cannot absorb the vitamin through the gut. Supplementation may
be required for life.
20. How is thalassemia differentiated from iron deficiency?
Both cause microcytic, hypochromic anemia, but thalassemia must be differentiated from
iron deficiency because iron levels are normal in thalassemia. Iron supplementation is con-
traindicated in patients with thalassemia because it may cause iron overload. Look for elevations
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102 Hematology
in hemoglobin A2 and hemoglobin F (beta thalassemia only); target cells, nucleated red blood
cells, and diffuse basophilia on peripheral smears; skull radiogaph with "crew-cut" appearance;
extramedullary hematopoiesis (see figure); splenomegaly; and positive family history. Tha-
lassemia is more common in blacks, Mediterraneans, and Asians.
Extramedullary hematopoiesis. A coronal MRI image of
the thorax in a patient with moderately severe (3-tha-
lassemia reveals multiple round masses in the center and
periphery of the thorax, reflecting foci of extramedullary
hematopoiesis arising from the paravertebral region and
ribs, respectively. (From Hoffbrand AV, Pettit JE: Color
Atlas of Clinical Hematology, 3rd ed. St. Louis, Mosby,
2000, p 95, with permission.)
21. What diagnostic test confirms a diagnosis of thalassemia? How is it treated?
Diagnosis is made by hemoglobin electrophoresis. There are four gene loci for the alpha
chain of hemoglobin but only two for the beta chain. Patients with alpha thalassemia are symp-
tomatic at birth or die in utero (fetal hydrops), whereas patients with beta thalassemia are not
symptomatic until 6 months of age.
No treatment is required for minor thalassemia. Patients are often asymptomatic because
they are used to living with a lower level of hemoglobin. Thalassemia major is more dramatic
and severe. Treat with transfusions, as needed, and iron chelation therapy to prevent secondary
hemochromatosis.
22. What two clues on the Step 2 exam often point to a diagnosis of sickle cell disease?
Peripheral smear and race. Eight percent of African Americans are heterozygous for sickle
cell trait. Know what sickled red blood cells look like. Patients usually have a high percentage of
reticulocytes (8-20%).
23. What are the clinical manifestations and complications of sickle cell disease?
¢ Aplastic crises (due to parvovirus B19 infection)
¢ Bone pain (due to infarcts; the classic example is avascular necrosis of the femoral head)
¢ Dactylitis (also known as hand-foot syndrome, seen in children)
¢ Renal papillary necrosis
¢ Splenic sequestration crisis
¢ Autosplenectomy (increased infections with encapsulated bugs such as Pneumococcus,
Haemophilus, and Neisseria species)
¢ Acute chest syndrome (mimics pneumonia)
¢ Pigment cholelithiasis
¢ Priapism
¢ Stroke
24. How is sickle cell disease diagnosed and treated?
Diagnosis is made by hemoglobin electrophoresis. Screening is done at birth, but symptoms
usually do not appear until around 6 months of age because of the lack of adult hemoglobin pro-
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Hematology 103
duction. Treat with prophylactic penicillin until at least 10 years of age, beginning as soon as the
diagnosis is made. Proper vaccination includes the pneumococcal and H. influenzae vaccines
(given to all children anyway). Other strategies include folate supplementation, early treatment
of infections, and proper hydration.
A sickle cell crisis involves severe pain in various sites due to red blood cell sickling. Treat
with oxygen, lots of intravenous fluids, and analgesics (do not be afraid to use narcotics). Con-
sider transfusions if symptoms and/or findings are severe.
25. What findings help you in the setting of acute blood loss as a cause of anemia?
The important point is that immediately after blood loss the hemoglobin may be normal; it
takes at least 3-4 hours, often more, for reequilibration. Look for obvious bleeding, pale, cold
skin, tachycardia, and hypotension (signs of hypovolemic shock). Transfuse if indicated, even
with a normal hemoglobin in the acute setting. Consider internal hemorrhage in the setting of
trauma and abdominal aortic aneurysm in patients with a pulsatile abdominal mass.
26. What are the commonly tested causes of autoimmune hemolytic anemia?
¢ Lupus erythematosus (or medications that cause lupus-like syndromes, such as pro-
cainamide, hydralazine, and isoniazid) and other autoimmune disorders
¢ Drugs (the classic example is methyldopa, but penicillins, cephalosporins, sulfa drugs, and
quinidine also have been implicated)
¢ Leukemia or lymphoma
¢ Infection (the classic examples are mycoplasmosis, Epstein-Barr virus, and syphilis)
27. What lab test is often positive in patients with autoimmune anemia?
The Coombs test is positive in most autoimmune anemias. You also may see spherocytes on
peripheral smear because of incomplete macrophage destruction (extravascular hemolysis) of red
blood cells.
28. What clues point to lead poisoning as a cause of anemia?
Lead poisoning causes a hypochromic, microcytic anemia, almost always in a child. With
acute lead poisoning, look for vomiting, ataxia, colicky abdominal pain, irritability (aggressive,
behavioral regression), and encephalopathy, cerebral edema, or seizures. Usually, however, poi-
soning is chronic and low-level with minimal nonspecific symptoms. Watch for basophilic stip-
pling on peripheral smear, elevated free erythrocyte protoporphyrin or lead level, and consider
risk factors for lead exposure (a child who eats paint chips or lives in an old, run-down building).
29. True or false: Children with risk factors should be screened for lead poisoning.
True. Screening all asymptomatic children with a serum lead level at 1 and 2 years old regard-
less of risk is becoming controversial. In children with risk factors, screening is very important
because chronic low-level exposure may lead to permanent neurologic sequelae. Screening should
start at 6 months in children with risk factors, such as pica (especially paint chips and dust in old
buildings that may have lead paint), residence in an old or neglected building, and/or residence
near or family members who work at a lead-smelting or battery-recycling plant. Screen and meas-
ure symptomatic exposure with serum lead levels (normal value: < 10 ug/dl).
30. How is lead poisoning treated?
Treat initially with decreased exposure (best strategy) as well as lead chelation therapy, if
needed. Use succimer in children and dimercaprol in adults; in severe cases, use dimercaprol plus
ethylenediamine tetraacetic acid (EDTA) for children or adults.
31. How can sideroblastic anemia be recognized on the Step 2 exam? Should the presence
of sideroblastic anemia raise concern about other conditions?
The typical description is a microcytic, hypochromic anemia with increased or normal iron, fer-
ritin, and total iron-binding capacity (transferrin). This description should immediately steer you
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104 Hematology
away from iron deficiency. Look for polychromatophilic stippling and the classic "ringed siderob-
last" in the bone marrow (know what it looks like). Sideroblastic anemia may be related to
myelodysplasia or future blood dyscrasia. Although probably you will not be asked about manage-
ment, treatment is supportive. In rare cases the anemia responds to pyridoxine. Do not give iron.
32. How do you recognize anemia of chronic disease?
First, look for the presence of a disease that causes chronic inflammation (e.g., rheumatoid
arthritis, lupus erythematosus, cancer, tuberculosis). The anemia is either normocytic or micro-
cytic. Serum iron is low, but so is total iron-binding capacity. Thus, the percent saturation may
be near normal. Serum ferritin is elevated (because ferritin is an acute-phase reactant, the level
should be increased). Treat the underlying disorder to correct the anemia. Do not give iron.
33. Describe the hallmarks of spherocytosis.
This normochromic, normocytic anemia is associated with spherocytes on peripheral smear,
positive family history (autosomal dominant), splenomegaly, positive osmotic fragility test, and
an increased mean corpuscular hemoglobin concentration (the only occasion on which this red
blood cell index is useful for the Step 2 exam). Treatment often involves splenectomy. Sphero-
cytes also may be seen in extravascular hemolysis, but the osmotic fragility test is normal.
34. Why do chronic renal disease patients develop anemia? How do you treat it?
All patients with chronic renal failure develop a normocytic, normochromic anemia with
decreased reticulocyte count due to decreased erythropoietin production. Give erythropoietin to
correct the anemia.
35. What clues point to a diagnosis of aplastic anemia?
Although aplastic anemia may be idiopathic, on the Step 2 exam watch for chemotherapy,
radiation, malignancy affecting the bone marrow (especially leukemias), benzene, and implicated
medications (e.g., chloramphenicol, carbamazepine, phenylbutazone, sulfa drugs, zidovudine,
gold). Decreased white blood cells and platelets accompany the anemia. Treat first by stopping
any possible causative medication; then try antithymocyte globulin, colony-stimulating factors
(such as erythropoietin, sargramostim, and filgrastim), or bone marrow transplant.
36. Define myelophthisic anemia. What clues on the peripheral smear suggest its presence?
Myelophthisic anemia is due to a space-occupying lesion in the bone marrow. The common
causes are malignant invasion that destroys bone marrow (most common) and myelodysplasia or
myelofibrosis. On the peripheral smear, look for marked anisocytosis (different size), poikilocy-
tosis (different shape), nucleated red blood cells, giant and/or bizarre-looking platelets, and
teardrop-shaped red blood cells. A bone marrow biopsy may reveal no cells ("dry tap" if the
marrow is fibrotic) or malignant-looking cells.
37. How do you recognize glucose-6-phosphatase deficiency on the USMLE?
This genetic disorder is X-linked recessive, affecting males. It is most common in blacks and
Mediterraneans. Look for sudden hemolysis or anemia after exposure to fava beans or certain
drugs (antimalarials, salicylates, sulfa drugs) or after infection. You may see Heinz bodies and
"bite cells" on peripheral smear. The diagnosis is made with a red blood cell enzyme assay, which
should not be done immediately after hemolysis because of the potential for a false-negative
result. All of the older red blood cells already have been destroyed, and the younger red blood
cells are not affected in most patients. Treat with avoidance of precipitating foods and medica-
tions; discontinue the triggering medication first.
38. Name some other causes of anemia.
¢ Endocrine failure (especially pituitary and thyroid; look for endocrine symptoms)
¢ Mechanical heart valves (hemolyzed red blood cells)
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Hematology 105
Disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and
hemolytic uremic syndrome (look for schistocytes and red blood cell fragments on smear
and other appropriate findings)
Other hemoglobinopathies (the hemoglobin C and E varieties are fairly common)
Paroxysmal nocturnal or cold hemoglobinuria;
Clostridium perfringens infection, malaria, and babesiosis (cause intravascular hemolysis
and fever)
Hypersplenism (associated with splenomegaly and often with low platelets and white
blood cells).
Thrombotic thrombocytopenic purpura
(TTP). Widespread confluent and necrotic
ecchymoses of the facial skin are seen in
this man with severe TTP. (From Hoff-
brand AV, Pettit JE: Color Atlas of Clini-
cal Hematology, 3rd ed. St. Louis,
Mosby, 2000, p 215, with permission.)
39. When is transfusion indicated for anemia (at what hemoglobin level)?
Always transfuse on clinical grounds; observe the symptoms. In other words, treat the
patient, not the lab value. There is no such thing as a "trigger value" for transfusion. Having said
this, hemoglobin levels < 7 or 8 gm/dl in the acute setting make most clinicians nervous.
40. What are the indications for the use of various blood products?
Whole blood: used only for rapid, massive blood loss or exchange transfusions (poisoning,
thrombotic thrombocytopenic purpura).
Packed red blood cells: used for routine transfusions.
Washed red blood cells: free of traces of plasma, white cells, and platelets; good for IgA
deficiency as well as allergic or previously sensitized patients.
Platelets: given for symptomatic thrombocytopenia (usually < 10,000/ul).
Granulocytes: used on rare occasions for neutropenia.
Fresh frozen plasma (FFP): contains all clotting factors; used for bleeding diathesis when
you cannot wait for vitamin K to take effect (e.g., disseminated intravascular coagulation, severe
warfarin poisoning) or when vitamin K will not work (liver failure).
Cryoprecipitate: contains fibrinogen and factor 8; used in hemophilia, von Willebrand's
disease, and disseminated intravascular coagulation.
41. What is the most common cause of a blood transfusion reaction? What blood type can
be given in an emergency to avoid a reaction?
The most common cause of a blood transfusion reaction is lab error. Type O negative blood
can be used to avoid a reaction when you cannot wait for blood typing or when the blood bank
does not have the patient's blood type.
42. Describe the signs and symptoms of a blood transfusion reaction.
Look for febrile reaction ( e.g., chills, fever, headache, back pain) from antibodies to white
blood cells; hemolytic reaction (e.g., anxiety or discomfort, dyspnea, chest pain, shock, jaun-
dice) from antibodies to red blood cells; or allergic reaction ( e.g., urticaria, edema, dizziness,
dyspnea, wheezing, anaphylaxis) to an unknown component in donor serum. Oliguria may be an
associated finding.
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106 Hematology
43. What should you do if you suspect a transfusion reaction?
The first step is to stop the transfusion. If oliguria is present, treat with intravenous fluids
and diuresis (mannitol or furosemide).
44. What are the other risks of transfusion?
There is a small but real risk of infection (usually viral infections such as hepatitis B and C,
human immunodeficiency virus, and cytomegalovirus) and hyperkalemia (from hemolysis). With
large transfusions (> 5 units of packed red blood cells), bleeding diathesis may result from dilu-
tional thrombocytopenia and citrate (a blood preservative and calcium chelator that prevents clot-
ting). Look for oozing from puncture or IV sites.
45. What are the most common causes of disseminated intravascular coagulation (DIC)?
The most common cause is pregnancy and obstetric complications (roughly 50% of cases),
followed by malignancy (33%), sepsis, and trauma (especially head trauma, prostate surgery, and
snake bites).
46. How do I recognize and treat DIC in a classic at-risk patient?
DIC usually manifests with bleeding diathesis but may have thrombotic tendencies. Look for
the classic oozing or bleeding from puncture and IV sites; prolonged prothrombin time (PT), par-
tial thromboplastin time (PTT), and bleeding time (BT). DIC is the only disorder on the Step 2
exam that prolongs all three tests. Other clues include positive D-dimer, increased fibrin degra-
dation products, thrombocytopenia, decreased fibrin, and decreased clotting factors (including
factor 8, which is normal in hepatic necrosis).
Treat the underlying cause (e.g., evacuate the uterus, give antibiotics). You may need to give
transfusions with fresh frozen plasma or, in rare cases, heparin (only if thrombosis occurs).
47. With what conditions is eosinophilia associated?
¢ Allergy, eczema, and atopy
¢ Angioedema
¢ Drug reactions
¢ Parasitic infections
¢ Blood dyscrasias (especially lymphoma)
¢ Loffler's syndrome (pulmonary eosinophilia)
¢ Autoimmune diseases (e.g., lupus erythematosus, rheumatoid arthritis)
¢ IgA deficiency
¢ Adrenal insufficiency
48. With what conditions is basophilia associated?
Allergies or neoplasm/blood dyscrasia.
49. True or false: The lupus anticoagulant causes a clotting tendency.
True. Although the lupus anticoagulant may cause a prolonged partial thromboplastin time,
the patient has a tendency toward thrombosis. Look for associated lupus symptoms, positive
results on the Venereal Disease Research Laboratory or rapid plasma reagin tests for syphilis,
and/or a history of miscarriages to help you recognize this condition.
50. What genetic causes of an increased tendency toward clot-forming may appear on the
Step 2 exam?
The list keeps growing. Watch for factor V Leiden mutation (or activated protein C resist-
ance), prothrombin G20210A mutation, or deficiencies in protein C, protein S, or antithrombin
III (all autosomal dominant except protein C deficiency) as causes of an increased tendency
toward thrombosis. All are treated with anticoagulant therapy to prevent deep venous thrombo-
sis and pulmonary embolus. Suspect these conditions if a person under age 35 develops recurrent
clots or has no risk factors for clot development.
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Hernatology 107
51. Which clotting tests measure which portions of the coagulation cascade? Which med-
ications affect these tests?
PT (prothrombin time) measures the function of the extrinsic clotting pathway (prolonged by
warfarin), activated PTT (partial thromboplastin time) measures the function of the intrinsic clot-
ting pathway (prolonged by heparin), and BT (bleeding time) measures platelet function (pro-
longed by aspirin).
52. How do specific diseases affect clotting tests? What are the main differential points?
PLATELET RBC
DISEASE PT PTT BT COUNT COUNT OTHER
Von Willebrand's Normal High High Normal Normal Autosomal dominant
disease (look for family history)
Hemophilia A/B Normal High Normal Normal Normal X-linked recessive, A =
low factor 8, B = low
factor 9
DIG High High High Low Normal/ Appropriate history, low
low level of factor 8
Liver failure High High Normal Normal/ Normal/ Jaundice, normal factor 8
low low level; do not give vitamin
K (ineffective); use FFP
Heparin Normal High Normal Normal/ Normal Watch for thrombocyto-
low penia and thrombosis
Warfarin High Normal Normal Normal Normal Vitamin K antagonist
(factors 2, 7, 9, and 10)
IIP Normal Normal High Low Normal Watch for preceding URI
TIP Normal Normal High Low Low Hemolysis (smear), CNS
symptoms; treat with
plasmapheresis; do not
give platelets!
Scurvy Normal Normal Normal Normal Normal Fingernail and gum
hemorrhages, bone
hemorrhages; caused by
vitamin C deficiency
PT = prothrombin time, PTT = partial thromboplastin time, BT = bleeding time, RBC = red blood cell,
DIG = disseminated intravascular coagulation, ITP = idiopathic thrombocytopenic purpura, TTP =
thrombotic thrombocytopenic purpura, FFP = fresh frozen plasma, URI = upper respiratory infection,
CNS = central nervous system.
53. What are the common causes of thrombocytopenia? What kind of bleeding problems
are caused by low platelet counts?
Common causes of thrombocytopenia include purpura (idiopathic or thrombotic), hemolytic
uremic syndrome, disseminated intravascular coagulation, HIV, splenic sequestration, heparin
(treat by first stopping heparin), other medications (especially quinidine and sulfa drugs), autoim-
mune disease, and alcohol. Bleeding from thrombocytopenia is in the form of petechiae, nose
bleeds, and easy bruising.
54. What causes petechiae or "platelet-type" bleeding in the setting of normal platelets?
Vitamin C deficiency (scurvy) causes bleeding similar to that seen with low platelets (splin-
ter and gum hemorrhages, petechiae); perifollicular and subperiosteal hemorrhages are unique to
scurvy. Patients have a poor dietary history (the classic example is hot dogs and soda or tea and
toast), myalgias and arthralgias, and capillary fragility (bleeding is due to collagen problems in
the vessels). Treat with oral vitamin C.
Other causes include uremia (platelet dysfunction), inherited connective tissue disorders (Ehlers-
Danlos syndrome, Marian's syndrome), and chronic corticosteroid use (causes capillary fragility).
--------------------------------------- 11
18. HYPERTENSION
1. How often should you screen for hypertension?
Although there is no absolutely correct answer, all people should be screened roughly every
2 years, starting at the age of three.
2. Define hypertension.
Persistent blood pressure greater than 140/90 mmHg. Recent efforts in the "war on hyper-
tension" label a systolic blood pressure of 120-139 mmHg and diastolic pressure of 80-89 mmHg
"prehypertension." Remember that 145/60 mmHg is hypertension, as is 115/95 mmHg (isolated
systolic or diastolic hypertension, respectively). Treatment is needed. In grading the severity of
hypertension, use the worst number, whether it be diastolic or systolic. See the table below for
the 2003 Joint National Committee (JNC) classification.
Systolic BP* Diastolic BP*
(mmHg) (mmHg) Classification
<120 <80 Normal
120-139 80-89 Prehypertension
140-159 90-99 Stage I hypertension
a 160 2 100 Stage II hypertension
*Classification is based on the worst number (e.g., 168/60 mm Hg is considered stage II hypertension
even though diastolic pressure is normal).
3. What is the "three-measurement" rule in the diagnosis of hypertension?
Classically, the blood pressure is measured three time on three separate office visits before
the diagnosis and pharmacologic treatment of hypertension. However, if asked, institute conser-
vative measures (see below) and address associated comorbidities ( e.g., obesity, diabetes) after
the first abnormal measurement. There are a few important exceptions to the "start conservative
and remeasure" strategy, however, and more aggressive approaches are gaining favor. If a
patient's blood pressure is greater than 200/120 mmHg (a hypertensive "urgency") or if end-
organ effects are evident (a hypertensive "emergency," see below), treatment should be instituted
immediately. In pregnant woman, preeclampsia may be the cause of hypertension. Waiting to
treat in this setting can have devastating consequences to mother and fetus.
4. What are the conservative (i.e., nonpharmacologic) treatments for hypertension?
Dietary changes (i.e., low salt, low fat, low calorie), reduced smoking and alcohol intake,
weight loss, and exercise may each have a positive effect on blood pressure and, in some cases,
get the patient back into the normotensive range. Medications should be started only after a 1-
to 2-month trial of lifestyle modifications for stage I hypertension. In patients with stage II
hypertension or those with diabetes or renal disease, early pharmacologic treatment is often
preferred.
5. List the first-line medications for treatment of hypertension.
Five classes of drugs are used as first-line therapy: thiazide diuretics, beta blockers,
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and
calcium channel blockers. Which you should use often depends on the individual patient and his
or her other medical problems.
108
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Hypertension 109
Drug Class Use in Patients with: Avoid in Patients with:
Thiazides Heart failure, diabetes, high risk for coro- Gout, electrolyte disturbances ( e.g.,
nary artery disease or stroke, osteoporosis hyponatremia), pregnancy
Beta blockers Stable angina, acute coronary syndrome/Asthma, chronic obstructive
unstable angina, acute or prior myo- pulmonary disease, heart block, sick
cardial infarction, high risk for coro-sinus syndrome
nary artery disease, atrial tachycardia/
fibrilliation, thyrotoxicosis (short-term),
essential tremor, migraines
ACE inhibitors Heart failure, diabetes, acute coronaryPregnancy, angioedema, renovascular
syndrome/unstable angina, acute or hypertension (may cause renal
prior myocardial infarction, high riskfailure)
for coronary artery disease or stroke,
chronic kidney disease
ARBs Heart failure, diabetes, chronic kidneyPregnancy, renovascular hypertension
disease (may cause renal failure)
Calcium channel Raynaud syndrome, atrial Heart block, sick sinus syndrome,
blockers tachyarrhythmias congestive heart failure (all related
to central-acting agents), pregnancy
Note: ACE inhibitors are first-line agents for congestive heart failure, because they reduce mortality
rates. In diabetes, ACE inhibitors retard progression to nephropathy and neuropathy. All patients with
stable congestive heart failure or diabetes should take an ACE inhibitor (if they can tolerate it) even in
the absence of hypertension.
6. What about women of reproductive age and pregnant women with hypertension?
Labetalol, hydralazine, and alpha-methyldopa are safe. If preeclampsia is present, remember
that magnesium sulfate lowers blood pressure.
7. Define hypertensive urgency. How is it different from hypertensive emergency?
Hypertensive urgency is defined as blood pressure > 200/120 mmHg without symptoms.
Hypertensive emergency is defined as blood pressure > 200/120 mmHg with symptoms or evi-
dence of end-organ damage. Examples: acute left ventricular failure, chest pain or angina,
myocardial infarction, encephalopathy (watch for headaches, confusion, papilledema, mental
status changes, vomiting, blurry vision, dizziness, and/or seizures), or acute renal failure (from
necrotizing arteriolitis, see figure). Both require immediate treatment, but hypertensive emer-
gency is more worrisome. Treat immediately with nitroprusside, nitroglycerin, labetalol, or dia-
zoxide (second-line agent).
Fibrinoid necrosis secondary to malignant hyperten-
sion. This change is due to rapid intimal cell prolifer-
ation with leakage of plasma proteins into and beyond
the arteriolar wall with resultant obliteration of the
wall by intensely eosinophilic amorphous proteina-
ceous material (P) and, often, luminal occlusion .
Damage to the vessel wall may also lead to thrombo-
sis within the lumen. A glomerulus can be seen on the
far right side of the image. (From Stevens A, et al:
Wheater's Basic Histopathology, 4th ed. New York,
Churchill Livingstone, 2002, p 116, with permission.)
8. What causes hypertension?
Roughly 90-95% of cases are idiopathic, multifactorial, or essential hypertension. About
5-10% of cases are due to secondary (known) causes.
--------------------------------------- 13
Biostatistics 11
negative test). It is calculated mathematically by dividing the number of true negatives by the
total number of people with a negative test. NPV also depends on the prevalence of the disease
and the sensitivity and specificity of the test (the higher the prevalence, the lower the NPV). In
addition, an overly sensitive test with lots of false positives makes the NPV higher.
6. Define attributable risk. How is it measured?
Attributable risk is the number of cases of a disease attributable to one risk factor (in other
words, the amount by which the incidence of a condition is expected to decrease if the risk factor
in question is removed). For example, if the incidence rate of lung cancer is 1/100 in the general
population and 10/100 in smokers, the attributable risk of smoking in causing lung cancer is
9/100 (assuming a properly matched control).
7. You need to develop the habit of drawing a 2 X 2 table for Step 2 statistics questions.
Given the 2X2 table below, define the formulas for calculating the following test values:
Disease Test Name Formula
Sensitivity A/(A + C)
Specificity D/(B + D)
Test (+) A B PPV A/(A + B)
NPV D/(C + D)
Exposure (-) C D Odds ratio (A X D)/(B X C)
Relative risk [A/(A + B)]/[C/(C + D)]
Attributable risk [A/(A + B)]-[C/(C + D)]
8. Define relative risk. From what type of studies can it be calculated?
Relative risk compares the disease risk in people exposed to a certain factor with the disease
risk in people who have not been exposed to the factor in question. Relative risk can be calcu-
lated only after prospective or experimental studies; it cannot be calculated from retrospective
data. If a Step 2 question asks you to calculate the relative risk from retrospective data, the answer
is "cannot be calculated" or "none of the above."
9. What is a clinically significant value for relative risk?
Any value for relative risk other than 1 is clinically significant. For example, if the relative
risk is 1.5, a person is 1.5 times more likely to develop the condition if exposed to the factor in
question. If the relative risk is 0.5, the person is only half as likely to develop the condition when
exposed to the factor; in other words, the factor protects the person from developing the disease.
10. Define odds ratio. From what type of studies is it calculated?
Odds ratio attempts to estimate relative risk with retrospective studies (e.g., case control). An
odds ratio compares (the incidence of disease in persons exposed to the factor and the incidence
of nondisease in persons not exposed to the factor) with (the incidence of disease in persons unex-
posed to the factor and the incidence of nondisease in persons exposed to the factor) to see
whether there is a difference between the two. As with relative risk, values other than 1 are sig-
nificant. The odds ratio is a less than perfect way to estimate relative risk (which can be calcu-
lated only from prospective or experimental studies).
11. What do you need to know about standard deviation (SD) for the USMLE?
You need to know that with a normal or bell-shaped distribution, 1 SD holds 68% of the
values, 2 SD hold 95% of the values and 3 SD hold 99.7% of the values. A classic question gives
you the mean and standard deviation and asks you what percentage of values will be above a
given value. Variations in this question are common.
12. Define mean, median, and mode.
The mean is the average value, the median is the middle value, and the mode is the most
common value. A question may give you several numbers and ask you for their mean, median,
and mode. For example, if the question gives you the numbers 2, 2, 4, and 8:
--------------------------------------- 14
no
Hypertension
9. What are the common causes of secondary hypertension in younger men and women?
In younger men, a common cause of secondary hypertension is excessive alcohol intake (get
the patient to quit!). In younger women, common and classic causes are birth control pills (stop
them!) and renal artery stenosis from fibromuscular dysplasia (which may cause a bruit and
should be treated with balloon angioplasty).
10. List less common causes of secondary hypertension.
Pheochromocytoma. Look for wild swings in blood pressure with diaphoresis and confu-
sion. As a screening test, order 24-hour urine collection to assess catecholamine products
(metanephrines, vanillylmandelic acid, homovanillic acid).
Renal artery stenosis (RAS). Unlike young patients with fibromuscular dysplasia, elderly
patients typically have RAS due to atherosclerosis. A renal artery bruit is classically present
(although not sensitive); magnetic resonance or conventional angiography makes the definitive
diagnosis. Giving ACE inhibitors to patients with RAS may precipitate acute renal failure (some-
times the first diagnostic clue to its presence).
Polycystic kidney disease. Look for flank mass, positive family history (autosomal domi-
nant pattern of inheritance), and elevations in creatinine and blood urea nitrogen.
Cushing's syndrome. Look for stigmata of Cushing's syndrome on exam. Order 24-urine
collection to assess free cortisol or dexamethasone suppression test
Conn's syndrome. The cause is an aldosterone-secreting adrenal neoplasm. Look for high
aldosterone levels, low renin levels, hypokalemia, metabolic alkalosis, and/or an adrenal mass on
computed tomography.
Coarctation of the aorta. Look for hypertension in the upper extremities only, with unequal
pulses, radiofemoral delay, and rib notching on chest radiograph; associated with Turner's syn-
drome. MRI or angiography makes a definitive diagnosis.
Renal failure from any cause. In children, watch for poststreptococcal glomerulonephritis
or hemolytic uremic syndrome.
Abdominal aortogram demonstrates
high-grade, proximal, left renal artery
stenosis (curved arrow). (From Katz DS,
Math KR, Groskin SA (eds): Radiology
Secrets. Philadelphia, Hanley & Belfus,
1998, p 185, with permission.)
11. What does lowering blood pressure accomplish?
Hypertension is the number-one modifiable risk factor for strokes. Lowering blood pressure
decreases heart disease, myocardial infarctions, atherosclerosis, renal failure, and dissecting
aortic aneurysms.
12. What is the most common cause of death among untreated patients with hypertension?
The same as for the general population”coronary artery disease.
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Hypertension 111
13. Which three tests should be ordered for every patient with a diagnosis of hypertension?
Why?
1. Electrocardiogram: to determine whether the heart has been affected (e.g., left ventric-
ular hypertrophy).
2. Chemistry 7 panel (i.e., basic metabolic panel): clues to possible secondary cause of
hypertension (e.g., electrolyte disturbances in Conn's syndrome).
3. Urinalysis: clues to possible secondary cause of hypertension (e.g., red blood cell casts
in poststreptococcal glomerulonephritis) and to kidney damage (proteinuria).
--------------------------------------- 16
19. IMMUNOLOGY
1. List the four classic types of hypersensitivity reactions.
¢ Anaphylactic (type I) ¢ Immune complex-mediated (type III)
¢ Cytotoxic (type II) ¢ Cell-mediated/delayed (type IV)
2. What causes type I hypersensitivity? Give the classic clinical examples.
Type I (anaphylactic) hypersensitivity is due to preformed IgE antibodies that cause release
of vasoactive amines (e.g.. histamine, leukotrienes) from mast cells and basophils. Examples are
anaphylaxis, atopy, hay fever, urticaria, allergic rhinitis, and some forms of asthma. Anaphylaxis
may be due to bee stings, food allergy (especially peanuts and shellfish), medications (especially
penicillins and sulfa drugs), or rubber glove allergy.
3. Describe the clinical findings with chronic type I hypersensitivity.
Look for eosinophilia, elevated IgE levels, positive family history, and seasonal exacerba-
tions. Patients also may have allergic "shiners" (bilateral infraorbital edema), and a transverse
nasal crease (due to frequent nose rubbing). Pale, bluish, edematous nasal turbinates with many
eosinophils in clear, watery nasal secretions are also classic.
4. What medication should be avoided in patients with nasal polyps?
Do not give aspirin, which may precipitate a severe asthma attack.
5. How do you recognize and treat true anaphylaxis?
Look for the classic triggers mentioned above just before the patient becomes agitated and
flushed and develops itching (urticaria), facial swelling (angioedema), and difficulty in breath-
ing. Symptoms tend to develop rapidly and dramatically.
Treat immediately by securing the airway (laryngeal edema may prevent intubation, in which
case do a cricothyrotomy, if needed) and give subcutaneous epinephrine. Antihistamines are only
useful for cutaneous reactions and itching, not for more severe reactions. Use corticosteroids only
if the initial treatment options are not available (not a first-line agent).
6. What usually causes hereditary angioedema?
A deficiency of Cl esterase inhibitor (complement) is the usual cause of hereditary
angioedema. Patients have diffuse swelling of lips, eyelids, and possibly the airway, unrelated to
allergen exposure. The disease is autosomal dominant; look for a positive family history. C4 com-
plement levels are low. Acute treatment is the same as for anaphylaxis. Androgens are used for
long-term treatment because they increase liver production of Cl esterase inhibitor.
7. What type of testing can identify an allergen if it is not obvious?
Skin or patch testing.
8. What causes type II hypersensitivity? List some classic clinical examples.
Type II (cytotoxic) hypersensitivity is due to preformed IgG and IgM antibodies that react
with the antigen and cause secondary inflammation. Examples include the following:
¢ Autoimmune hemolytic anemia (classically caused by methyldopa, penicillins, or sulfa
drugs) or other cytopenias caused by antibodies ( e.g., idiopathic thrombocytopenic pur-
pura)
¢ Transfusion reactions
¢ Erythroblastosis fetalis (Rh incompatibility)
112
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immunology 113
Patch testing. A battery of common 1 I |
and suspected allergens isapplied to
the back for 48 hours. The skin is then
examined at 96 hours. Irritant reac-
tions disappear, allergic ones do not.
Two positives are present. (From du
Vivier A: Atlas of Clinical Dermatol-
ogy, 3rd ed. New York, Churchill Liv-
ingstone, 2002, p 65, with permission.)
¢ Goodpasture's syndrome (watch for linear immunofluorescence on kidney biopsy)
¢ Myasthenia gravis
¢ Graves' disease
¢ Pernicious anemia
¢ Pemphigus vulgaris
¢ Hyperacute transplant rejection (as soon as the anastomosis is made at transplant surgery,
the transplanted organ deteriorates in front of the surgeon's eyes).
9. What lab test is usually positive with a type II hypersensitivity that causes anemia?
Coombs' test (usually the direct Coombs' test).
10. What causes type III hypersensitivity? List some classic clinical examples.
Type III (immune complex-mediated) hypersensitivity is due to antigen-antibody complexes
that usually are deposited in vessels and cause an inflammatory response. Examples include
serum sickness, lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, cryoglobuline-
mia, and certain types of glomerulonephritis ( e.g., from chronic hepatitis).
11. What causes type IV hypersensitivity? How is it related to tuberculosis testing?
Type IV (cell-mediated/delayed) hypersensitivity is due to sensitized T lymphocytes that
release inflammatory mediators. The tuberculosis skin test (purified protein derivative [PPD])
exploits this immune system reaction. Other examples include contact dermatitis (especially
poison ivy, nickel earrings, cosmetics, and medications), chronic transplant rejection, and granu-
lomas (e.g., sarcoidosis).
12. What sexually transmitted infectious disease should be in the back of your mind when
a patient presents with a sore throat and mononucleosis-like syndrome?
Human immunodeficiency virus (HIV) infection, because initial seroconversion may present
as a mononucleosis-like syndrome (e.g., fever, malaise, pharyngitis, rash, lymphadenopathy).
13. How is HIV diagnosed? How long after exposure does the HIV test become positive?
Diagnosis is made with the enzyme-linked immunosorbent assay (ELISA), which, if posi-
tive, should be confirmed with a Western blot test. All of these tests should be done before you
tell the patient anything. It takes at least 1 month for antibodies to develop. Therefore, if a patient
wants testing because of recent risk-taking behavior, you should retest the patient in 6 months if
the initial test is negative.
14. What is the reason for doing "control" tests when a PPD tuberculosis test is done in
HIV-positive patients?
Though now more controversial, control tests make sure that a negative PPD result is mean-
ingful. If a patient is anergic or fails to mount an immune response, a negative PPD means little.
If the control skin tests (usually candidal infection and mumps, to which everyone in the U.S. is
--------------------------------------- 18
114 Immunology
exposed ) give positive results (which are normal in healthy people) and the PPD gives a nega-
tive result, you should feel more comfortable in saying that the patient probably does not have
tuberculosis (although the PPD test is not 100% sensitive).
15. How do you recognize Pneumocystis carinii pneumonia (PCP)?
For the Step 2 exam, think of PCP first in any patient with HIV and pneumonia, even though
community-acquired pneumonia is more common even in patients with AIDS. Look for severe
hypoxia with normal radiographs or diffuse, bilateral interstitial infiltrates (see figure). Patients
usually have a dry, nonproductive cough. PCP may be detected with silver stains (Wright-
Giemsa, Giemsa, or methenamine silver) applied to induced sputum; if not, you can use bron-
choscopy with bronchoalveolar lav age and brush biopsy to make the diagnosis. High levels of
lactate dehydrogenase are suspicious in the appropriate setting. PCP is now usually treated pre-
sumptively, with diagnostic testing reserved for those in whom the diagnosis is unclear or initial
treatment fails.
Pneumocystis carinii pneumonia in a patient with AIDS.
Extensive, predominantly central, interstitial opacities are
present bilaterally, right greater than left. (From Hoffbrand
AV, Pettit IE: Color Atlast of Clinical hematology, 3rd ed. St.
Louis, Mosby, 2000, p 136, with permission.)
16. What is the most common primary immunodeficiency? How do you recognize it?
IgA deficiency, which causes recurrent respiratory and gastrointestinal infections. IgA levels
are always low, and levels of IgG subclass 2 may be low. Do not give immunoglobulins, which
may cause anaphylaxis due to development of anti-IgA antibodies. Alternatively, if any patient
develops anaphylaxis after immunoglobulin exposure, you should think of IgA deficiency.
17. How do you recognize Bruton's agammaglobulinemia?
Bruton's agammaglobulinemia (X-linked agammaglobulinemia) is an X-linked recessive
disorder with low or absent B cells that affects males. Infections begin after 6 months when
maternal antibodies disappear. Look for recurrent lung or sinus infections with Streptococcus and
Hemophilus species.
18. What causes DiGeorge's syndrome? How do you recognize it?
DiGeorge's syndrome is caused by hypoplasia of the third and fourth pharyngeal pouches.
Look for hypocalcemia and tetany (from hypocalcemia due to absent parathyroid glands) in the
first 24-48 hours of life. The thymus also may be absent or hypoplastic, and congenital heart
defects and typical facies often are present.
19. What is the classic cause of severe combined immunodeficiency? How does it present?
Severe combined immunodeficiency may be autosomal recessive or X-linked. The classic
cause is adenosine deaminase deficiency (autosomal recessive). Patients have B- and T-cell
defects and severe infections in the first few months of life. Other symptoms include cutaneous
anergy and absent or dysplastic thymus and lymph nodes.
--------------------------------------- 19
Immunology 115
20. What triad indicates the diagnosis of Wiskott-Aldrich syndrome?
Wiskott-Aldrich deficiency is an X-linked recessive disorder that affects males. The classic
triad consists of eczema, thrombocytopenia (look for bleeding), and recurrent infections (usually
respiratory).
21. How do you recognize Chediak-Higashi syndrome?
Chediak-Higashi syndrome is usually an autosomal recessive disorder characterized by giant
granules in neutrophils, infections, and often oculocutaneous albinism. It is caused by a defect in
microtubule polymerization.
22. Describe the pathophysiology of chronic granulomatous disease.
Chronic granulomatous disease is usually an X-linked recessive disorder that affects males.
Because of a defect in the activity of reduced nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase, patients have recurrent infections with catalase-positive organisms (e.g.,
Staphylococcus aureus, Pseudomonas species). Diagnosis is clinched if the question mentions
deficient nitroblue tetrazolium dye reduction by granulocytes. This test measures the respiratory
burst, which patients with chronic granulomatous disease lack.
23. Cover the right-hand column, and answer the questions about HIVmanagement on the
left.
QUESTION ANSWER
After HIV diagnosis, how often do you check the CD4 Every 6 months
count?
When do you start antiretroviral therapy? When the CD4 count is < 500/mm 3
(or sooner)
When do you start PCP prophylaxis? When the CD4 count is < 200/mm 3
What is the drug of choice for PCP prophylaxis? Trimethoprim-sulfamethoxazole
(Bactrim)
What other agents are used in patients with allergy or Dapsone and pentamidine
intolerance to Bactrim?
When should you start Mycobacterium avium complex When the CD4 count is < 100/mm 3
(MAC) prophylaxis?
What drugs are used for MAC prophylaxis? Clarithromycin, azithromycin,
or rifabutin
True or false: Once the CD4 is < 200/mm 3, the patient isTrue
automatically considered to have AIDS (even without
opportunistic infections).
True or false: Give the measles-mumps-rubella vaccine. True (only live vaccine that is
given)
True or false: Do not give annual influenza vaccines. False (give every year)
True or false: PPD testing should be done annually. True
True or false: Oral polio vaccine should be given to patientsFalse (use inactive polio vaccine
and their contacts. injection)
The risk of which cancer is increased on skin and in theKaposi's sarcoma
mouth?
The risk of which type of blood cell cancer is increased?Non-Hodgkin's lymphoma
(usually primary B-cell lym-
phomas of CNS)
What do positive India ink preparations of the cerebrospinalCryptococcus neoformans
fluid mean? meningitis
What do ring-enhancing lesions in the brain on CT or MR Toxoplasmosis, cysticercosis/
scans usually mean? Taenia solium, or lymphoma
True or false: HIV may cause thrombocytopenia. True
Table continued on next page
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116 Immunology
QUESTION ANSWER
True or false: Give pneumococcal and hepatitis vaccines.True
True or false: HIV can cause dementia. True
True or false: HIV protects against peripheral neuropathies.False (HIV can cause them)
True or false: HIV mothers may breast-feed their infants.False (breast milk transmits HIV)
First-choice agent for cytomegalovirus retinitis. Ganciclovir/valganciclovir
Second-choice agents for cytomegalovirus retinitis. Foscarnet or cidofovir
True or false: Pregnant patients should take zidovudine (AZT)True.
True or false: Infants born to HIV-positive mothers shouldTrue (for the first 6 weeks after
take AZT. delivery)
True or false: Cesarean section increases maternal HIV False (it may decrease transmission
transmission. to child)
Most likely cause of pneumonia in HIV patient Streptococcus pneumoniae
Most likely cause of opportunistic pneumonia in HIV patienPneumocystist carinii
Stain used on sputum to detect PCP Silver (Wright-Giemsa or Giemsa)
Two pathogens that cause chronic diarrhea only in AIDS. Cryptosporidium and Isospora spp.
True or false: Herpes-zoster infection in young adults =True (suggests immunodeficiency)
possible HIVinfection.
True or false: Thrush in young adults may mean HIV True (also assocated with diabetes,
infection leukemia, and steroids)
True or false: A positive HIV antibody test in a newborn iTruse (maternal antibodies in the
unreliable neonate can give a false-positive
result for the first 6 months)
24. Complement deficiencies of C5 through C9 cause recurrent infections with which genus
of bacteria?
Neisseria spp.
25. Define chronic mucocutaneous candidiasis.
Chronic mucocutaneous candidiasis is a cellular immunodeficiency specific for candidal
infection. Patients have thrush and candidal infections of the scalp, skin, and nails as well as
anergy to Candida sp. with skin testing. Often it is associated with hypothyroidism. The rest of
the immune function is intact; no other types of infections are present.
26. Give the classic description of hyper-IgE syndrome (Job-Buckley syndrome).
Patients with hyper-IgE syndrome have recurrent staphylococcal infections (especially of the
skin) and have extremely high IgE levels. They also commonly have fair skin, red hair, and
eczema.
--------------------------------------- 21
20. INFECTIOUS DISEASES
1. Cover the middle and right-hand columns and specify which bugs are associated with
each type of infection and what type of empiric antibiotic should be used while waiting for
culture results.
CONDITION MAIN ORGANISM(S) EMPIRICAL ANTIBIOTICS
Urinary tract infection Escherichia coli Trimethoprim-sulfamethoxazole,
nitrofurantoin, amoxicillin,
quinolones
Bronchitis Virus, Haemophilus influenzae,Amoxicillin, erythromycin
Moraxella spp.
Pneumonia (classic) Streptococcus pneumoniae, Third-generation cephalosporin,
H. influenzae azithromycin
Pneumonia (atypical) Mycoplasma, Chlamydia spp. Macrolide antibiotic, doxycylcine
Osteomyelitis Staphyloccous aureus, Antistaphylococcal penicillin,!
Salmonella spp. vancomycin
Cellulitis Streptococci, staphylococci Antistaphylococcal penicillin (covers
both)
Meningitis (neonate) Streptococci B, E. coli, ListeriaAmpicillin + aminoglycoside, third-
spp. generation cephalosporin
Meningitis (child/adult)S. pneumoniae, Neisseria Third-generation cephalosporin or
meningitidis* meropenem + vancomycin +
dexamethasone
Sepsis Gram-negative organisms, Third-generation penicillin/
streptococci, cephalosporin staphylococci +
aminoglycoside, imipenem
Septic arthritis^ S. aureus Antistaphylococcal penicillin,
vancomycin
Gonococci Ceftriaxone, penicillin, spectinomycin
Endocarditis Staphylococci, streptococci Antistaphaylococcal penicillin (or
vancomycin) + aminoglycoside
*H. influenzae is no longer as common a cause of meningitis in children because of widespread vac-
cination. In a child with no history of immunization, H. influenzae is the most likely cause of menin-
gitis.
fExamples: dicloxacillin, methicillin.
$Think of staphylococci if the patient is monogamous or not sexually active. Think of gonorrhea for
younger adults who are sexually active.
2. Cover the right-hand columns and specify the empirical antibiotic of choice for each
organism.
ORGANISM* ANTIBIOTIC OTHER CHOICES
Strep A or B Pencillin, cephazolin Erythromycin
S. pneumoniae 3rd gen. cephalosporin, fluroquinolonFluoroquinolonee (e.g. levofloxacin)
Enterococcus Penicillin or ampicillin + Vancomycin + aminoglycoside
aminoglycoside
Staphylococcus aureus Anti-Staph Penicillin (e.g. methicillinVancomyci)n (MRSA)
Gonococcusf Ceftriaxone or fluoroquinolone Spectinomycin
Table continued on next page
117
--------------------------------------- 22 --------------------------------------- 22
118 Infectious Diseases
ORGANISM* ANTIBIOTIC OTHER CHOICES
Meningococcus Penicillin/ampicillin Cefotaxime, chloramphenicol
Haemophilus 2nd or 3rd gen. cephalosporin Ampicillin
Pseudomonas Antipseudomonal penicillin + Aztreonam, imipenem
aminoglycoside
Bacteroides Metronidazole Clindamycin
Mycoplasma Erythromycin, azithromycin Doxycycline
Treponema pallidum Penicillin Doxycycline
Chlamydia Doxycycline, azithromycin Erythromycin, fluoroquinolone
Lyme disease Ceftriaxone, doxycycline Erythromycin, amoxicillin
*Always use culture sensitivities
1. How do you analyze arterial blood gas values?
Remember three basic points:
1. pH tells you whether you are dealing with acidosis or alkalosis as the primary event. The
body will compensate as much as it can (secondary event).
2. Look at the carbon dioxide (CO 2) value. If it is high, the patient either has respiratory aci-
dosis (pH: < 7.4) or is compensating for metabolic alkalosis (pH: > 7.4). If CO2 is low, the patient
either has respiratory alkalosis (pH: > 7.4) or is compensating for metabolic acidosis (pH: < 7.4).
3. Look at the bicarbonate value. If it is high, the patient either has metabolic alkalosis (pH:
> 7.4) or is compensating for respiratory acidosis (pH: < 7.4). If bicarbonate is low, the patient
either has metabolic acidosis (pH: < 7.4) or is compensating for respiratory alkalosis (pH: > 7.4).
2. True or false: The body does not compensate beyond a normal pH.
True. For example, a patient with metabolic acidosis will eliminate CO, to help restore a
normal pH. However, if respiratory alkalosis is a compensatory mechanism (and not a rare, sep-
arate primary disturbance), the pH will not correct to > 7.4 . Overcorrection does not occur.
3. List the common causes of acidosis.
Respiratory acidosis: chronic obstructive pulmonary disease, asthma, drugs ( e.g., opioids,
benzodiazepines, barbiturates, alcohol, other respiratory depressants), chest wall problems
(paralysis, pain), and sleep apnea.
Metabolic acidosis: ethanol, diabetic ketoacidosis, uremia, lactic acidosis ( e.g., sepsis,
shock, bowel ischemia), methanol/ethylene glycol, aspirin/salicylate overdose, diarrhea, and car-
bonic anhydrase inhibitors.
4. List the common causes of alkalosis.
Respiratory alkalosis: anxiety/hyperventilation and aspirin/salicylate overdose.
Metabolic alkalosis: diuretics (except carbonic anhydrase inhibitors), vomiting, volume
contraction, antacid abuse/milk-alkali syndrome, and hyperaldosteronism.
5. What type of acid-base disturbance does aspirin overdose cause?
Respiratory alkalosis and metabolic acidosis (two different primary disturbances). Look for
coexisting tinnitus, hypoglycemia, vomiting, and a history of "swallowing several pills." Alka-
linization of the urine (with bicarbonate) speeds excretion.
6. What happens to the blood gas of patients with chronic lung conditions?
In certain people with chronic lung conditions (especially those with sleep apnea), pH may
be alkaline during the day because they breathe better when awake. In addition, just after an
episode of bronchitis or other respiratory disorder, the metabolic alkalosis that usually compen-
sates for respiratory acidosis is no longer a compensatory mechanism and becomes the primary
disturbance (elevated pH and bicarbonate). As a side note, remember that sleep apnea, like other
chronic lung diseases, can cause right-sided heart failure (cor pulmonale).
7. Should you give bicarbonate to a patient with acidosis?
For purposes of the Step 2 boards, almost never. First try intravenous fluids and correction
of the underlying disorder. If all other measures fail and the pH remains < 7.0, bicarbonate may
be given.
--------------------------------------- 2
3. BIOSTATISTICS
1. How is the sensitivity of a test defined? What are highly sensitive tests used for clinically?
Sensitivity is defined as the ability of a test to detect disease”mathematically, the number
of true positives divided by the number of people with the disease. Tests with high sensitivity are
used for disease screening. False positives occur, but the test does not miss many people with the
disease (low false-negative rate).
2. How is the specificity of a test defined? What are highly specific tests used for clinically?
Specificity is defined as the ability of a test to detect health (or nondisease)”mathematically,
the number of true negatives divided by the number of people without the disease. Tests with high
specificity are used for disease confirmation. False negatives occur, but the test does not call anyone
sick who is actually healthy (low false-positive rate). The ideal confirmatory test must have high
sensitivity and high specificity; otherwise, people with the disease may be called healthy.
3. Explain the concept of a trade-off between sensitivity and specificity.
The trade-off between sensitivity and specificity is a classic statistics question. For example,
you should understand how changing the cut-off glucose value in screening for diabetes (or chang-
ing the value of any of several screening tests) will change the number of true- and false-negative
as well as true- and false-positive results. If the cut-off glucose value is raised, fewer people will
be called diabetic (more false negatives, fewer false positives), whereas if the cut-off glucose value
is lowered, more people will be called diabetic (fewer false negatives, more false positives).
If the cut-off serum glucose value for a
Normal Diabetic diagnosis of diabetes mellitus is set at
subjects patients point A, no cases of diabetes will be
missed, but many people without dia-
betes will be mislabeled as diabetics (i.e.,
higher sensitivity, lower specificity,
lower positive predictive value, higher
negative predictive value). If the cut-off
is set at B, the diagnosis of diabetes will
not be made in healthy people, but many
cases of true diabetes will go undiag-
nosed (i.e., lower sensitivity, higher
A B
specificity, higher positive predictive
value, lower negative predictive value).
Glucose levels The optimal diagnostic value lies some-
where between points A and B.
4. Define positive predictive value (PPV). On what does it depend?
When a test is positive for disease, the PPV measures how likely it is that the patient has the
disease (probability of having a condition, given a positive test). PPV is calculated mathemati-
cally by dividing the number of true positives by the total number of people with a positive test.
PPV depends on the prevalence of a disease (the higher the prevalence, the higher the PPV) and
the sensitivity and specificity of the test ( e.g., an overly sensitive test that gives more false posi-
tives has a lower PPV).
5. Define negative predictive value (NPV). On what does it depend?
When a test comes back negative for disease, the NPV measures how likely it is that the
patient is healthy and does not have the disease (probability of not having a condition, given a
10
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100 Hematology
7. What are reticulocytes? Why is a reticulocyte count routinely ordered in an anemia
work-up?
Reticulocytes are immature red blood cells. If their count is abnormally decreased in the setting
of anemia, the marrow is not responding properly and is the problem. A high reticulocyte count
should make you think of hemolysis or blood loss as the cause (the marrow is responding prop-
erly and is not the problem).
8. Which test comes next?
At this point, it depends. If you have a complete history and results of the other three tests,
most possibilities will be eliminated and you can order a confirmatory test. If the answer is still
not clear, consider a bone marrow biopsy. For the Step 2 exam biopsy is unlikely to be necessary
unless malignancy is the cause of the anemia.
9. What are the classic causes of microcytic, normocytic, and macrocytic anemia? Which
of these tends to have an inappropriately low reticulocyte count?
Microcytic Normocytic
With normal or elevated reticulocyte count With normal or elevated reticulocyte count
Thalassemia/hemoglobinopathy Acute blood loss
(e.g., sickle cell disease) Hemolytic (multiple causes)
Medications (antibody-causing)
With low reticulocyte count With low reticulocyte count
Lead poisoning Cancer/dysplasia (e.g., myelophthisic,
Sideroblastic anemia acute leukemia)
Anemia of chronic disease (some cases) Anemia of chronic disease (some cases)
Iron deficiency Aplastic anemia/medications causing
bone marrow suppression
Endocrine failure (thyroid, pituitary)
Renal failure
Macrocytic (all types have low reticulocyte count)
Folate deficiency Cirrhosis, liver disease
Vitamin B12 deficiency Alcohol abuse (interferes with folate use)
Medications (methotrexate, phenytoin)
10. What clues point to hemolysis as the cause for anemia?
¢ Elevated lactate dehydrogenase (LDH)
¢ Elevated bilirubin (unconjugated as well as conjugated if the liver is functioning)
¢ Jaundice
¢ Low or absent haptoglobin (intravascular hemolysis only)
¢ Urobilinogen, bilirubin, and hemoglobin in urine (only conjugated bilirubin shows up in
the urine, and hemoglobin shows up in the urine only when haptoglobin has been satu-
rated, as in brisk intravascular hemolysis)
¢ Pigmented gallstones or history of cholecystectomy (usually at a young age)
11. What is the most common cause of anemia in the U.S.?
Iron deficiency anemia.
12. Why do people get iron deficiency?
Iron deficiency is common in women of reproductive age because of menstrual blood loss.
In all patients over age 40 (men and especially postmenopausal women), it is important to rule
out colon cancer as a cause of chronic, asymptomatic blood loss. Increased requirements also
may lead to iron deficiency in children and pregnant or breast-feeding women. Give iron sup-
plements or iron-containing formula to all infants except full-term infants who are exclusively
breast-fed. Giving cow's milk before 1 year of age may lead to anemia by causing GI bleeding.
--------------------------------------- 4
Hematology 101
Start iron supplementation at 4-6 months for full-term infants and at 2 months for preterm
infants. Iron supplements also are commonly given during pregnancy and lactation (because of
the increased demand).
13. What are the classic laboratory abnormalities in iron deficiency anemia? What weird
cravings may occur with iron deficiency?
Look for low iron and low ferritin levels, elevated total iron-binding capacity (TIBC; also
known as transferrin), and low TIBC saturation. Rare patients may develop a craving for ice or
dirt (pica).
14. What is Plummer-Vinson syndrome?
A triad of unknown etiology: esophageal web resulting in dysphagia; iron deficiency anemia;
and glossitis.
15. How is iron deficiency treated?
First you must determine the cause. In a menstruating woman, a presumptive diagnosis of
menstrual blood loss is often made. In patients over 40, be sure to test the stool for occult blood
and strongly consider colonoscopy to detect occult colon cancer. Postmenopausal vaginal bleed-
ing may also cause anemia and warrants screening for gynecologic cancer. Treat with iron sup-
plements for 3-6 months in uncomplicated cases to replete body iron stores.
16. What causes folate deficiency? In what patient populations is it commonly seen?
Folate deficiency is commonly seen in alcoholics (poor intake) and pregnant women
(increased need). All women of reproductive age should take folate supplements to prevent neural
tube defects in their offspring. Rare causes of folate deficiency include poor diet (e.g., tea and
toast), methotrexate, prolonged therapy with trimethoprim-sulfamethoxazole, anticonvulsant
therapy (especially phenytoin), and malabsorption. Look for macrocytes and hypersegmented
neutrophils (either one should make you think of the diagnosis) with no neurologic symptoms
or signs and low folate levels in serum or red blood cells. Treat with oral folate,
17. What is the most common cause of vitamin B 12 deficiency?
Pernicious anemia. This megaloblastic anemia is caused by antiparietal cell antibodies.
Remember the physiology of B, 2 absorption with intrinsic factor secretion by parietal cells and
absorption of the B 12”intrinsic factor complex in the ileum. Achlorhydria (no stomach acid
secretion and elevated stomach pH) and antibodies to parietal cells are generally present in per-
nicious anemia.
18. What else may cause vitamin B, 2 deficiency? How is B,2 deficiency diagnosed?
Gastrectomy, terminal ileum resection or disease ( e.g., Crohn's disease), strict vegan diet,
chronic pancreatitis, and the infamous Diphyilobothrium latum (fish tapeworm) infection. The
peripheral smear looks the same as in folate deficiency (macrocytes, hypersegmented neu-
trophils), but patients have neurologic deficiencies (e.g., loss of sensation and position sense,
paresthesias, ataxia, spasticity, hyperreflexia, positive Babinski sign, dementia). Diagnosis is
clinched by a low serum B, 2 level. A Schilling test usually determines the etiology.
19. How is vitamin B 12 deficiency treated?
Vitamin B 12 supplements are given. The usual replacement is via parenteral (intramuscular)
injection, because most patients cannot absorb the vitamin through the gut. Supplementation may
be required for life.
20. How is thalassemia differentiated from iron deficiency?
Both cause microcytic, hypochromic anemia, but thalassemia must be differentiated from
iron deficiency because iron levels are normal in thalassemia. Iron supplementation is con-
traindicated in patients with thalassemia because it may cause iron overload. Look for elevations
--------------------------------------- 5
102 Hematology
in hemoglobin A2 and hemoglobin F (beta thalassemia only); target cells, nucleated red blood
cells, and diffuse basophilia on peripheral smears; skull radiogaph with "crew-cut" appearance;
extramedullary hematopoiesis (see figure); splenomegaly; and positive family history. Tha-
lassemia is more common in blacks, Mediterraneans, and Asians.
Extramedullary hematopoiesis. A coronal MRI image of
the thorax in a patient with moderately severe (3-tha-
lassemia reveals multiple round masses in the center and
periphery of the thorax, reflecting foci of extramedullary
hematopoiesis arising from the paravertebral region and
ribs, respectively. (From Hoffbrand AV, Pettit JE: Color
Atlas of Clinical Hematology, 3rd ed. St. Louis, Mosby,
2000, p 95, with permission.)
21. What diagnostic test confirms a diagnosis of thalassemia? How is it treated?
Diagnosis is made by hemoglobin electrophoresis. There are four gene loci for the alpha
chain of hemoglobin but only two for the beta chain. Patients with alpha thalassemia are symp-
tomatic at birth or die in utero (fetal hydrops), whereas patients with beta thalassemia are not
symptomatic until 6 months of age.
No treatment is required for minor thalassemia. Patients are often asymptomatic because
they are used to living with a lower level of hemoglobin. Thalassemia major is more dramatic
and severe. Treat with transfusions, as needed, and iron chelation therapy to prevent secondary
hemochromatosis.
22. What two clues on the Step 2 exam often point to a diagnosis of sickle cell disease?
Peripheral smear and race. Eight percent of African Americans are heterozygous for sickle
cell trait. Know what sickled red blood cells look like. Patients usually have a high percentage of
reticulocytes (8-20%).
23. What are the clinical manifestations and complications of sickle cell disease?
¢ Aplastic crises (due to parvovirus B19 infection)
¢ Bone pain (due to infarcts; the classic example is avascular necrosis of the femoral head)
¢ Dactylitis (also known as hand-foot syndrome, seen in children)
¢ Renal papillary necrosis
¢ Splenic sequestration crisis
¢ Autosplenectomy (increased infections with encapsulated bugs such as Pneumococcus,
Haemophilus, and Neisseria species)
¢ Acute chest syndrome (mimics pneumonia)
¢ Pigment cholelithiasis
¢ Priapism
¢ Stroke
24. How is sickle cell disease diagnosed and treated?
Diagnosis is made by hemoglobin electrophoresis. Screening is done at birth, but symptoms
usually do not appear until around 6 months of age because of the lack of adult hemoglobin pro-
--------------------------------------- 6
Hematology 103
duction. Treat with prophylactic penicillin until at least 10 years of age, beginning as soon as the
diagnosis is made. Proper vaccination includes the pneumococcal and H. influenzae vaccines
(given to all children anyway). Other strategies include folate supplementation, early treatment
of infections, and proper hydration.
A sickle cell crisis involves severe pain in various sites due to red blood cell sickling. Treat
with oxygen, lots of intravenous fluids, and analgesics (do not be afraid to use narcotics). Con-
sider transfusions if symptoms and/or findings are severe.
25. What findings help you in the setting of acute blood loss as a cause of anemia?
The important point is that immediately after blood loss the hemoglobin may be normal; it
takes at least 3-4 hours, often more, for reequilibration. Look for obvious bleeding, pale, cold
skin, tachycardia, and hypotension (signs of hypovolemic shock). Transfuse if indicated, even
with a normal hemoglobin in the acute setting. Consider internal hemorrhage in the setting of
trauma and abdominal aortic aneurysm in patients with a pulsatile abdominal mass.
26. What are the commonly tested causes of autoimmune hemolytic anemia?
¢ Lupus erythematosus (or medications that cause lupus-like syndromes, such as pro-
cainamide, hydralazine, and isoniazid) and other autoimmune disorders
¢ Drugs (the classic example is methyldopa, but penicillins, cephalosporins, sulfa drugs, and
quinidine also have been implicated)
¢ Leukemia or lymphoma
¢ Infection (the classic examples are mycoplasmosis, Epstein-Barr virus, and syphilis)
27. What lab test is often positive in patients with autoimmune anemia?
The Coombs test is positive in most autoimmune anemias. You also may see spherocytes on
peripheral smear because of incomplete macrophage destruction (extravascular hemolysis) of red
blood cells.
28. What clues point to lead poisoning as a cause of anemia?
Lead poisoning causes a hypochromic, microcytic anemia, almost always in a child. With
acute lead poisoning, look for vomiting, ataxia, colicky abdominal pain, irritability (aggressive,
behavioral regression), and encephalopathy, cerebral edema, or seizures. Usually, however, poi-
soning is chronic and low-level with minimal nonspecific symptoms. Watch for basophilic stip-
pling on peripheral smear, elevated free erythrocyte protoporphyrin or lead level, and consider
risk factors for lead exposure (a child who eats paint chips or lives in an old, run-down building).
29. True or false: Children with risk factors should be screened for lead poisoning.
True. Screening all asymptomatic children with a serum lead level at 1 and 2 years old regard-
less of risk is becoming controversial. In children with risk factors, screening is very important
because chronic low-level exposure may lead to permanent neurologic sequelae. Screening should
start at 6 months in children with risk factors, such as pica (especially paint chips and dust in old
buildings that may have lead paint), residence in an old or neglected building, and/or residence
near or family members who work at a lead-smelting or battery-recycling plant. Screen and meas-
ure symptomatic exposure with serum lead levels (normal value: < 10 ug/dl).
30. How is lead poisoning treated?
Treat initially with decreased exposure (best strategy) as well as lead chelation therapy, if
needed. Use succimer in children and dimercaprol in adults; in severe cases, use dimercaprol plus
ethylenediamine tetraacetic acid (EDTA) for children or adults.
31. How can sideroblastic anemia be recognized on the Step 2 exam? Should the presence
of sideroblastic anemia raise concern about other conditions?
The typical description is a microcytic, hypochromic anemia with increased or normal iron, fer-
ritin, and total iron-binding capacity (transferrin). This description should immediately steer you
--------------------------------------- 7
104 Hematology
away from iron deficiency. Look for polychromatophilic stippling and the classic "ringed siderob-
last" in the bone marrow (know what it looks like). Sideroblastic anemia may be related to
myelodysplasia or future blood dyscrasia. Although probably you will not be asked about manage-
ment, treatment is supportive. In rare cases the anemia responds to pyridoxine. Do not give iron.
32. How do you recognize anemia of chronic disease?
First, look for the presence of a disease that causes chronic inflammation (e.g., rheumatoid
arthritis, lupus erythematosus, cancer, tuberculosis). The anemia is either normocytic or micro-
cytic. Serum iron is low, but so is total iron-binding capacity. Thus, the percent saturation may
be near normal. Serum ferritin is elevated (because ferritin is an acute-phase reactant, the level
should be increased). Treat the underlying disorder to correct the anemia. Do not give iron.
33. Describe the hallmarks of spherocytosis.
This normochromic, normocytic anemia is associated with spherocytes on peripheral smear,
positive family history (autosomal dominant), splenomegaly, positive osmotic fragility test, and
an increased mean corpuscular hemoglobin concentration (the only occasion on which this red
blood cell index is useful for the Step 2 exam). Treatment often involves splenectomy. Sphero-
cytes also may be seen in extravascular hemolysis, but the osmotic fragility test is normal.
34. Why do chronic renal disease patients develop anemia? How do you treat it?
All patients with chronic renal failure develop a normocytic, normochromic anemia with
decreased reticulocyte count due to decreased erythropoietin production. Give erythropoietin to
correct the anemia.
35. What clues point to a diagnosis of aplastic anemia?
Although aplastic anemia may be idiopathic, on the Step 2 exam watch for chemotherapy,
radiation, malignancy affecting the bone marrow (especially leukemias), benzene, and implicated
medications (e.g., chloramphenicol, carbamazepine, phenylbutazone, sulfa drugs, zidovudine,
gold). Decreased white blood cells and platelets accompany the anemia. Treat first by stopping
any possible causative medication; then try antithymocyte globulin, colony-stimulating factors
(such as erythropoietin, sargramostim, and filgrastim), or bone marrow transplant.
36. Define myelophthisic anemia. What clues on the peripheral smear suggest its presence?
Myelophthisic anemia is due to a space-occupying lesion in the bone marrow. The common
causes are malignant invasion that destroys bone marrow (most common) and myelodysplasia or
myelofibrosis. On the peripheral smear, look for marked anisocytosis (different size), poikilocy-
tosis (different shape), nucleated red blood cells, giant and/or bizarre-looking platelets, and
teardrop-shaped red blood cells. A bone marrow biopsy may reveal no cells ("dry tap" if the
marrow is fibrotic) or malignant-looking cells.
37. How do you recognize glucose-6-phosphatase deficiency on the USMLE?
This genetic disorder is X-linked recessive, affecting males. It is most common in blacks and
Mediterraneans. Look for sudden hemolysis or anemia after exposure to fava beans or certain
drugs (antimalarials, salicylates, sulfa drugs) or after infection. You may see Heinz bodies and
"bite cells" on peripheral smear. The diagnosis is made with a red blood cell enzyme assay, which
should not be done immediately after hemolysis because of the potential for a false-negative
result. All of the older red blood cells already have been destroyed, and the younger red blood
cells are not affected in most patients. Treat with avoidance of precipitating foods and medica-
tions; discontinue the triggering medication first.
38. Name some other causes of anemia.
¢ Endocrine failure (especially pituitary and thyroid; look for endocrine symptoms)
¢ Mechanical heart valves (hemolyzed red blood cells)
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Hematology 105
Disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and
hemolytic uremic syndrome (look for schistocytes and red blood cell fragments on smear
and other appropriate findings)
Other hemoglobinopathies (the hemoglobin C and E varieties are fairly common)
Paroxysmal nocturnal or cold hemoglobinuria;
Clostridium perfringens infection, malaria, and babesiosis (cause intravascular hemolysis
and fever)
Hypersplenism (associated with splenomegaly and often with low platelets and white
blood cells).
Thrombotic thrombocytopenic purpura
(TTP). Widespread confluent and necrotic
ecchymoses of the facial skin are seen in
this man with severe TTP. (From Hoff-
brand AV, Pettit JE: Color Atlas of Clini-
cal Hematology, 3rd ed. St. Louis,
Mosby, 2000, p 215, with permission.)
39. When is transfusion indicated for anemia (at what hemoglobin level)?
Always transfuse on clinical grounds; observe the symptoms. In other words, treat the
patient, not the lab value. There is no such thing as a "trigger value" for transfusion. Having said
this, hemoglobin levels < 7 or 8 gm/dl in the acute setting make most clinicians nervous.
40. What are the indications for the use of various blood products?
Whole blood: used only for rapid, massive blood loss or exchange transfusions (poisoning,
thrombotic thrombocytopenic purpura).
Packed red blood cells: used for routine transfusions.
Washed red blood cells: free of traces of plasma, white cells, and platelets; good for IgA
deficiency as well as allergic or previously sensitized patients.
Platelets: given for symptomatic thrombocytopenia (usually < 10,000/ul).
Granulocytes: used on rare occasions for neutropenia.
Fresh frozen plasma (FFP): contains all clotting factors; used for bleeding diathesis when
you cannot wait for vitamin K to take effect (e.g., disseminated intravascular coagulation, severe
warfarin poisoning) or when vitamin K will not work (liver failure).
Cryoprecipitate: contains fibrinogen and factor 8; used in hemophilia, von Willebrand's
disease, and disseminated intravascular coagulation.
41. What is the most common cause of a blood transfusion reaction? What blood type can
be given in an emergency to avoid a reaction?
The most common cause of a blood transfusion reaction is lab error. Type O negative blood
can be used to avoid a reaction when you cannot wait for blood typing or when the blood bank
does not have the patient's blood type.
42. Describe the signs and symptoms of a blood transfusion reaction.
Look for febrile reaction ( e.g., chills, fever, headache, back pain) from antibodies to white
blood cells; hemolytic reaction (e.g., anxiety or discomfort, dyspnea, chest pain, shock, jaun-
dice) from antibodies to red blood cells; or allergic reaction ( e.g., urticaria, edema, dizziness,
dyspnea, wheezing, anaphylaxis) to an unknown component in donor serum. Oliguria may be an
associated finding.
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106 Hematology
43. What should you do if you suspect a transfusion reaction?
The first step is to stop the transfusion. If oliguria is present, treat with intravenous fluids
and diuresis (mannitol or furosemide).
44. What are the other risks of transfusion?
There is a small but real risk of infection (usually viral infections such as hepatitis B and C,
human immunodeficiency virus, and cytomegalovirus) and hyperkalemia (from hemolysis). With
large transfusions (> 5 units of packed red blood cells), bleeding diathesis may result from dilu-
tional thrombocytopenia and citrate (a blood preservative and calcium chelator that prevents clot-
ting). Look for oozing from puncture or IV sites.
45. What are the most common causes of disseminated intravascular coagulation (DIC)?
The most common cause is pregnancy and obstetric complications (roughly 50% of cases),
followed by malignancy (33%), sepsis, and trauma (especially head trauma, prostate surgery, and
snake bites).
46. How do I recognize and treat DIC in a classic at-risk patient?
DIC usually manifests with bleeding diathesis but may have thrombotic tendencies. Look for
the classic oozing or bleeding from puncture and IV sites; prolonged prothrombin time (PT), par-
tial thromboplastin time (PTT), and bleeding time (BT). DIC is the only disorder on the Step 2
exam that prolongs all three tests. Other clues include positive D-dimer, increased fibrin degra-
dation products, thrombocytopenia, decreased fibrin, and decreased clotting factors (including
factor 8, which is normal in hepatic necrosis).
Treat the underlying cause (e.g., evacuate the uterus, give antibiotics). You may need to give
transfusions with fresh frozen plasma or, in rare cases, heparin (only if thrombosis occurs).
47. With what conditions is eosinophilia associated?
¢ Allergy, eczema, and atopy
¢ Angioedema
¢ Drug reactions
¢ Parasitic infections
¢ Blood dyscrasias (especially lymphoma)
¢ Loffler's syndrome (pulmonary eosinophilia)
¢ Autoimmune diseases (e.g., lupus erythematosus, rheumatoid arthritis)
¢ IgA deficiency
¢ Adrenal insufficiency
48. With what conditions is basophilia associated?
Allergies or neoplasm/blood dyscrasia.
49. True or false: The lupus anticoagulant causes a clotting tendency.
True. Although the lupus anticoagulant may cause a prolonged partial thromboplastin time,
the patient has a tendency toward thrombosis. Look for associated lupus symptoms, positive
results on the Venereal Disease Research Laboratory or rapid plasma reagin tests for syphilis,
and/or a history of miscarriages to help you recognize this condition.
50. What genetic causes of an increased tendency toward clot-forming may appear on the
Step 2 exam?
The list keeps growing. Watch for factor V Leiden mutation (or activated protein C resist-
ance), prothrombin G20210A mutation, or deficiencies in protein C, protein S, or antithrombin
III (all autosomal dominant except protein C deficiency) as causes of an increased tendency
toward thrombosis. All are treated with anticoagulant therapy to prevent deep venous thrombo-
sis and pulmonary embolus. Suspect these conditions if a person under age 35 develops recurrent
clots or has no risk factors for clot development.
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Hernatology 107
51. Which clotting tests measure which portions of the coagulation cascade? Which med-
ications affect these tests?
PT (prothrombin time) measures the function of the extrinsic clotting pathway (prolonged by
warfarin), activated PTT (partial thromboplastin time) measures the function of the intrinsic clot-
ting pathway (prolonged by heparin), and BT (bleeding time) measures platelet function (pro-
longed by aspirin).
52. How do specific diseases affect clotting tests? What are the main differential points?
PLATELET RBC
DISEASE PT PTT BT COUNT COUNT OTHER
Von Willebrand's Normal High High Normal Normal Autosomal dominant
disease (look for family history)
Hemophilia A/B Normal High Normal Normal Normal X-linked recessive, A =
low factor 8, B = low
factor 9
DIG High High High Low Normal/ Appropriate history, low
low level of factor 8
Liver failure High High Normal Normal/ Normal/ Jaundice, normal factor 8
low low level; do not give vitamin
K (ineffective); use FFP
Heparin Normal High Normal Normal/ Normal Watch for thrombocyto-
low penia and thrombosis
Warfarin High Normal Normal Normal Normal Vitamin K antagonist
(factors 2, 7, 9, and 10)
IIP Normal Normal High Low Normal Watch for preceding URI
TIP Normal Normal High Low Low Hemolysis (smear), CNS
symptoms; treat with
plasmapheresis; do not
give platelets!
Scurvy Normal Normal Normal Normal Normal Fingernail and gum
hemorrhages, bone
hemorrhages; caused by
vitamin C deficiency
PT = prothrombin time, PTT = partial thromboplastin time, BT = bleeding time, RBC = red blood cell,
DIG = disseminated intravascular coagulation, ITP = idiopathic thrombocytopenic purpura, TTP =
thrombotic thrombocytopenic purpura, FFP = fresh frozen plasma, URI = upper respiratory infection,
CNS = central nervous system.
53. What are the common causes of thrombocytopenia? What kind of bleeding problems
are caused by low platelet counts?
Common causes of thrombocytopenia include purpura (idiopathic or thrombotic), hemolytic
uremic syndrome, disseminated intravascular coagulation, HIV, splenic sequestration, heparin
(treat by first stopping heparin), other medications (especially quinidine and sulfa drugs), autoim-
mune disease, and alcohol. Bleeding from thrombocytopenia is in the form of petechiae, nose
bleeds, and easy bruising.
54. What causes petechiae or "platelet-type" bleeding in the setting of normal platelets?
Vitamin C deficiency (scurvy) causes bleeding similar to that seen with low platelets (splin-
ter and gum hemorrhages, petechiae); perifollicular and subperiosteal hemorrhages are unique to
scurvy. Patients have a poor dietary history (the classic example is hot dogs and soda or tea and
toast), myalgias and arthralgias, and capillary fragility (bleeding is due to collagen problems in
the vessels). Treat with oral vitamin C.
Other causes include uremia (platelet dysfunction), inherited connective tissue disorders (Ehlers-
Danlos syndrome, Marian's syndrome), and chronic corticosteroid use (causes capillary fragility).
--------------------------------------- 11
18. HYPERTENSION
1. How often should you screen for hypertension?
Although there is no absolutely correct answer, all people should be screened roughly every
2 years, starting at the age of three.
2. Define hypertension.
Persistent blood pressure greater than 140/90 mmHg. Recent efforts in the "war on hyper-
tension" label a systolic blood pressure of 120-139 mmHg and diastolic pressure of 80-89 mmHg
"prehypertension." Remember that 145/60 mmHg is hypertension, as is 115/95 mmHg (isolated
systolic or diastolic hypertension, respectively). Treatment is needed. In grading the severity of
hypertension, use the worst number, whether it be diastolic or systolic. See the table below for
the 2003 Joint National Committee (JNC) classification.
Systolic BP* Diastolic BP*
(mmHg) (mmHg) Classification
<120 <80 Normal
120-139 80-89 Prehypertension
140-159 90-99 Stage I hypertension
a 160 2 100 Stage II hypertension
*Classification is based on the worst number (e.g., 168/60 mm Hg is considered stage II hypertension
even though diastolic pressure is normal).
3. What is the "three-measurement" rule in the diagnosis of hypertension?
Classically, the blood pressure is measured three time on three separate office visits before
the diagnosis and pharmacologic treatment of hypertension. However, if asked, institute conser-
vative measures (see below) and address associated comorbidities ( e.g., obesity, diabetes) after
the first abnormal measurement. There are a few important exceptions to the "start conservative
and remeasure" strategy, however, and more aggressive approaches are gaining favor. If a
patient's blood pressure is greater than 200/120 mmHg (a hypertensive "urgency") or if end-
organ effects are evident (a hypertensive "emergency," see below), treatment should be instituted
immediately. In pregnant woman, preeclampsia may be the cause of hypertension. Waiting to
treat in this setting can have devastating consequences to mother and fetus.
4. What are the conservative (i.e., nonpharmacologic) treatments for hypertension?
Dietary changes (i.e., low salt, low fat, low calorie), reduced smoking and alcohol intake,
weight loss, and exercise may each have a positive effect on blood pressure and, in some cases,
get the patient back into the normotensive range. Medications should be started only after a 1-
to 2-month trial of lifestyle modifications for stage I hypertension. In patients with stage II
hypertension or those with diabetes or renal disease, early pharmacologic treatment is often
preferred.
5. List the first-line medications for treatment of hypertension.
Five classes of drugs are used as first-line therapy: thiazide diuretics, beta blockers,
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and
calcium channel blockers. Which you should use often depends on the individual patient and his
or her other medical problems.
108
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Hypertension 109
Drug Class Use in Patients with: Avoid in Patients with:
Thiazides Heart failure, diabetes, high risk for coro- Gout, electrolyte disturbances ( e.g.,
nary artery disease or stroke, osteoporosis hyponatremia), pregnancy
Beta blockers Stable angina, acute coronary syndrome/Asthma, chronic obstructive
unstable angina, acute or prior myo- pulmonary disease, heart block, sick
cardial infarction, high risk for coro-sinus syndrome
nary artery disease, atrial tachycardia/
fibrilliation, thyrotoxicosis (short-term),
essential tremor, migraines
ACE inhibitors Heart failure, diabetes, acute coronaryPregnancy, angioedema, renovascular
syndrome/unstable angina, acute or hypertension (may cause renal
prior myocardial infarction, high riskfailure)
for coronary artery disease or stroke,
chronic kidney disease
ARBs Heart failure, diabetes, chronic kidneyPregnancy, renovascular hypertension
disease (may cause renal failure)
Calcium channel Raynaud syndrome, atrial Heart block, sick sinus syndrome,
blockers tachyarrhythmias congestive heart failure (all related
to central-acting agents), pregnancy
Note: ACE inhibitors are first-line agents for congestive heart failure, because they reduce mortality
rates. In diabetes, ACE inhibitors retard progression to nephropathy and neuropathy. All patients with
stable congestive heart failure or diabetes should take an ACE inhibitor (if they can tolerate it) even in
the absence of hypertension.
6. What about women of reproductive age and pregnant women with hypertension?
Labetalol, hydralazine, and alpha-methyldopa are safe. If preeclampsia is present, remember
that magnesium sulfate lowers blood pressure.
7. Define hypertensive urgency. How is it different from hypertensive emergency?
Hypertensive urgency is defined as blood pressure > 200/120 mmHg without symptoms.
Hypertensive emergency is defined as blood pressure > 200/120 mmHg with symptoms or evi-
dence of end-organ damage. Examples: acute left ventricular failure, chest pain or angina,
myocardial infarction, encephalopathy (watch for headaches, confusion, papilledema, mental
status changes, vomiting, blurry vision, dizziness, and/or seizures), or acute renal failure (from
necrotizing arteriolitis, see figure). Both require immediate treatment, but hypertensive emer-
gency is more worrisome. Treat immediately with nitroprusside, nitroglycerin, labetalol, or dia-
zoxide (second-line agent).
Fibrinoid necrosis secondary to malignant hyperten-
sion. This change is due to rapid intimal cell prolifer-
ation with leakage of plasma proteins into and beyond
the arteriolar wall with resultant obliteration of the
wall by intensely eosinophilic amorphous proteina-
ceous material (P) and, often, luminal occlusion .
Damage to the vessel wall may also lead to thrombo-
sis within the lumen. A glomerulus can be seen on the
far right side of the image. (From Stevens A, et al:
Wheater's Basic Histopathology, 4th ed. New York,
Churchill Livingstone, 2002, p 116, with permission.)
8. What causes hypertension?
Roughly 90-95% of cases are idiopathic, multifactorial, or essential hypertension. About
5-10% of cases are due to secondary (known) causes.
--------------------------------------- 13
Biostatistics 11
negative test). It is calculated mathematically by dividing the number of true negatives by the
total number of people with a negative test. NPV also depends on the prevalence of the disease
and the sensitivity and specificity of the test (the higher the prevalence, the lower the NPV). In
addition, an overly sensitive test with lots of false positives makes the NPV higher.
6. Define attributable risk. How is it measured?
Attributable risk is the number of cases of a disease attributable to one risk factor (in other
words, the amount by which the incidence of a condition is expected to decrease if the risk factor
in question is removed). For example, if the incidence rate of lung cancer is 1/100 in the general
population and 10/100 in smokers, the attributable risk of smoking in causing lung cancer is
9/100 (assuming a properly matched control).
7. You need to develop the habit of drawing a 2 X 2 table for Step 2 statistics questions.
Given the 2X2 table below, define the formulas for calculating the following test values:
Disease Test Name Formula
Sensitivity A/(A + C)
Specificity D/(B + D)
Test (+) A B PPV A/(A + B)
NPV D/(C + D)
Exposure (-) C D Odds ratio (A X D)/(B X C)
Relative risk [A/(A + B)]/[C/(C + D)]
Attributable risk [A/(A + B)]-[C/(C + D)]
8. Define relative risk. From what type of studies can it be calculated?
Relative risk compares the disease risk in people exposed to a certain factor with the disease
risk in people who have not been exposed to the factor in question. Relative risk can be calcu-
lated only after prospective or experimental studies; it cannot be calculated from retrospective
data. If a Step 2 question asks you to calculate the relative risk from retrospective data, the answer
is "cannot be calculated" or "none of the above."
9. What is a clinically significant value for relative risk?
Any value for relative risk other than 1 is clinically significant. For example, if the relative
risk is 1.5, a person is 1.5 times more likely to develop the condition if exposed to the factor in
question. If the relative risk is 0.5, the person is only half as likely to develop the condition when
exposed to the factor; in other words, the factor protects the person from developing the disease.
10. Define odds ratio. From what type of studies is it calculated?
Odds ratio attempts to estimate relative risk with retrospective studies (e.g., case control). An
odds ratio compares (the incidence of disease in persons exposed to the factor and the incidence
of nondisease in persons not exposed to the factor) with (the incidence of disease in persons unex-
posed to the factor and the incidence of nondisease in persons exposed to the factor) to see
whether there is a difference between the two. As with relative risk, values other than 1 are sig-
nificant. The odds ratio is a less than perfect way to estimate relative risk (which can be calcu-
lated only from prospective or experimental studies).
11. What do you need to know about standard deviation (SD) for the USMLE?
You need to know that with a normal or bell-shaped distribution, 1 SD holds 68% of the
values, 2 SD hold 95% of the values and 3 SD hold 99.7% of the values. A classic question gives
you the mean and standard deviation and asks you what percentage of values will be above a
given value. Variations in this question are common.
12. Define mean, median, and mode.
The mean is the average value, the median is the middle value, and the mode is the most
common value. A question may give you several numbers and ask you for their mean, median,
and mode. For example, if the question gives you the numbers 2, 2, 4, and 8:
--------------------------------------- 14
no
Hypertension
9. What are the common causes of secondary hypertension in younger men and women?
In younger men, a common cause of secondary hypertension is excessive alcohol intake (get
the patient to quit!). In younger women, common and classic causes are birth control pills (stop
them!) and renal artery stenosis from fibromuscular dysplasia (which may cause a bruit and
should be treated with balloon angioplasty).
10. List less common causes of secondary hypertension.
Pheochromocytoma. Look for wild swings in blood pressure with diaphoresis and confu-
sion. As a screening test, order 24-hour urine collection to assess catecholamine products
(metanephrines, vanillylmandelic acid, homovanillic acid).
Renal artery stenosis (RAS). Unlike young patients with fibromuscular dysplasia, elderly
patients typically have RAS due to atherosclerosis. A renal artery bruit is classically present
(although not sensitive); magnetic resonance or conventional angiography makes the definitive
diagnosis. Giving ACE inhibitors to patients with RAS may precipitate acute renal failure (some-
times the first diagnostic clue to its presence).
Polycystic kidney disease. Look for flank mass, positive family history (autosomal domi-
nant pattern of inheritance), and elevations in creatinine and blood urea nitrogen.
Cushing's syndrome. Look for stigmata of Cushing's syndrome on exam. Order 24-urine
collection to assess free cortisol or dexamethasone suppression test
Conn's syndrome. The cause is an aldosterone-secreting adrenal neoplasm. Look for high
aldosterone levels, low renin levels, hypokalemia, metabolic alkalosis, and/or an adrenal mass on
computed tomography.
Coarctation of the aorta. Look for hypertension in the upper extremities only, with unequal
pulses, radiofemoral delay, and rib notching on chest radiograph; associated with Turner's syn-
drome. MRI or angiography makes a definitive diagnosis.
Renal failure from any cause. In children, watch for poststreptococcal glomerulonephritis
or hemolytic uremic syndrome.
Abdominal aortogram demonstrates
high-grade, proximal, left renal artery
stenosis (curved arrow). (From Katz DS,
Math KR, Groskin SA (eds): Radiology
Secrets. Philadelphia, Hanley & Belfus,
1998, p 185, with permission.)
11. What does lowering blood pressure accomplish?
Hypertension is the number-one modifiable risk factor for strokes. Lowering blood pressure
decreases heart disease, myocardial infarctions, atherosclerosis, renal failure, and dissecting
aortic aneurysms.
12. What is the most common cause of death among untreated patients with hypertension?
The same as for the general population”coronary artery disease.
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Hypertension 111
13. Which three tests should be ordered for every patient with a diagnosis of hypertension?
Why?
1. Electrocardiogram: to determine whether the heart has been affected (e.g., left ventric-
ular hypertrophy).
2. Chemistry 7 panel (i.e., basic metabolic panel): clues to possible secondary cause of
hypertension (e.g., electrolyte disturbances in Conn's syndrome).
3. Urinalysis: clues to possible secondary cause of hypertension (e.g., red blood cell casts
in poststreptococcal glomerulonephritis) and to kidney damage (proteinuria).
--------------------------------------- 16
19. IMMUNOLOGY
1. List the four classic types of hypersensitivity reactions.
¢ Anaphylactic (type I) ¢ Immune complex-mediated (type III)
¢ Cytotoxic (type II) ¢ Cell-mediated/delayed (type IV)
2. What causes type I hypersensitivity? Give the classic clinical examples.
Type I (anaphylactic) hypersensitivity is due to preformed IgE antibodies that cause release
of vasoactive amines (e.g.. histamine, leukotrienes) from mast cells and basophils. Examples are
anaphylaxis, atopy, hay fever, urticaria, allergic rhinitis, and some forms of asthma. Anaphylaxis
may be due to bee stings, food allergy (especially peanuts and shellfish), medications (especially
penicillins and sulfa drugs), or rubber glove allergy.
3. Describe the clinical findings with chronic type I hypersensitivity.
Look for eosinophilia, elevated IgE levels, positive family history, and seasonal exacerba-
tions. Patients also may have allergic "shiners" (bilateral infraorbital edema), and a transverse
nasal crease (due to frequent nose rubbing). Pale, bluish, edematous nasal turbinates with many
eosinophils in clear, watery nasal secretions are also classic.
4. What medication should be avoided in patients with nasal polyps?
Do not give aspirin, which may precipitate a severe asthma attack.
5. How do you recognize and treat true anaphylaxis?
Look for the classic triggers mentioned above just before the patient becomes agitated and
flushed and develops itching (urticaria), facial swelling (angioedema), and difficulty in breath-
ing. Symptoms tend to develop rapidly and dramatically.
Treat immediately by securing the airway (laryngeal edema may prevent intubation, in which
case do a cricothyrotomy, if needed) and give subcutaneous epinephrine. Antihistamines are only
useful for cutaneous reactions and itching, not for more severe reactions. Use corticosteroids only
if the initial treatment options are not available (not a first-line agent).
6. What usually causes hereditary angioedema?
A deficiency of Cl esterase inhibitor (complement) is the usual cause of hereditary
angioedema. Patients have diffuse swelling of lips, eyelids, and possibly the airway, unrelated to
allergen exposure. The disease is autosomal dominant; look for a positive family history. C4 com-
plement levels are low. Acute treatment is the same as for anaphylaxis. Androgens are used for
long-term treatment because they increase liver production of Cl esterase inhibitor.
7. What type of testing can identify an allergen if it is not obvious?
Skin or patch testing.
8. What causes type II hypersensitivity? List some classic clinical examples.
Type II (cytotoxic) hypersensitivity is due to preformed IgG and IgM antibodies that react
with the antigen and cause secondary inflammation. Examples include the following:
¢ Autoimmune hemolytic anemia (classically caused by methyldopa, penicillins, or sulfa
drugs) or other cytopenias caused by antibodies ( e.g., idiopathic thrombocytopenic pur-
pura)
¢ Transfusion reactions
¢ Erythroblastosis fetalis (Rh incompatibility)
112
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immunology 113
Patch testing. A battery of common 1 I |
and suspected allergens isapplied to
the back for 48 hours. The skin is then
examined at 96 hours. Irritant reac-
tions disappear, allergic ones do not.
Two positives are present. (From du
Vivier A: Atlas of Clinical Dermatol-
ogy, 3rd ed. New York, Churchill Liv-
ingstone, 2002, p 65, with permission.)
¢ Goodpasture's syndrome (watch for linear immunofluorescence on kidney biopsy)
¢ Myasthenia gravis
¢ Graves' disease
¢ Pernicious anemia
¢ Pemphigus vulgaris
¢ Hyperacute transplant rejection (as soon as the anastomosis is made at transplant surgery,
the transplanted organ deteriorates in front of the surgeon's eyes).
9. What lab test is usually positive with a type II hypersensitivity that causes anemia?
Coombs' test (usually the direct Coombs' test).
10. What causes type III hypersensitivity? List some classic clinical examples.
Type III (immune complex-mediated) hypersensitivity is due to antigen-antibody complexes
that usually are deposited in vessels and cause an inflammatory response. Examples include
serum sickness, lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, cryoglobuline-
mia, and certain types of glomerulonephritis ( e.g., from chronic hepatitis).
11. What causes type IV hypersensitivity? How is it related to tuberculosis testing?
Type IV (cell-mediated/delayed) hypersensitivity is due to sensitized T lymphocytes that
release inflammatory mediators. The tuberculosis skin test (purified protein derivative [PPD])
exploits this immune system reaction. Other examples include contact dermatitis (especially
poison ivy, nickel earrings, cosmetics, and medications), chronic transplant rejection, and granu-
lomas (e.g., sarcoidosis).
12. What sexually transmitted infectious disease should be in the back of your mind when
a patient presents with a sore throat and mononucleosis-like syndrome?
Human immunodeficiency virus (HIV) infection, because initial seroconversion may present
as a mononucleosis-like syndrome (e.g., fever, malaise, pharyngitis, rash, lymphadenopathy).
13. How is HIV diagnosed? How long after exposure does the HIV test become positive?
Diagnosis is made with the enzyme-linked immunosorbent assay (ELISA), which, if posi-
tive, should be confirmed with a Western blot test. All of these tests should be done before you
tell the patient anything. It takes at least 1 month for antibodies to develop. Therefore, if a patient
wants testing because of recent risk-taking behavior, you should retest the patient in 6 months if
the initial test is negative.
14. What is the reason for doing "control" tests when a PPD tuberculosis test is done in
HIV-positive patients?
Though now more controversial, control tests make sure that a negative PPD result is mean-
ingful. If a patient is anergic or fails to mount an immune response, a negative PPD means little.
If the control skin tests (usually candidal infection and mumps, to which everyone in the U.S. is
--------------------------------------- 18
114 Immunology
exposed ) give positive results (which are normal in healthy people) and the PPD gives a nega-
tive result, you should feel more comfortable in saying that the patient probably does not have
tuberculosis (although the PPD test is not 100% sensitive).
15. How do you recognize Pneumocystis carinii pneumonia (PCP)?
For the Step 2 exam, think of PCP first in any patient with HIV and pneumonia, even though
community-acquired pneumonia is more common even in patients with AIDS. Look for severe
hypoxia with normal radiographs or diffuse, bilateral interstitial infiltrates (see figure). Patients
usually have a dry, nonproductive cough. PCP may be detected with silver stains (Wright-
Giemsa, Giemsa, or methenamine silver) applied to induced sputum; if not, you can use bron-
choscopy with bronchoalveolar lav age and brush biopsy to make the diagnosis. High levels of
lactate dehydrogenase are suspicious in the appropriate setting. PCP is now usually treated pre-
sumptively, with diagnostic testing reserved for those in whom the diagnosis is unclear or initial
treatment fails.
Pneumocystis carinii pneumonia in a patient with AIDS.
Extensive, predominantly central, interstitial opacities are
present bilaterally, right greater than left. (From Hoffbrand
AV, Pettit IE: Color Atlast of Clinical hematology, 3rd ed. St.
Louis, Mosby, 2000, p 136, with permission.)
16. What is the most common primary immunodeficiency? How do you recognize it?
IgA deficiency, which causes recurrent respiratory and gastrointestinal infections. IgA levels
are always low, and levels of IgG subclass 2 may be low. Do not give immunoglobulins, which
may cause anaphylaxis due to development of anti-IgA antibodies. Alternatively, if any patient
develops anaphylaxis after immunoglobulin exposure, you should think of IgA deficiency.
17. How do you recognize Bruton's agammaglobulinemia?
Bruton's agammaglobulinemia (X-linked agammaglobulinemia) is an X-linked recessive
disorder with low or absent B cells that affects males. Infections begin after 6 months when
maternal antibodies disappear. Look for recurrent lung or sinus infections with Streptococcus and
Hemophilus species.
18. What causes DiGeorge's syndrome? How do you recognize it?
DiGeorge's syndrome is caused by hypoplasia of the third and fourth pharyngeal pouches.
Look for hypocalcemia and tetany (from hypocalcemia due to absent parathyroid glands) in the
first 24-48 hours of life. The thymus also may be absent or hypoplastic, and congenital heart
defects and typical facies often are present.
19. What is the classic cause of severe combined immunodeficiency? How does it present?
Severe combined immunodeficiency may be autosomal recessive or X-linked. The classic
cause is adenosine deaminase deficiency (autosomal recessive). Patients have B- and T-cell
defects and severe infections in the first few months of life. Other symptoms include cutaneous
anergy and absent or dysplastic thymus and lymph nodes.
--------------------------------------- 19
Immunology 115
20. What triad indicates the diagnosis of Wiskott-Aldrich syndrome?
Wiskott-Aldrich deficiency is an X-linked recessive disorder that affects males. The classic
triad consists of eczema, thrombocytopenia (look for bleeding), and recurrent infections (usually
respiratory).
21. How do you recognize Chediak-Higashi syndrome?
Chediak-Higashi syndrome is usually an autosomal recessive disorder characterized by giant
granules in neutrophils, infections, and often oculocutaneous albinism. It is caused by a defect in
microtubule polymerization.
22. Describe the pathophysiology of chronic granulomatous disease.
Chronic granulomatous disease is usually an X-linked recessive disorder that affects males.
Because of a defect in the activity of reduced nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase, patients have recurrent infections with catalase-positive organisms (e.g.,
Staphylococcus aureus, Pseudomonas species). Diagnosis is clinched if the question mentions
deficient nitroblue tetrazolium dye reduction by granulocytes. This test measures the respiratory
burst, which patients with chronic granulomatous disease lack.
23. Cover the right-hand column, and answer the questions about HIVmanagement on the
left.
QUESTION ANSWER
After HIV diagnosis, how often do you check the CD4 Every 6 months
count?
When do you start antiretroviral therapy? When the CD4 count is < 500/mm 3
(or sooner)
When do you start PCP prophylaxis? When the CD4 count is < 200/mm 3
What is the drug of choice for PCP prophylaxis? Trimethoprim-sulfamethoxazole
(Bactrim)
What other agents are used in patients with allergy or Dapsone and pentamidine
intolerance to Bactrim?
When should you start Mycobacterium avium complex When the CD4 count is < 100/mm 3
(MAC) prophylaxis?
What drugs are used for MAC prophylaxis? Clarithromycin, azithromycin,
or rifabutin
True or false: Once the CD4 is < 200/mm 3, the patient isTrue
automatically considered to have AIDS (even without
opportunistic infections).
True or false: Give the measles-mumps-rubella vaccine. True (only live vaccine that is
given)
True or false: Do not give annual influenza vaccines. False (give every year)
True or false: PPD testing should be done annually. True
True or false: Oral polio vaccine should be given to patientsFalse (use inactive polio vaccine
and their contacts. injection)
The risk of which cancer is increased on skin and in theKaposi's sarcoma
mouth?
The risk of which type of blood cell cancer is increased?Non-Hodgkin's lymphoma
(usually primary B-cell lym-
phomas of CNS)
What do positive India ink preparations of the cerebrospinalCryptococcus neoformans
fluid mean? meningitis
What do ring-enhancing lesions in the brain on CT or MR Toxoplasmosis, cysticercosis/
scans usually mean? Taenia solium, or lymphoma
True or false: HIV may cause thrombocytopenia. True
Table continued on next page
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116 Immunology
QUESTION ANSWER
True or false: Give pneumococcal and hepatitis vaccines.True
True or false: HIV can cause dementia. True
True or false: HIV protects against peripheral neuropathies.False (HIV can cause them)
True or false: HIV mothers may breast-feed their infants.False (breast milk transmits HIV)
First-choice agent for cytomegalovirus retinitis. Ganciclovir/valganciclovir
Second-choice agents for cytomegalovirus retinitis. Foscarnet or cidofovir
True or false: Pregnant patients should take zidovudine (AZT)True.
True or false: Infants born to HIV-positive mothers shouldTrue (for the first 6 weeks after
take AZT. delivery)
True or false: Cesarean section increases maternal HIV False (it may decrease transmission
transmission. to child)
Most likely cause of pneumonia in HIV patient Streptococcus pneumoniae
Most likely cause of opportunistic pneumonia in HIV patienPneumocystist carinii
Stain used on sputum to detect PCP Silver (Wright-Giemsa or Giemsa)
Two pathogens that cause chronic diarrhea only in AIDS. Cryptosporidium and Isospora spp.
True or false: Herpes-zoster infection in young adults =True (suggests immunodeficiency)
possible HIVinfection.
True or false: Thrush in young adults may mean HIV True (also assocated with diabetes,
infection leukemia, and steroids)
True or false: A positive HIV antibody test in a newborn iTruse (maternal antibodies in the
unreliable neonate can give a false-positive
result for the first 6 months)
24. Complement deficiencies of C5 through C9 cause recurrent infections with which genus
of bacteria?
Neisseria spp.
25. Define chronic mucocutaneous candidiasis.
Chronic mucocutaneous candidiasis is a cellular immunodeficiency specific for candidal
infection. Patients have thrush and candidal infections of the scalp, skin, and nails as well as
anergy to Candida sp. with skin testing. Often it is associated with hypothyroidism. The rest of
the immune function is intact; no other types of infections are present.
26. Give the classic description of hyper-IgE syndrome (Job-Buckley syndrome).
Patients with hyper-IgE syndrome have recurrent staphylococcal infections (especially of the
skin) and have extremely high IgE levels. They also commonly have fair skin, red hair, and
eczema.
--------------------------------------- 21
20. INFECTIOUS DISEASES
1. Cover the middle and right-hand columns and specify which bugs are associated with
each type of infection and what type of empiric antibiotic should be used while waiting for
culture results.
CONDITION MAIN ORGANISM(S) EMPIRICAL ANTIBIOTICS
Urinary tract infection Escherichia coli Trimethoprim-sulfamethoxazole,
nitrofurantoin, amoxicillin,
quinolones
Bronchitis Virus, Haemophilus influenzae,Amoxicillin, erythromycin
Moraxella spp.
Pneumonia (classic) Streptococcus pneumoniae, Third-generation cephalosporin,
H. influenzae azithromycin
Pneumonia (atypical) Mycoplasma, Chlamydia spp. Macrolide antibiotic, doxycylcine
Osteomyelitis Staphyloccous aureus, Antistaphylococcal penicillin,!
Salmonella spp. vancomycin
Cellulitis Streptococci, staphylococci Antistaphylococcal penicillin (covers
both)
Meningitis (neonate) Streptococci B, E. coli, ListeriaAmpicillin + aminoglycoside, third-
spp. generation cephalosporin
Meningitis (child/adult)S. pneumoniae, Neisseria Third-generation cephalosporin or
meningitidis* meropenem + vancomycin +
dexamethasone
Sepsis Gram-negative organisms, Third-generation penicillin/
streptococci, cephalosporin staphylococci +
aminoglycoside, imipenem
Septic arthritis^ S. aureus Antistaphylococcal penicillin,
vancomycin
Gonococci Ceftriaxone, penicillin, spectinomycin
Endocarditis Staphylococci, streptococci Antistaphaylococcal penicillin (or
vancomycin) + aminoglycoside
*H. influenzae is no longer as common a cause of meningitis in children because of widespread vac-
cination. In a child with no history of immunization, H. influenzae is the most likely cause of menin-
gitis.
fExamples: dicloxacillin, methicillin.
$Think of staphylococci if the patient is monogamous or not sexually active. Think of gonorrhea for
younger adults who are sexually active.
2. Cover the right-hand columns and specify the empirical antibiotic of choice for each
organism.
ORGANISM* ANTIBIOTIC OTHER CHOICES
Strep A or B Pencillin, cephazolin Erythromycin
S. pneumoniae 3rd gen. cephalosporin, fluroquinolonFluoroquinolonee (e.g. levofloxacin)
Enterococcus Penicillin or ampicillin + Vancomycin + aminoglycoside
aminoglycoside
Staphylococcus aureus Anti-Staph Penicillin (e.g. methicillinVancomyci)n (MRSA)
Gonococcusf Ceftriaxone or fluoroquinolone Spectinomycin
Table continued on next page
117
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118 Infectious Diseases
ORGANISM* ANTIBIOTIC OTHER CHOICES
Meningococcus Penicillin/ampicillin Cefotaxime, chloramphenicol
Haemophilus 2nd or 3rd gen. cephalosporin Ampicillin
Pseudomonas Antipseudomonal penicillin + Aztreonam, imipenem
aminoglycoside
Bacteroides Metronidazole Clindamycin
Mycoplasma Erythromycin, azithromycin Doxycycline
Treponema pallidum Penicillin Doxycycline
Chlamydia Doxycycline, azithromycin Erythromycin, fluoroquinolone
Lyme disease Ceftriaxone, doxycycline Erythromycin, amoxicillin
*Always use culture sensitivities