Unformatted text preview: A 30-year-old man with a 10-year history of chronic alcoholism complains of headache, chills,
nausea, and dizziness, which started 24 hours ago. He says he has been "cooped up" in his oneroom apartment using a gas heater to keep warm. His temperature is 37°C (98.6°F), and findings
on physical examination are unremarkable. While in the emergency department, the patient
What abnormality would most likely be detected if this patient's oxygen-hemoglobin dissociation
curve were evaluated? A decrease in binding affinity for oxygen in free binding sites of hemoglobin
A decrease in the oxygen-carrying capacity of hemoglobin
A decrease in the partial pressure of arterial oxygen
A shift to the right in partial pressure of oxygen at which the hemoglobin is 50% saturated
An increase in offloading of oxygen in tissues
Clinical findings of headache, nausea, and dizziness in the setting of a potential carbon
monoxide (CO) exposure (gas heater in a poorly ventilated one-room apartment) are suggestive
of CO poisoning.
The symptoms and signs of CO poisoning are highly variable and largely nonspecific. Patients
often present with constitutional symptoms, including headache (the most common presenting
symptom), malaise, nausea, and dizziness.
Acute CO poisoning is usually suspected on the basis of a suggestive history; potential sources
of CO include poorly functioning heating systems, improperly vented fuel-burning devices (eg,
kerosene heaters, charcoal grills, camping stoves, gasoline-powered electrical generators), and
motor vehicles operating in poorly ventilated areas.
CO binds to the oxygen-binding sites of hemoglobin with an affinity 250 times that of oxygen.
This results in both decreased oxyhemoglobin saturation and decreased oxygen-carrying
capacity. A basic oxygen-hemoglobin dissociation curve is shown in the image. CO exposure
can be diagnosed by measuring the carboxyhemoglobin fraction in blood. Treatment is 100%
oxygen or hyperbaric oxygen therapy.
The other answer choices do not reflect abnormalities related to CO poisoning: CO increases hemoglobin's affinity for oxygen. The presence of CO will cause a left
shift in the oxygen-hemoglobin dissociation curve because CO has a higher affinity for
hemoglobin and thus will replace oxygen. A decrease in binding affinity would represent
a rightward shift of the oxygen-hemoglobin dissociation curve—typically seen in
conditions such as increased temperature, increased 2,3-diphophosphoglycerate (2,3DPG), or decreased pH—and would NOT be seen in the presence of CO.
CO binding to hemoglobin is independent of the partial pressure of arterial oxygen
(Pao2). Furthermore, Pao2 reflects the amount of oxygen gas dissolved directly in blood,
not the amount bound to hemoglobin. Pao2 would be unaffected by the presence of CO. Because CO increases hemoglobin's affinity for oxygen, it shifts the partial pressure of
oxygen at which the hemoglobin is 50% saturated (P50) to the left. This means that,
in the presence of CO, hemoglobin would be 50% saturated with oxygen at a lower Pao2
than under normal conditions. A rightward shift of P50 would be the opposite and is not
seen when CO is present.
CO causes a left shift of the oxygen-hemoglobin dissociation curve. There is
consequently a decrease in the amount of oxygen offloaded to peripheral tissues.
Essentially, the oxygen is "stuck" to the carboxyhemoglobin. Because the hemoglobin
cannot unload the oxygen, "cherry-red" blood results, as well as tissue ischemia and
hypoxia. A 32-year-old woman with a history of Hashimoto disease comes to her primary care physician
because of progressive muscle weakness for the past 6 months. She states that she used to work
as yoga teacher but now cannot make it through a class because the repetitive movements
become increasingly difficult. The patient also reports that she has lost 10 lb in the past 6 months
because she finds chewing food to be tiring, and describes double vision when trying to read at
night. Her only medications include combined oral contraceptives and levothyroxine. She does
not smoke or drink alcohol. Her family history is significant for a mother with rheumatoid
arthritis. On physical examination, vital signs are normal. Muscles are nontender and deep
tendon reflexes are intact. Strength in all four extremities is 5/5 on initial testing but her strength
decreases throughout the examination. Thyroid stimulating hormone concentration is within
Which of the following is the most likely mechanism of this patient’s condition? Antibody-mediated damage to presynaptic cells at the neuromuscular junction
Delayed (type IV) hypersensitivity reaction
Endomysial inflammation with CD8+ cells.
Hereditary segmental demyelination of distal nerves
Toxin-mediated inhibition of acetylcholine release at the neuromuscular junction
Type III hypersensitivity
This young woman with a history of autoimmune thyroid disease and progressive weakness,
bulbar dysfunction (pain while chewing) and diplopia has a likely diagnosis of Myasthenia
gravis (MG), which is caused by a type II hypersensitivity reaction.
Cytotoxic (type II)hypersensitivity reactions are caused by the action of IgG autoantibodies
against cell surface antigens. In the case of MG, autoantibodies are directed against postsynaptic
nicotinic acetylcholine (ACh) receptors at the neuromuscular junction (NMJ), leading to
complement-mediated injury to the motor endplate.
The illustration shows the pathophysiology of MG.
Myasthenia gravis typically manifests in young women in their twenties and thirties and in older
men in their sixties through eighties. Symptoms include fluctuating muscle weakness that
worsens with use and therefore manifests most severely in the evening. Ocular and bulbar
symptoms are also seen. Ocular symptoms include diplopia and ptosis; bulbar symptoms include
dysarthria, dysphagia, and difficulty chewing.
Although it is no longer performed in clinical practice, improvement of symptoms after the
administration of edrophonium (an acetylcholinesterase inhibitor), also referred to as a positive
tensilon test, is diagnostic of MG. The preferred diagnostic test of choice for the condition is a positive serology for IgG antibodies against acetylcholine receptors. All patients with MG should
also be evaluated with chest imaging (either CT or MRI) for the presence of a possible thymoma,
which is commonly associated with anti-ACh autoantibody formation. In the long term, patients
with MG are treated with pyridostigmine, an acetylcholinesterase inhibitor.
Why incorrect answers are wrong: The presence of autoantibodies to presynaptic voltage-gated calcium channels at the
neuromuscular junction is characteristic of Lambert-Eaton syndrome, a paraneoplastic
syndrome typically associated with lung cancer. In this condition, muscle weakness
improves with use and reflexes are classically decreased.
Toxin-mediated prevention of acetylcholine release at the neuromuscular junction can
occur with exposure to botulinum toxin. Botulism would result in more rapid-onset
descending flaccid paralysis and autonomic dysfunction. The disorder is classically
associated with the consumption of canned foods.
Delayed (type IV) hypersensitivity reaction against myelin and Schwann cells is
characteristic of Guillain-Bàrre syndrome (GBS), which typically occurs after an
infection (eg, with Campylobacter jejuni). GBS presents with ascending muscle
weakness and decreased-to-absent deep tendon reflexes due to demyelination of spinal
motor nerve roots and peripheral nerves.
Type III hypersensitivity, as seen in SLE, involves the deposition of immune complexes
in unwanted locations and can lead to serum sickness, the arthus reaction, and some
symptoms of SLE.
Hereditary segmental demyelination of distal nerves due to Charcot-Marie-Tooth
disease can lead to progressive muscle weakness. Pes cavus can be seen on physical
exam, as well as legs classically described as being in the shape of inverted champagne
bottles due to muscle atrophy. Symptoms are gradual in onset and would be present at a
younger age. Ocular and bulbar symptoms are not typical.
Endomysial inflammation with CD8+ T cells leads to skeletal muscle damage
characteristic of polymyositis, which presents with progressive, symmetric proximal
muscle weakness and tenderness. A 22-year-old college student presents to the emergency department with sudden-onset severe
epigastric pain that radiates to the back. He has a history of heavy alcohol abuse, and lab tests
show a markedly elevated amylase level.
The organ involved in this patient's pathology plays a key role in normal gastrointestinal
physiology. Under normal physiologic conditions, the organ is stimulated by a hormone that
increases the secretion of bicarbonate.
Which of the following will increase release of this hormone? Acid and fatty acids in the duodenal lumen
Increased stomach distention
The presence of fatty acids, amino acids, and oral glucose in the duodenum and jejunum
This young man presenting with acute-onset epigastric pain that is radiating to the back has a
history of alcoholism. Classically, this clinical picture is consistent with an episode of
pancreatitis, which is most commonly caused by gallstones and alcohol. The amylase level is
elevated during an episode of acute pancreatitis. Thus the organ of interest is the pancreas.
The hormone secretin acts on pancreatic duct cells to stimulate bicarbonate secretion, which
facilitates functioning of pancreatic enzymes by neutralizing gastric acid. Secretin is released by
duodenal S cells in response to increased acid and fatty acids in the lumen of the duodenum.
A fasting state increases release of motilin (from the small intestine) and ghrelin (from the
stomach). Stomach distention and vagal stimulation increase release of gastrin (from the
antrum of the stomach and duodenum). Fatty acids, amino acids, and oral glucose reaching
the duodenum and jejunum increase release of glucose-dependent insulinotropic peptide (GIP)
from duodenal and jejunal K cells. None of these hormones increase bicarbonate secretion from
The image provides an overview of the locations of gastrointestinal secretory cells. A 64-year-old man is brought to the emergency department by his wife after she noticed slurring
of his speech during dinner 30 minutes ago. He has a history of hypertension and diabetes, for
which he takes metoprolol and metformin. On physical examination, his temperature is 36.4°C
(97.5°F), heart rate is 90/min, blood pressure is 130/88 mm Hg, and respiratory rate is 18/min.
He has 3/5 strength in his right upper and lower extremities. A picture of his face is shown
below. He is unable to express himself verbally but is able to follow commands appropriately. A
computed tomographic (CT) scan of the head shows no sign of hemorrhage. A medication is
administered intravenously. What is the mechanism of action of the medication most likely used to treat this patient? Activates antithrombin III
Catalyzes conversion of plasminogen to plasmin
Direct inhibitor of thrombin Monoclonal antibody against GPIIb/IIIa
Phosphodiesterase III inhibitor
his patient presents with acute onset of weakness, facial drooping, and expressive aphasia, which
are strong indications that he has had an ischemic stroke. A CT scan is important in
differentiating between ischemic and hemorrhagic strokes. If a patient who has had an ischemic
stroke presents within 3 hours and has no contraindications, the standard treatment is tissue
plasminogen activator (tPA). As shown in the diagram, tissue plasminogen activator is secreted
by endothelial cells and is the enzyme most directly responsible for degrading the fibrin matrix.
Recombinant tPA (alteplase) and streptokinase are similar medications that are used to treat
diseases in which fibrin clots prevent adequate blood flow to tissue, such as stroke, pulmonary
embolus, and myocardial infarction. Activation of antithrombin III is the mechanism of action of heparin, which is used as
an anticoagulant in acute situations such as pulmonary embolisms or DVTs and acute
Phosphodiesterase III inhibitors, such as dipyridamole and cilostazol, are antiplatelet
medications commonly used to treat claudication.
Direct thrombin inhibitors, such as lepirudin and bivalirudin, are oral medications that
can be used in the event of heparin-induced thrombocytopenia.
A monoclonal antibody to GPIIb/IIIa (abciximab) inhibits platelet aggregation and is
used in treatment of acute coronary syndromes. Heparin works by binding to and activating the enzyme antithrombin III. Binding of heparin to
antithrombin III increases binding of the protease to factors II and X. Heparin is used for
immediate anticoagulation in cases of pulmonary embolisms, myocardial infarction, and deep
venous thrombosis. Given this patient’s presentation, a different medication was used to treat his
Lepirudin and bivalirudin are anticoagulant medications that work via direct inhibition of
thrombin. They are used as an alternative to heparin if the patient is at risk for heparin-induced
thrombocytopenia. These drugs would not be administered to this patient, given his clinical
Abciximab is a monoclonal antibody against the GPIIb/IIIa receptor on platelets. Binding of
fibrinogen to GPIIb/IIIa receptors joins adjacent platelets during platelet aggregation. Abciximab
is used in the treatment of acute coronary syndromes and would not have a role in the treatment
of this patient.
The antiplatelet drugs dipyridamole and cilostazol act via inhibition of phosphodiesterase III.
Inhibition of phosphodiesterase III causes increased concentrations of cyclic adenosine monophosphate within platelets, which leads to impaired platelet aggregation. These medications
are used to treat claudication.
Fibrinolysis begins in endothelial cells with the secretion of tissue plasminogen activator (tPA).
This catalyzes the conversion of plasminogen to plasmin.
Coagulation and kinin pathways Coagulation cascade components
Vitamin K deficiency: synthesis of factors II, VII, I X , X, protein C, protein S. Warfarin inhibits vitamin K epoxide reductase. Vitamin K administration can potentially
reverse inhibitory effect of warfarin on clotting factor synthesis. FFP or PCC administration
reverses action of warfarin immediately and can be given with vitamin K in cases of severe
Neonates lack enteric bacteria, which produce vitamin K. Early administration of vitamin K
overcomes neonatal deficiency/coagulopathy.
Factor VII—Shortest half life.
Factor II—Longest half life.
vWF carries/protects factor V I I I ; volksWagen F
actories make gr8 cars. Anticoagulation
Antithrombin inhibits activated forms of factors II, VII, I X , X, XI, XII.
Heparin enhances the activity of antithrombin.
Principal targets of antithrombin: thrombin and factor Xa.
Factor V Leiden mutation produces a factor V resistant to inhibition by activated protein C.
tPA is used clinically as a thrombolytic. Thrombogenesis Formation of insoluble fibrin mesh.
Aspirin irreversibly inhibits cyclooxygenase, thereby inhibiting T X A 2 synthesis.
Clopidogrel, prasugrel, and ticlopidine inhibit ADP-induced expression of GpIIb/IIIa by irreversibly
blocking P2Y12 receptor.
Abciximab, eptifibatide, and tirofiban inhibit GpIIb/IIIa directly.
Ristocetin activates vWF to bind GpIb. Failure of aggregation with ristocetin assay occurs in
von Willebrand disease and Bernard-Soulier syndrome. A healthy 21-year-old woman with no history of significant illness comes to the physician
requesting combination oral contraceptives. She is sexually active and always uses condoms as
contraception. She does not have a history of migraines and no personal or family history of
clotting disorders. Blood pressure is 123/76 mm Hg, height is 172 cm (5', 8"), weight is 68 kg
(150 lb), and BMI is 23 kg/m2. No abnormalities are noted on physical examination. Urine βHCG results are negative. The physician decides to prescribe combination oral contraceptives to
the patient, which will decrease the amount of endogenous follicle-stimulating hormone (FSH)
Which of the following events will most likely be affected immediately? Blastocyst implantation
Fertilization of ovum
Follicular phase estradiol concentration
Mid-cycle surge of luteinizing hormone (LH)
This patient is a 21-year-old healthy woman who is sexually active and desires oral
contraceptives (OCPs). She has no contraindications (relative or absolute) to combination OCPs
(no personal or family history of thromboembolic disease, normal blood pressure, nonsmoker).
After having a conversation with her physician about all forms of contraception, the patient
decides that she should be prescribed OCPs if she desires.
To understand the mechanism of action of OCPs, it is helpful to understand the hormonal
changes that occur in the normal menstrual cycle, which is shown in the image above. The
normal menstrual cycle consists of the follicular phase (usually ~14-21 days) and the luteal phase
The follicular phase begins after the onset of menstruation and is characterized by folliclestimulating hormone (FSH)-stimulated growth of one or more dominant follicles that release
estrogen. Estrogen causes the uterine endometrium to enter the follicular phase, which is
characterized by a thickened endometrium with an increased number of glands. For most of the
follicular phase, estrogen also works to exert negative feedback on FSH and luteinizing hormone
(LH) production, but late in the follicular phase, high serum estrogen begins to have a positive
feedback effect on LH production, leading to the LH surge (a 10-fold increase in serum LH
The LH surge characterizes the start of the luteal phase and subsequent ovulation.The oocyte of
the dominant follicle completes its first meiotic division and is released from the follicle ~36
hours after the LH surge. The remnant follicle becomes the corpus luteum, which releases
progesterone in the mid- to late-luteal phase. Progesterone causes the endometrium to cease
thickening and causes glands to “organize” (“secretory endometrium”). The corpus luteum
begins to resolve in the late-luteal phase, which occurs when LH release declines via negative
feedback mechanisms from the rising serum progesterone concentrations. As the corpus luteum
resolves, serum concentrations of progesterone and estrogen decrease, resulting in loss of
endometrial blood supply, endometrial sloughing, and the onset of menses. Standard combined OCPs consist of progesterone and estrogen. Progesterone provides negative
feedback to decrease the release of GnRH from the hypothalamus, which then decreases the
secretion of FSH and LH by the anterior pituitary. The immediate effect of decreased FSH is to
inhibit follicular development and to prevent the increase in estrogen concentration during the
follicular phase. Without the end-follicular peak in estrogen concentration, positive feedback
with LH release cannot occur, and thus the LH surge cannot happen. Without the LH surge,
ovulation cannot occur.
,The incorrect answers are wrong for the following reasons: Though the decreased concentrations of FSH lead to the downstream effect of ovulation
inhibition, ovulation is not the process that is most immediately and directly affected by
the decrease in FSH concentrations. Decreased FSH concentrations lead to decreased
follicular-phase estrogen concentrations, which subsequently prevents the LH surge and
It is only by way of decreased estrogen concentrations that decreased FSH concentrations
serve to prevent the LH surge. Specifically, decreased FSH concentrations lead to
decreased follicular-phase estrogen concentrations, which subsequently prevents the LH
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- Spring '16
- Dr. Damuni