Increased lipolysis of fat stores, which can result from starvation, diabetes mellitus, or corticosteroid use, is most likely to cause steatosis (fatty liver) through which one of the following mechanisms?
A.Decreased free fatty acid excretion from the liver leads to free fatty acid accumulation in hepatocytes
B.Excess NADH (high NADH/NAD ratio) causes excess production of lactate from pyruvate, which accumulates in hepatocytes
C.Increased free fatty acid delivery to the liver leads to triglyceride accumulation in hepatocytes
D.Inhibition of apoprotein synthesis by the liver leads to phospholipid accumulation in hepatocytes
E.Inhibition of HMG-CoA reductase activity leads to cholesterol accumulation in hepatocytes
An adult patient presents with the sudden onset of massive diarrhea. Grossly, this individual’s stool has the appearance of “rice-water” because of the presence of flecks of mucus. Cultures of this patient’s stool grow Vibrio cholerae, a curved, gram-negative rod that secretes an enterotoxin consisting of a toxic A subunit and a binding B subunit. The cholera enterotoxin causes massive diarrhea by which of the following mechanisms?
A.Inhibiting the conversion of Gi-GDP to Gi-GTP
B.Inhibiting the conversion of Gs-GTP to Gs-GDP
C.Stimulating the conversion of Gi-GDP to Gi-GTP
D.Stimulating the conversion of Gs-GDP to Gs-GTP
E.Stimulating the conversion of Gs-GTP to Gs-GDP
A 24-year-old female presents with severe pain during menses (dysmenorrhea). To treat her symptoms, you advise her to take indomethacin in the hopes that it will reduce her pain by interfering with the production of which of the following
A 23-year-old female presents with progressive bilateral loss of central vision. You obtain a detailed family history from this patient and produce the associated pedigree (dark circles or squares indicate affected individuals). Which of the following transmission patterns is most consistent with this patient’s family history?
An 8-month-old male infant is admitted to the hospital because of a bacterial respiratory infection. The infant responds to appropriate antibiotic therapy, but is readmitted several weeks later because of severe otitis media. Over the next several months, the infant is admitted to the hospital multiple times for recurrent bacterial infections. Workup reveals extremely low serum antibody levels. The infant has no previous history of viral or fungal infections. Which of the following is the most likely diagnosis?
A.Isolated IgA deficiency
B.Chronic granulomatous disease
E.linked agammaglobulinemia of Bruton
A 35-year-old male living in a southern region of Africa presents with increasing abdominal pain and jaundice. He has worked as a farmer for many years, and sometimes his grain has become moldy. Physical examination reveals a large mass involving the right side of his liver, and a biopsy specimen from this mass confirms the diagnosis of liver cancer (hepatocellular carcinoma). The pathogenesis of this tumor involves which of the following substances?
B.Direct-acting alkylating agents
A 54-year-old male develops a thrombus in his left anterior descending coronary artery. The area of myocardium supplied by this vessel is irreversibly injured. The thrombus is destroyed by the infusion of streptokinase, which is a plasminogen activator, and the injured area is reperfused. The patient, however, develops an arrhythmia and dies. An electron microscopic (EM) picture taken of the irreversibly injured myocardium reveals the presence of large, dark, irregular amorphic densities within mitochondria, which are referred to as which of the following
Histologic sections of an enlarged tonsil from a 9-year-old female reveal an increased number of reactive follicles containing germinal centers with proliferating B lymphocytes. Which one of the following terms best describes this pathologic process?
A.B lymphocyte hypertrophy
D.Germinal center atrophy
E.Germinal center metaplasia
A 19-year-old female is being evaluated for recurrent facial edema, especially around her lips. She also has recurrent bouts of intense abdominal pain and cramps, sometimes associated with vomiting. Laboratory examination finds decreased C4, while levels of C3, decay-accelerating factor, and IgE are within normal limits. These findings are most likely to be associated with which of the following deficiencies?
B.C1 esterase inhibitor
D.Complement components C3 and C5
Which one of the following laboratory findings is most consistent with an individual who is not taking any medication but has a familial deficiency of coagulation factor VII, assuming all other coagulation factors to be within normal limits?
Answers & explanation
The answer is: C
Free fatty acids are normally taken up by the liver and esterified to triglyceride, converted to cholesterol, oxidized into ketone bodies, or incorporated into phospholipids that can be excreted from the liver as very-low-density lipoproteins (VLDLs). Abnormalities involving any of these normal metabolic pathways may lead to the accumulation of triglycerides within the hepatocytes. This accumulation of triglycerides is called fatty change or steatosis. Examples of abnormalities that produce hepatic steatosis include diseases that cause excess delivery of free fatty acids to the liver or diseases that cause impaired lipoprotein synthesis. Excess delivery of free fatty acids occurs in conditions that increase lipolysis of adipose tissue, such as starvation, diabetes mellitus, and corticosteroid use. Increased formation of triglycerides can result from alcohol use, as alcohol causes excess NADH formation (high NADH/NAD ratio), increases fatty acid synthesis, and decreases fatty acid oxidation. Impaired apoprotein synthesis occurs with carbon tetrachloride poisoning, phosphorous poisoning, and protein malnutrition. Inhibition of HMG-CoA reductase activity is the mechanism of lovastatin, which indirectly increases liver LDL receptors and increases LDL clearance from the blood.
The answer is: B
Many extracellular substances cause intracellular actions via second-messenger systems. These second messengers may bind to receptors that are located either on the surface of the cell or within the cell itself. Substances that react with intracellular receptors are lipid-soluble (lipophilic) molecules that can pass through the lipid plasma membrane. Examples of these lipophilic substances include thyroid hormones, steroid hormones, and the fat-soluble vitamins A and D. Once inside the cell these substances generally travel to the nucleus and bind to the hormone response element (HRE) of DNA.
Some substances that react with cell surface receptors bind to guanine-nucleotide regulatory proteins. These proteins, called G proteins, may be classified into four categories, namely Gs, Gi, Gt, and Gq. Two of these receptors, Gs and Gi, regulate the intracellular concentration of cyclic adenosine 5'-monophosphate (cAMP). In contrast, Gt regulates the intracytoplasmic levels of cyclic guanosine 5'-monophosphate (cGMP), and Gq regulates the intracytoplasmic levels of calcium ions. Gs and Gi regulate intracellular cAMP levels by their actions on adenyl cyclase, an enzyme located on the inner surface of the plasma membrane that catalyzes the formation of cAMP from ATP. The adenylate cyclase G protein complex is composed of the following components: the receptor, the catalytic enzyme (i.e., adenyl cyclase), and a coupling unit. The coupling unit consists of GTP-dependent regulatory proteins (G proteins), which may either be stimulatory (Gs) or inhibitory (Gi). When bound to GTP and active, Gs stimulates adenyl cyclase and increases cAMP levels. (Gs can be thought of as the “on switch.”) In contrast, when bound to GTP and active, Gi inhibits adenyl cyclase and decreases cAMP levels. (Gi can be thought of as the “off switch.”) It is important to note that cholera toxin and pertussis toxin both act by altering this adenyl cyclase pathway. Cholera toxin inhibits the conversion of Gs-GTP to Gs-GDP. In contrast, pertussis toxin inhibits the activation of Gi-GDP to Gi-GTP. Therefore, both cholera toxin and pertussis toxin prolong the functioning of adenyl cyclase and therefore increase intracellular cAMP, but their mechanisms are different. Cholera toxin keeps the “on switch” in the “on” position, while pertussis toxin keeps the “off switch” in the “off” position.
The answer is: E
Certain drugs are important in the control of acute inflammation because they inhibit portions of the metabolic pathways involving arachidonic acid. For example, corticosteroids induce the synthesis of lipocortins, a family of proteins that are inhibitors of phospholipase A2. They decrease the formation of arachidonic acid and its metabolites, prostaglandins and leukotrienes. Aspirin, indomethacin, and other nonsteroidal anti-inflammatory drugs (NSAIDs), in contrast, inhibit cyclooxygenase and therefore inhibit the synthesis of prostaglandins and thromboxanes. The prostaglandins have several important functions. For example, prostaglandin E2 (PGE2), produced within the anterior hypothalamus in response to interleukin 1 secretion from leukocytes, results in fever. Therefore aspirin can be used to treat fever by inhibiting PGE2 production. PGE2 is also a vasodilator that can keep a ductus arteriosus open. At birth, breathing decreases pulmonary resistance and reverses the flow of blood through the ductus arteriosus. The oxygenated blood flowing from the aorta into the ductus inhibits prostaglandin production and closes the ductus arteriosus. Therefore prostaglandin E2 can be given clinically to keep the ductus arteriosus open, while indomethacin can be used to close a patent ductus. Prostaglandin F2 (PGF2) causes uterine contractions, which can result in dysmenorrhea. Indomethacin can be used to treat dysmenorrhea by inhibiting the production of PGF2. Bradykinin is a nonapeptide that increases vascular permeability, contracts smooth muscle, dilates blood vessels, and causes pain. It is part of the kinin system and is formed from high-molecular-weight kininogen (HMWK). Histamine, a vasoactive amine that is stored in mast cells, basophils, and platelets, acts on H1 receptors to cause dilation of arterioles and increased vascular permeability of venules.
The answer is: E
Almost all genes occur on chromosomes within the nucleus. There are a few genes, however, that are located within the mitochondria. These mitochondrial genes are found on mitochondrial DNA (mtDNA). These genes are all of maternal origin, possibly because ova have mitochondria within the large amount of cytoplasm while sperm do not. This maternal origin means that mothers transmit all of the mtDNA to both male and female offspring, but only the daughters transmit it further. No transmission occurs through males. This mtDNA contains genes that mainly code for oxidative phosphorylation enzymes, such as NADH dehydrogenase, cytochrome c oxidase, and ATP synthase. Symptoms of deficiencies of these enzymes occur in organs that require large amounts of ATP, such as the brain, muscle, liver, and kidneys. The mtDNA of these patients may be composed of either a mixture of mutant and normal DNA (heteroplasm) or of mutant DNA entirely (homoplasmy). The severity of these diseases correlates with the amount of mutant mtDNA that is present. One disease associated with mitochondrial inheritance is Leber hereditary optic neuropathy (LHON), which is characterized by progressive bilateral loss of central vision and usually occurs between 15 and 35 years of age. Other examples of mitochondrial inheritance include mitochondrial myopathies, which are characterized by the presence in muscle of mitochondria having abnormal sizes and shapes. These abnormal mitochondria may result in the histologic appearance of the muscle as ragged red fibers. Electron microscopy reveals the presence within large mitochondria of rectangular crystals that have a “parking lot” appearance.
The answer is: E
In X-linked agammaglobulinemia of Bruton, B cells are absent but numbers and function of T cells are normal. This abnormality results from defective maturation of B lymphocytes beyond the pre-B stage. This maturation defect leads to decreased or absent numbers of plasma cells, and therefore immunoglobulin levels are markedly decreased. Male infants with Bruton’s disease begin having trouble with recurrent bacterial infections at about the age of 9 months, which is when maternal antibodies are no longer present in the affected infant. Therapy for Bruton’s disease consists primarily of IV gamma globulin.
Isolated deficiency of IgA is probably the most common form of immunodeficiency. It is due to a block in the terminal differentiation of B lymphocytes. Most patients are asymptomatic, but some develop chronic sinopulmonary infections. Patients are prone to developing diarrhea (Giardia infection) and also have an increased incidence of autoimmune disease, such as Hashimoto’s thyroiditis. In patients with chronic granulomatous disease (CGD), the neutrophils and macrophages have deficient H2O2 production due to abnormalities involving the enzyme NADPH oxidase. These individuals have frequent infections that are caused by catalase-positive organisms, such as S. aureus, because the catalase produced by these organisms destroys the little hydrogen peroxide that is produced. DiGeorge’s syndrome is a T cell–deficiency disorder that results from hypoplasia of the thymus due to abnormal development of the third and fourth pharyngeal pouches. The parathyroid glands are also abnormal, and these individuals develop hypocalcemia and tetany. Congenital heart defects are also present. Wiskott-Aldrich syndrome is also an X-linked recessive disorder, but it is characterized by thrombocytopenia, eczema, and immune deficiency. The immune abnormalities are characterized by progressive loss of T cell function and decreased IgM. The other immunoglobulin levels are normal or increased. There are decreased numbers of lymphocytes in the peripheral blood and paracortical (T cell) areas of lymph nodes. Both cellular and humoral immunity are affected, and, because patients fail to produce antibodies to polysaccharides, they are vulnerable to infections with encapsulated organisms.
The answer is: A
Many chemicals are associated with an increased incidence of malignancy. These substances are called chemical carcinogens. Although there are direct-acting chemical carcinogens, such as the direct-acting alkylating agents that are used in chemotherapy, most organic carcinogens first require conversion to a more reactive compound. Polycyclic aromatic hydrocarbons, aromatic amines, and azo dyes must be metabolized by cytochrome P450–dependent mixed-function oxidases to active metabolites. Vinyl chloride is metabolized to an epoxide and is associated with angiosarcoma of the liver, not hepatocellular carcinoma. Azo dyes, such as butter yellow and scarlet red, are metabolized to active compounds that have induced hepatocellular cancer in rats, but no human cases have been reported. -naphthylamine is an exception to the general rule involving cytochrome P450, as the hydrolysis of the nontoxic conjugate occurs in the urinary bladder by the urinary enzyme glucuronidase. In the past there has been an increase in bladder cancer in workers in the aniline dye and rubber industries who have been exposed to these compounds. Aflatoxin B1, a natural product of the fungus Aspergillus flavus, is metabolized to an epoxide. The fungus can grow on improperly stored peanuts and grains and is associated with the high incidence of hepatocellular carcinoma in some areas of Africa and the Far East. Hepatitis B virus is also highly associated with liver cancer in these regions
The answer is: B
With prolonged ischemia, certain cellular events occur that are not reversible, even with restoration of oxygen supply. These cellular changes are referred to as irreversible cellular injury. This type of injury is characterized by severe damage to mitochondria (vacuole formation), extensive damage to plasma membranes and nuclei, and rupture of lysosomes. Severe damage to mitochondria is characterized by the influx of calcium ions into the mitochondria and the subsequent formation of large, flocculent densities within the mitochondria. These flocculent densities are characteristically seen in irreversibly injured myocardial cells that undergo reperfusion soon after injury. Less severe changes in mitochondria, such as mitochondrial swelling, are seen with reversible injury. Cytochrome c released from damaged mitochondria can induce apoptosis, a process through which irreversibly injured cells can shrink and increase the eosinophilia of their cytoplasm. These shrunken apoptotic cells (apoptotic bodies) may be engulfed by adjacent cells or macrophages. Myelin figures are derived from plasma membranes and organelle membranes and can be seen with either reversible or irreversible injury. Psammoma bodies are small, laminated calcifications, while Russell bodies are round, eosinophilic aggregates of immunoglobulin.
The answer is: C
There are many adaptive mechanisms of cells to persistent stimuli. Hypertrophy is an increase in the size of cells. Examples of hypertrophy include enlarged skeletal muscle in response to repeated exercise or anabolic steroid use and enlarged cardiac muscle in response to volume overload or hypertension. In contrast to hypertrophy, hyperplasia is an increase in the number of cells. Hyperplasia may be the result of a physiologic response or a pathologic process. Examples of physiologic hyperplasia include the increased size of the female breast or uterus in response to hormones. Pathologic hyperplasia may be compensatory to some abnormal process, or it may be a purely abnormal process. Examples of compensatory pathologic hyperplasia include the regenerating liver, increased numbers of erythrocytes in response to chronic hypoxia, and increased numbers of lymphocytes within lymph nodes in response to bacterial infections [follicular (nodular) hyperplasia]. Examples of purely pathologic hyperplasia include abnormal enlargement of the endometrium (endometrial hyperplasia) and the prostate (benign prostatic hyperplasia). Atrophy is a decrease in the size and function of cells. Examples of atrophy include decreased size of limbs immobilized by a plaster cast or paralysis, or decreased size of organs affected by endocrine insufficiencies or decreased blood flow. Metaplasia is a term that describes the conversion of one histologic cell type to another. Examples of metaplasia include respiratory epithelium changing to stratified squamous epithelium (squamous metaplasia) in response to prolonged smoking, the normal glandular epithelium of the endocervix changing to stratified squamous epithelium (squamous metaplasia) in response to chronic inflammation, or the normal stratified squamous epithelium of the lower esophagus changing to gastric-type mucosa in response to chronic reflux. In contrast to metaplasia, dysplasia refers to disorganized growth and is characterized by the presence of atypical or dysplastic cells. Dysplasia can be seen in many organs, such as within the epidermis in response to sun damage (actinic keratosis), the respiratory tract, or the cervix (cervical dysplasia).
The answer is: B
Deficiencies of components of the complement system are associated with specific abnormalities. Patients with congenital deficiencies in the early components of the complement cascade have recurrent symptoms resembling those of systemic lupus erythematosus due to the deposition of immune complexes. Patients with deficiencies of the middle complement components (C3 and C5) are at risk for recurrent pyogenic infections, while those lacking terminal complement components (C6, C7, or C8, but not C9) are prone to developing recurrent infections with Neisseria species. A deficiency of decay-accelerating factor (DAF), which breaks down the C3 convertase complex, is seen in paroxysmal nocturnal hemoglobinuria (PNH), a disorder that is characterized by recurrent episodes of hemolysis of red cells because of the excessive intravascular activation of complement. Deficiencies of C1 esterase inhibitor result in recurrent angioedema, which refers to episodic nonpitting edema of soft tissue, such as the face. Severe abdominal pain and cramps, occasionally accompanied by vomiting, may be caused by edema of the gastrointestinal tract. To understand how a deficiency of C1 inhibitor can cause vascularly produced edema (angioedema), note that not only does C1 inhibitor inactivate C1, but it also inhibits other pathways, such as the conversion of prekallikrein to kallikrein and kininogen to bradykinin. A deficiency of C1 inhibitor also leads to excess production of C2, a product of C2 called C2 kinin, and bradykinin. It is the uncontrolled activation of bradykinin that produces the angioedema, as bradykinin increases vascular permeability, stimulates smooth muscle contraction, dilates blood vessels, and causes pain. In contrast, a defect involving 2-integrins is seen with leukocyte adhesion deficiency, while defects involving NADPH of leukocytes are characteristic of chronic granulomatous disease.
The answer is: A
The coagulation cascade involves the formation of fibrin through the intrinsic, extrinsic, and common pathways. The intrinsic pathway is initiated by contact of factor XII with several types of biologic surfaces. Activated XII (XIIa) initiates the formation of XIa and IXa. The extrinsic pathway is initiated by contact of tissue factor with factor VII. Activated factor VII acts together with IXa, VIIIa, and platelet factor 3 (PF-3), which is a phospholipid complex located on the surface of platelets, to produce activated factor X. This begins the common pathway, which continues with the interaction of Xa, Va, PF-3, and Ca++ to cleave prothrombin, forming thrombin, which in turn cleaves fibrinogen to form fibrin.
Two laboratory tests that are used to evaluate the functioning of the coagulation cascade are prothrombin time (PT) and partial thromboplastin time (PTT). Abnormalities of the extrinsic pathway prolong (not shorten) the PT, while abnormalities of the intrinsic pathway prolong (not shorten) the PTT. Note that abnormalities of the common pathway prolong both the PT and the PTT. To illustrate, deficiencies of factor VII produce an abnormal (prolonged) PT with a normal PTT. Compare these results to each of the following: a normal PT with an abnormal PTT can be seen with deficiencies of factors XII, XI, IX, or VIII, while abnormal PT and PTT are seen with deficiencies of X, V, prothrombin, or fibrinogen.
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