Evaluation of a pedigree for a certain abnormality reveals the following information: there are skipped generations with male-to-male transmission; females are affected at the same rate as are males; and the disease is produced in the homozygous state, while heterozygous individuals are carriers. What is the inheritance pattern for this disorder?

7. Evaluation of a pedigree for a certain abnormality reveals the following
information: there are skipped generations with male-to-male transmission;
females are affected at the same rate as are males; and the disease is
produced in the homozygous state, while heterozygous individuals are carriers.
What is the inheritance pattern for this disorder?
a. Autosomal dominant
b. Autosomal recessive
c. X-linked dominant
d. X-linked recessive
e. Mitochondrial


Answer The answer is b. (Cotran, pp 143–146.) Inheritance of single abnormal
genes generally follows one of the following patterns of inheritance: autosomal
dominant, autosomal recessive, or X-linked. Characteristics of autosomal
dominant (AD) inheritance include symptoms manifested in the
heterozygous state, males and females affected equally, and vertical transmission.
The latter term refers to the finding of successive generations
affected. Also with autosomal dominant inheritance, children with one
affected parent have one chance in two of having the disease (50%). This is
also the recurrence risk. Note that unaffected family members cannot
transmit the disease. Characteristics of autosomal recessive (AR) inheritance
include manifestations in the homozygous state, horizontal transmission,
males and females affected equally, and common occurrence of
complete penetrance and consanguineous relations. Horizontal transmission
refers to finding the disease in siblings but not parents. That is, with
84 Pathology
autosomal recessive disorders, parents are usually heterozygous and are
clinically normal, while symptoms occur in one-fourth of siblings. Also
note that one-half of siblings are carriers (heterozygous) for the trait.
X-linked patterns of inheritance are seen with disorders involving
genes located on the X chromosome. The key point about X-linked disorders
is that there is no male-to-male transmission. Note that in males the
terms dominant and recessive do not apply (since they have only one X
chromosome). Also note that X-linked inheritance is different from sexinfluenced
autosomal dominant inheritance, an example of which is baldness.
Characteristics of X-linked dominant disorders, which are quite rare,
include no skipped generations (dominant inheritance) and no male-tomale
transmission (x-linked inheritance). A key point is to note that
females are affected twice as often as males. Affected females transmit the
disease to 50% of their daughters and 50% of their sons. Affected males
transmit the disease to all of their daughters and none of their sons. A subtype
of X-linked dominant disease is seen when the condition is lethal in
utero in hemizygous males. Therefore the condition is seen clinically in
heterozygous females, who also have an increase in the number of abortions.
Characteristics of X-linked recessive disorders include: an affected
male does not transmit the disease to his sons, but all daughters are carriers,
sons of carrier females have a one in two chance of the disorder, but all
daughters are asymptomatic, and the trait occurs in maternal uncles and in
male cousins descended from the mother’s sisters (oblique transmission).
Affected females are rare and may be homozygous for the disease or may
have an unfavorable lyonization.

A 25-year-old female presents with a history of losing four pregnancies in the past 5 years

MCQ6. 

A 25-year-old female presents with a history of losing four pregnancies
in the past 5 years. She also has a history of recurrent pains in her legs secondary
to recurrent thrombosis. Her symptoms are most likely due to a
deficiency of
a. PA inhibitors
b. Protein C
c. Plasmin
d. Thrombin
e. C′1 inactivator


Answer The answer is b. (Henry, pp 726–727. Cotran, pp 122–126. Ayala, p
208.) Two important control points of the coagulation cascade are the fibrinolytic
system and certain plasma protease inhibitors. The main component
of the fibrinolytic system is plasmin, which is converted from
plasminogen by either factor XII or a plasminogen activator (PA). Examples
of PAs include tissue plasminogen activator (tPA), urokinase plasminogen
activator, and streptokinase. Once formed, plasmin splits fibrin and also
General Pathology Answers 83
degrades both fibrinogen and coagulation factors VIII and V. Plasma protease
inhibitors include antithrombin III and protein C. Antithrombin III in
the presence of heparin inhibits thrombin, XIIa, XIa, Xa, and IXa, while
protein C inhibits Va and VIIIa. The significance of these control mechanisms
is illustrated by the fact that abnormalities of these systems, such as
deficiencies of antithrombin III, protein C, or protein S, are associated with
hypercoagulable states and increased risk of thrombosis, as the main factors
leading to thrombosis include injury to endothelium, alterations in
blood flow, and hypercoagulability of the blood. Hypercoagulability may
be a primary (genetic) or secondary abnormality. Primary hypercoagulable
states include the previously mentioned deficiencies of antithrombin III,
protein C, or protein S. These deficiencies are associated with recurrent
thromboembolism in early adult life and recurrent spontaneous abortions
in women. The causes of secondary hypercoagulable states are numerous
and include severe trauma, burns, disseminated cancer, and pregnancy.
Lower risk factors for the development of secondary hypercoagulable states
include age, smoking, and obesity. Some patients with high titers of
autoantibodies against anionic phospholipids such as cardiolipin (the antibody
being called a lupus anticoagulant) have a high frequency of arterial
and venous thrombosis. To summarize, it is important to remember that
the differential diagnosis of recurrent spontaneous abortions in women
includes deficiencies of protein C and protein S, and the presence of the
lupus anticoagulant, which is part of the anti-phospholipid syndrome.

Which one of the listed statements is the best histologic definition of an abscess?

MCQ5. 

Which one of the listed statements is the best histologic definition of an
abscess?
a. A circumscribed collection of neutrophils with necrotic cellular debris
b. A localized defect that results from the sloughing of necrotic inflammatory tissue
from the surface of an organ
c. A localized proliferation of fibroblasts and small blood vessels
d. An aggregate of two or more activated macrophages
e. The excessive secretion of mucus from a mucosal surface

AnswerThe answer is a. (Cotran, pp 84–87.) An abscess is a localized collection
of neutrophils and necrotic debris. It is basically a localized form of
suppurative (purulent) inflammation, which is associated with pyogenic
bacteria and is characterized by edema fluid admixed with neutrophils and
necrotic cells (liquefactive necrosis or pus). S. aureus classically produces
abscesses, because it is coagulase-positive and coagulase helps to produce
fibrinous material that localizes the infection. Other morphologic patterns
of inflammation include serous inflammation, fibrinous inflammation, and
pseudomembranous inflammation. Fibrinous inflammation is associated
with the deposition of fibrin in body cavities, which subsequently stimulates
coagulation. Histologically, fibrin is seen as amorphic eosinophilic
material. Fibrinous inflammation within the pericardial cavity (fibrinous
pericarditis) produces a characteristic “bread-and-butter” appearance
grossly. Serous inflammation produces a thin fluid, such as is present in
skin blisters or body cavities. In contrast to fibrinous inflammation, there
is not enough fibrinogen present in serous inflammation to form fibrin.
Pseudomembranous inflammation refers to the formation of necrotic membranes
on mucosal surfaces. Two infections classically associated with
pseudomembrane formation are Clostridium difficile, which produces a
characteristic “mushroom-shaped” pseudomembrane in the colon of people
taking broad-spectrum antibiotics, and C. diphtheriae, which produces
a pseudomembrane in the larynx.
In contrast to an abscess, an ulcer is a defect of epithelium in which
the epithelial lining is sloughed and is replaced by inflammatory necrotic
material. A localized proliferation of fibroblasts and small blood vessels
describes granulation tissue, while an aggregate of two of more activated
macrophages refers to a granuloma. The excessive secretion of mucus from
a mucosal surface refers to catarrhal (phlegmonous or coryzal) inflammation,
such as seen with a runny nose.

A 24-year-old female presents with severe pain during menses (dysmenorrhea).

MCQ4

 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
a. Bradykinin
b. Histamine
c. Leukotrienes
d. Phospholipase A2
e. Prostaglandin F2

Answer The answer is e. (Cotran, 6/e, pp 70–72.) 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.

3. In an evaluation of an 8-year-old boy who has had recurrent infections since the first year of life, findings include enlargement of the liver and spleen, lymph node inflammation, and a superficial dermatitis resembling eczema. Microscopic examination of a series of peripheral blood smears taken during the course of a staphylococcal infection indicates that the bactericidal capacity of the boy’s neutrophils is impaired or absent. What is the most likely cause of this child’s illness? a. Defect in the enzyme NADPH oxidase b. Defect in the enzyme adenosine deaminase (ADA) c. Defect in the IL-2 receptor d. Developmental defect at the pre-B stage e. Developmental failure of pharyngeal pouches 3 and 4 4.

MCQ3 

In an evaluation of an 8-year-old boy who has had recurrent infections
since the first year of life, findings include enlargement of the liver and
spleen, lymph node inflammation, and a superficial dermatitis resembling
eczema. Microscopic examination of a series of peripheral blood smears
taken during the course of a staphylococcal infection indicates that the bactericidal
capacity of the boy’s neutrophils is impaired or absent. What is the
most likely cause of this child’s illness?


a. Defect in the enzyme NADPH oxidase
b. Defect in the enzyme adenosine deaminase (ADA)
c. Defect in the IL-2 receptor
d. Developmental defect at the pre-B stage
e. Developmental failure of pharyngeal pouches 3 and 4



AnswerThe answer is a. (Cotran, pp 65, 231–236. Rubin, pp 67, 1088.)
Patients with chronic granulomatous disease have defective functioning of
phagocytic neutrophils and monocytes due to an inability to produce
hydrogen peroxide. That is, their phagocytic cells have a decreased oxidative
or respiratory burst. The most common cause of chronic granulomatous
disease is defective NADPH oxidase, which is an enzyme on the
membrane of lysosomes that converts O2 to superoxide and stimulates
oxygen burst. This deficiency results in recurrent infections with catalasepositive
organisms, such as S. aureus. The classic form of chronic granulomatous
disease usually affects boys and causes death before the age of 10.
Key findings in chronic granulomatous disease include lymphadenitis,
General Pathology Answers 81
hepatosplenomegaly, eczematoid dermatitis, pulmonary infiltrates that are
associated with hypergammaglobulinemia, and defective ability of neutrophils
to kill bacteria.
A defect in the enzyme adenosine deaminase (ADA) is seen in the
autosomal recessive (Swiss) form of severe combined immunodeficiency
disease (SCID), while a defect in the IL-2 receptor is seen in the X-linked
recessive form of SCID. A developmental defect at the pre-B stage is seen in
X-linked agammaglobulinemia of Bruton, while developmental failure of
pharyngeal pouches 3 and 4 is characteristic of DiGeorge’s syndrome.

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

MCQ2

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


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




AnswerThe answer is b. (Alberts, pp 734–749. Cotran, pp 92–93, 343–344.)
Many extracellular substances cause intracellular actions via secondmessenger
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 guaninenucleotide
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.

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 listed mechanisms

MCQ1




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 listed 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

Answer The answer is c. (Cotran, pp 39–40, 859. Chandrasoma, 3/e, pp 8–10.)
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.