B2.SEQs
What I said
Radioactive uptake testing would reveal very little uptake of iodine by the thyroid gland. This is because the patient is consuming exogenous T3 and there is not any real hyperfunction of the thyroid gland.
Vignette 2
A 45-year-old man complains of feeling jittery and shaky when he gets up in the morning. He has had several episodes of waking up around 4am with hunger pangs, profuse sweating and heart palpitations. He always feels better after eating. Today, he was confused upon awakening and his wife called 911. The emergency personnel found that his blood glucose was 34 mg/dl. Once he was given intravenous dextrose, he quickly improved and felt completely normal.
W2SEQs - Vignette 1
A mother brings her 9-year-old daughter to the doctor because she has been very listless for the past month. She has lost 10 pounds during the last two months despite a good appetite. She drinks two liters of pop a day and is using the bathroom with unusual frequency. The blood sugar is found to be very high, and the urine tests positive for glucose and ketones. The doctor takes a family history and finds that it is negative for diabetes mellitus. Then the patient's mother remembers that she had an uncle who developed diabetes mellitus when he was about 50 years old. She remembers that he was treated with pills
1-1. The lab report on Joan's amniocentesis designates the karyotype shown in Figure 1 as 47,XX,+21. A. What is a karyotype? B. What does each component of the report (47 XX and +21) provide to you? C. Will Joan and Jeremy's child have Down syndrome? What is the most common mechanism causing Down syndrome?
A. A karyotype is a specific test designed to examine the number and structure of the chromosomes taken from a sample of cells. B. The standard nomenclature used for a karyotype always includes the total number of chromosomes and the number of sex chromosomes. If the sample shows an abnormal chromosome, the report would also indicate the type of abnormality. Each component of this report shows: 47 = number of chromosomes in the metaphase XX = sex chromosome constitution of the metaphase +21 = indicates that the 47th chromosome is an extra chromosome 21. C. The karyotype is consistent with a diagnosis of a female fetus with Down syndrome. Down syndrome is a common chromosomal abnormality that occurs in about 1 in 750 live births. About 95% of individuals with Down syndrome have a karyotype with 47 total chromosomes including three complete chromosomes 21. Down syndrome is also caused Trisomy 21, because the symptoms are due to the extra chromosome 21. The most common mechanism causing trisomy 21 is called non-disjunction.
1-2. You explain that, in most cases, the extra chromosome is present due to an error during meiosis. A. Name and describe the meiotic mechanism by which the fetus inherited the extra chromosome 21.
A. Nondisjunction of the two chromosomes 21 in the meiotic divisions of Joan's gametes is the mechanism by which she contributed the extra 21 to the fetus. In Meiosis I nondisjunction, instead of segregating normally to opposite poles, homologous chromosome pairs move together (nondisjoin) to the same pole. The second meiotic division is normal. Two of the four resulting meiotic products contain no chromosomes 21 while the remaining two cells have an extra (ie a second) chromosome 21. In Meiosis II nondisjunction, Meiosis I occurs normally but nondisjunction occurs in the second meiotic division. As a result two sister chromatids of one chromosome do not separate normally to opposite poles but instead, move together (nondisjoin) to the same pole. As a result, one of the four meiotic products will contain an extra chromosome 21, another will contain no chromosomes 21 while the remaining two will have one chromosome 21, as expected.
1-3. Joan and Jeremy ask if it is possible to determine if the extra chromosome 21 in their fetus came from Joan, or if it came from Jeremy. You talk to the laboratory's cytogeneticist and learn that the best way to track a specific chromosome is to isolate a molecular marker (such as a repetitive DNA sequence) unique to chromosome 21 from each individual using polymerase chain reaction (PCR). Joan and Jeremy agree to have their blood drawn for molecular analysis. A. Briefly describe PCR.
A. Polymerase chain reaction is a molecular technique that is widely used for both scientific as well as clinical genetic studies to isolate specific DNA sequences for study. The reaction amplifies a specific region of DNA by means of primer directed DNA synthesis.
MY answer
Although there are risks associated with amniocentesis such as infection and possible rupture of the membrane, it may be necessary in this case. Since the ultrasound indicated omphalocele, the ultrasound would have also shown excess amniotic fluid (polyhydramnios). This is because the baby's gastrointestinal issue is likely affecting baby's ability to swallow the fluid, leading to an accumulation of fluid in utero. Since the two routine tests (AFP and ultrasound) were suspicious, the next step would be a diagnostic test like amniocentesis to check for genetic disorders or neural tube defects.
W3 SEQ - Vignette 2
As a 3rd year medical student, you are assigned to interview and examine two patients in the neonatal intensive care unit (NICU). The first infant is a six-hour-old, 3200 gram (between 25-50 percentile) boy born at 37 weeks gestational age to a 24-year-old otherwise healthy mother. An abdominal wall defect identified as a gastroschisis was seen on a prenatal ultrasound done in the second trimester. Your exam shows a non-dysmorphic infant with intestines extruding through a defect on one side of the umbilicus. The second infant is a 4-day-old boy born to a 28-year-old mother at 34 weeks gestation. The infant was large for dates and had an omphalocele repaired soon after delivery. He had a large tongue and creases on his ear lobe. An ultrasound of his abdomen showed large liver and kidneys. Other than his surgery, you find that he has been treated for hypoglycemia and that a karyotype is pending.
1-2 B. What are other causes of Trisomy 21.
B. Down syndrome (Trisomy 21) can also occur when part of chromosome 21 becomes attached (translocated) to another chromosome during the formation of reproductive cells (eggs and sperm) or very early in fetal development. Affected people have two copies of chromosome 21 plus extra material from chromosome 21 attached to another chromosome, resulting in three copies of genetic material from chromosome 21. Affected individuals with this genetic change are said to have translocation Down syndrome. An example of a translocation is a Robertsonian translocation - this occurs when participating chromosomes break at their centromeres and the long arms fuse to form a single, large chromosome with a single centromere. In humans, Robertsonian translocations generally occur in the five acrocentric chromosome pairs, namely 13, 14, 15, 21 and 22. In a very small percentage of cases, Down syndrome results from an extra copy of chromosome 21 in only some of the body's cells. In these people, the condition is called mosaic Down syndrome.
B. How would molecular markers, such as short tandem repeat (STR) sequences, help in determining the origin of a specific chromosome?
B. Short tandem repeat (STR) sequences consist of repeating units of two or more nucleotides. These are also known as microsatellites. Some of these are unique to specific chromosomal locations and have been used for mapping studies, family studies, and forensics. Importantly, a person will have two copies of a specific STR; one inherited from their mother and the other from their father. Thus, the STR analysis will identify both alleles (or both copies) of each STR in Joan, Jeremy, and their fetus.This information can then be used to determine which alleles the fetus carries.In this manner, it would be possible to determine which parent the extra chromosome came from
1-4. Joan and Jeremy's DNA was amplified using the PCR technique for a marker located near the centromere of chromosome 21 (21q11.1). Figure 2 shows the number of repeats for each allele for Joan, Jeremy and their fetus. Which parent contributed the extra chromosome 21 in the fetus? In your answer, explain the segregation of the alleles.
Comparing the fetus' STR repeat numbers with those of the parents reveals that the fetus has two copies of Joan's STR (allele 2 with 14 repeats) and one copy of Jeremy's (allele 2 of 12 repeats). Thus, the additional chromosome 21 is maternal in origin. Furthermore, these results indicate that the nondisjunction event which resulted in Joan and Jeremy's fetus having trisomy 21 occurred in Meiosis II.
Vignette 2
Daniel, a 54-year-old ex-smoker, has been taking oral glucocorticoids (i.e. steroids) for 6 months to treat his chronic obstructive airway disease (COPD). Now that his pulmonary symptoms have improved, his physician wants to stop the glucocorticoids. However, every time he goes off these medications, Daniel feels extremely weak, dizzy and has a drop in his blood pressure.
My answer
Environmental factors are more closely linked with type 2 DM than type 1. Environmental factors such as sedentary lifestyle, lack of exercise, and a high fat and high refined carbohydrate diet are associated with type 2 DM. However, in type 1 an environmental trigger such as a viral infection may induce the autoimmune response against pancreatic beta cells.
My answer
Figure 1 is type 2 DM due to the deposition of amyloid in the islets. Figure 2 is normal pancreas. Figure 3 is type 1 DM due to the pockets of lymphocytes.
Causes of goiter
Grave's disease: The excessive production of hormones makes the thyroid increase in size. Inflammation: Some people develop thyroiditis, an inflammation of the thyroid that can cause a goiter Hashimoto's/Hypothyroidism: the thyroid doesn't produce enough thyroid hormone, causing hypothyroidism. The low thyroid hormone causes the pituitary gland to make more thyroid-stimulating hormone (TSH), which causes the thyroid to swell. Nodules: Solid or fluid-containing cysts may appear on the thyroid and cause it to swell. These nodules are often noncancerous. Thyroid Cancer: Cancer may affect the thyroid, which causes swelling on one side of the gland. Thyroid cancer is not as common as the formation of benign nodules. Pregnancy: Being pregnant can sometimes cause the thyroid to become larger.
8 You meet with the patient and his wife in your longitudinal medical school clinic. His wife tells you that she looked up her husband's symptoms on the internet and thinks that he has "low blood glucose". How would you explain the definition of "low blood glucose" or hypoglycemia to this patient? In your answer discuss whether a solitary glucose measurement is enough for a diagnosis of hypoglycemia, and if not, what other elements are required.
Hypoglycemia is a state usually when blood glucose is less than 45 mg/dl or 40 mg/dl. However, the occurrence of blood glucose measurement at or below this level in itself does not truly define hypoglycemia. Hypoglycemia is considered to be present if an individual has low blood glucose level in presence of symptoms of hypoglycemia, and these symptoms are relieved by correcting blood glucose values. This triad of 1. Symptoms 2. Low blood glucose 3. Resolution of symptoms on correction of blood glucose is what is used to make a correct diagnosis of hypoglycemia (Whipple's Triad).
Given the above findings on history and physical examination, describe three tests to confirm the diagnosis of secondary adrenal insufficiency.
Ideal Answer: 1. You could inject synthetic ACTH into the patient and demonstrate a lack of stimulation of cortisol secretion. The adrenal glands would not respond to the injection of synthetic ACTH because they atrophy when they are deprived of the "trophic" effect of ACTH. ("Trophic" effect means that ACTH is needed to maintain the size, growth, and vascularity of the adrenal glands.) 2. You could inject insulin into the patient, causing hypoglycemia. Hypoglycemia is a stress that normally stimulates the hypothalamic-pituitary-adrenal axis. If the pituitary corticotroph cells are not working, then hypoglycemia will not stimulate increased cortisol secretion. 3. Once you have confirmed that the patient has adrenal insufficiency, you must measure blood ACTH levels. In primary adrenal insufficiency the ACTH level will be high due to lack of negative feedback inhibition of cortisol on CRH and ACTH secretion. In secondary (pituitary) adrenal insufficiency, ACTH levels will not be elevated.
1. Three genetic conditions which result in female genital development in a fetus with a normal male karyotype are 5-alpha-reductase deficiency, androgen insensitivity syndrome (AIS), and SRY translocations. Describe the incidence, gene, and inheritance pattern for each of these conditions.
Ideal Answer: 5 alpha-reductase deficiency (5-ARD): Incidence: Unknown, rare Inheritance pattern and gene: Autosomal recessive gene mutation in the 5-ARD type 2 gene Congenital insensitivity to androgens (androgen insensitivity syndrome): Incidence: 2-5/100,000 Inheritance pattern and gene: Caused by mutations in the androgen receptor gene, located on the x chromosome. The trait is inherited as x-linked recessive condition. Given that these deficiencies in females do not affect fertility, this contributes to the prevalence of 2-5/100,000 for complete androgen insensitivity syndrome and are based on estimates derived from otherwise healthy phenotypic females found to have histologically normal inguinal or abdominal testes. SRY translocations: Incidence: 1 in 20,000 newborn males Inheritance pattern and gene: Most cases are caused by a de novo translocation of genetic material, including the SRY gene, between the X and Y chromosomes. Typically, SRY mutations are sporadic, although familial transmission has been documented in one-third of all identified SRY
1—1 Suppose a patient were secretly taking excessive amounts of Cytomel. What would the patient's blood levels of free T4, free T3, and TSH be?
Ideal Answer: A patient taking excessive amounts of T3 would obviously have an elevated serum free T3 level. The high levels of serum T3 would exert negative feedback inhibition on the hypothalamus to inhibit TRH and on pituitary to decrease secretion of TSH. So serum TSH is below normal. Since there is low TSH, the thyroid gland takes up less iodine and there is also decrease in thyroid hormone synthesis. Thus, the T4 level in the blood would be low. So the patient would have elevated T3, low T4, and low TSH in serum. Additional Information: The patient would still be clinically thyrotoxic because the body would be exposed to an excessive amount of T3, which is an active form of thyroid hormone.
1. What is alpha-fetoprotein (AFP) and why was it elevated?
Ideal Answer: Alpha-fetoprotein is an abundant protein made by the embryonic yolk sac and the fetal liver. Severe congenital anomalies of the fetus can compromise fetal tissue integrity, causing leakage of serum into the amniotic cavity and the maternal serum. Alpha-fetoprotein can be measured in the maternal serum and is elevated in pregnancies with openings of the spinal cord, brain, or abdominal cavity. Elevated alpha-fetoprotein can also be a marker for a hepatoma or teratoma in the non-pregnant adult.
For each of these three genetic conditions, describe the likely internal urogenital and external genital constitution of the fetus and the mechanism. What pattern of secondary sexual development is expected to occur at puberty for each of these conditions?
Ideal Answer: Antimüllerian hormone activity is present since there are normal testes, and the individual does not have müllerian development (uterus, cervix, and fallopian tubes). (AIS) In androgen insensitivity syndrome, the androgen receptor mediated of Wolffian duct development does not occur. However, antimüllerian hormone activity is present and the individual does not have müllerian development. The vagina is short and it ends blindly. The uterus and fallopian tubes are absent and the testes are normally developed, but abnormally positioned. Testosterone production is normal or is slightly increased. The diagnosis is likely when an individual presents following breast development at puberty with primary amenorrhea, scant or absent pubic and axillary hair and a short vagina, as well as an absent cervix and uterus. Children with inguinal hernias and/or inguinal masses, the possibility of undescended testis should be considered. In congenital insensitivity to androgens, individuals have normal breast development and growths spurt at puberty but do not have menses due to lack of a uterus. On examination, these patients have scant or absent pubic and axillary hair, a short vagina, and an absent cervix and uterus. Children with inguinal hernias and/or inguinal masses should be suspected of having androgen insensitivity syndrome. It is very important to do careful investigation of other family members, since this syndrome follows an X linked recessive pattern. (SRY) With deletion of SRY, the cascade of male sexual differentiation is not initiated, and internal and external sexual development is female. Streak gonads are present instead of ovaries, and internal sex organs are usually female. The external genitals may vary between normal female and normal male, with the majority female. Since there is no gonad, and therefore no antimüllerian hormone, the internal genitalia is female. When SRY is mutated, no secondary sexual (male or female) characteristics develop at puberty, and menstruation does not occur due to lack of estrogen. Since they have no gonads, they do not have a growth spurt and their pubic hair develops scantly. They are usually brought to a doctor due to "infantilism" with lack of secondary sexual characteristics and growth. They need to be placed on "hormones" to develop due to gonadal failure. (5 ARD) 5-alpha-reductase deficiency differs from the complete forms of androgen insensitivity or SRY mutations because at puberty masculinization occurs due to increased secretion of testosterone at puberty. Normal testicular function occurs at puberty and there is some response to endogenous or exogenous androgen and there is growth of the clitoris into a small or sometimes well developed penis, and partial or complete fusion of the labia. At birth, however, the external genitalia are similar to that of androgen insensitivity or SRY mutations. Many of these patients are reared as girls with an enlarged clitoris. At birth steroid levels are normal, ruling out the possibility of adrenal disorders. Patients with 5 ARD retain their fertility and there are reports of live births.
1-2 What symptoms and signs of thyrotoxicosis would the patient have? Which ones would be absent compared to the other causes of thyrotoxicosis?
Ideal Answer: Because of the elevated levels of T3, the patient would be expected to complain of typical symptoms of thyrotoxicosis such as weight loss, restlessness, irritability, heat intolerance with excessive sweating, hyperdefecation, hair loss, tremors, palpitations, and (if a woman) amenorrhea or irregular periods. On physical examination you will find that the patient had a tremor and onycholysis, a condition where the nail cracks or lifts from the nail bed. The skin would be smooth, velvety, warm, and moist. The patient would likely have lid lag. The pulse would probably be fast and the systolic blood pressure would be elevated. However, there are some physical findings that are sometimes seen with endogenous thyrotoxicosis that you would not find in this patient. For example, you would not expect this patient to have a goiter. Since TSH is suppressed and TSH is a trophic hormone (means promote growth) for thyroid, the thyroid gland shrinks in size. You would also not expect to see those findings that are only present in patients with Graves' disease, such as proptosis and pretibial myxedema.
10. Again referring to her reading on the internet, his wife asks whether her husband is diabetic and needs insulin. You remind her that diabetic patients have high glucose levels that could require the use of insulin to regulate and lower the glucose levels. You later investigate the role between glucose and insulin. Do the levels of serum insulin and glucagon change in a normal person having hypoglycemia? How does measuring the level of serum insulin help in determining the cause of hypoglycemia?
Ideal Answer: If a person with normal physiology becomes hypoglycemic after fasting, the insulin levels are suppressed and the glucagon levels are elevated. This subsequently suppresses glycogenesis, and increases glycogenolysis and gluconeogenesis. In other words, the metabolism starts producing available energy and stops storing energy. However, if a person with hypoglycemia has a normal or elevated serum insulin level, then an abnormality in insulin regulation has occurred. Additional Information: One cause of hypoglycemia is an excess secretion of insulin. For example, pancreatic islet cell tumors called insulinomas can secrete unregulated insulin and suppress the glucose level. However, the most common cause of hypoglycemia with a normal or high serum insulin level is excess treatment with injected insulin or ingested sulphonylurea in a patient with diabetes mellitus. (Note to student: metabolism will be taught as part of the Block 3 curriculum. You only need to know the basics for this SEQ).
Compare and contrast the developmental defects in gastroschisis and omphalocele. In your answer, relate both anomalies to normal mid-gut development.
Ideal Answer: In gastroschisis, midgut herniation, rotation and retraction occurs normally, then the midgut herniates through a rupture of the body wall. In omphalocele, the retraction of the midgut fails, and the midgut persists outside the abdomen after 11 weeks. In omphalocele, the herniated midgut normally remains closely covered by the amnion.
In particular, how might a serum thyroglobulin level help to identify why the patient was thyrotoxic?
Ideal Answer: The above process would leave you with a differential diagnosis that only included thyrotoxicosis factitia and painless thyroiditis. In painless thyroiditis the thyroid gland is being attacked by the immune system. Thyroid follicular cells are being destroyed and thyroid follicles are disrupted. Thyroid hormone and other contents of the thyroid follicles are released from the damaged follicles. Follicular contents are therefore being released into the blood stream. Since the thyroid follicular cells synthesize thyroid hormone by starting with a large protein called "thyroglobulin," it stands to reason that there would be a lot of thyroglobulin in the blood stream in a patient with painless thyroiditis. On the other hand, in thyrotoxicosis factitia the thyroid is not being stimulated by TSH. Therefore the thyroid is inactive. Serum thyroglobulin levels would therefore be low. Additional Information: This is how a serum thyroglobulin level would finally help you determine that the patient had thyrotoxicosis factitia from excessive T3 ingestion rather than painless thyroiditis. Also, one would expect both the free T4 and the free T3 to be elevated in painless thyroiditis, since both of these thyroid hormones would be leaking from the thyroid gland.
1-4After finding out the result of the radioactive iodine uptake and scan, what features in the patient's history, physical examination, and laboratory testing might help narrow the differential diagnosis (i.e. What are the possible diagnoses?) to enable you to figure out why the patient was thyrotoxic? Explain your answers
Ideal Answer: The differential diagnosis of thyrotoxicosis with a low radioactive iodine uptake in the thyroid includes:1) painless thyroiditis, 2) subacute thyroiditis, 3) iodine-induced thyrotoxicosis, 4) thyrotoxicosis factitia, Additional Information: Struma ovarii and widely metastatic well-differentiated thyroid cancer: Struma ovarii is an ovarian dermoid tumor containing thyroid tissue. You can rule this out during the radioactive iodine scan by looking to see if there is any abnormal area of radioactive iodine uptake in the patient's pelvis. Likewise, the radioactive iodine uptake in the neck would be very low in patients with widely metastatic differentiated thyroid cancer, but you would expect to see abnormal uptake in the lungs or bones. Iodine-induced thyrotoxicosis could be ruled out by eliciting a negative history for ingestion of iodine containing drugs like amiodarone or recent exposure to x-ray contrast dye (which contains iodine). In addition, a 24-hour urine iodine level that was not elevated would also rule out iodine-induced thyrotoxicosis. Painless thyroditis and thyrotoxicosis factitia cannot be ruled out without further testing. See below. In subacute thyroiditis the thyroid gland is typically enlarged, painful, and tender. The absence of an enlarged, painful, tender thyroid gland would make subacute thyroiditis unlikely.
You take a complete history and perform a physical exam, noting that Daniel does not have skin hyperpigmentation. What other signs and symptoms might he have during the history and physical? Why is skin hyperpigmentation, which is a finding in patients with primary adrenal insufficiency, not found in Daniel?
Ideal Answer: The patient may have symptoms such as lethargy, easy fatigability, anorexia, orthostatic dizziness, myalgias and arthralgias. The physical examination would reveal an orthostatic drop in the blood pressure and rise in the pulse, suggesting hypovolemia. The patient would not be hyperpigmented because he has hypothalamic or secondary form of adrenal insufficiency. The levels of ACTH would be low in hypothalamic adrenal insufficiency, because the hypothamalo-pituitary-adrenal (HAP) axis is suppressed. In primary adrenal insufficiency, which could be caused by destruction of the adrenal glands, the lack of glucocorticoid production leads to an absence of negative feedback on ACTH secretion and a rise in serum ACTH. The elevated ACTH can cause skin hyperpigmentation.
What other abnormal laboratory tests (related to hemoglobin, white cells and blood chemistry) might you expect in a patient with isolated ACTH deficiency?
Ideal Answer: The patient would be expected to have many of the typical laboratory abnormalities seen in chronic adrenal insufficiency. This would include a low serum sodium concentration, a mild anemia, and an increase in certain white blood cells called "eosinophils". The blood sugars might also be low. Additional Information: The acidosis and high potassium levels seen in primary adrenal insufficiency are caused by loss of another adrenal hormone, aldosterone. ("Primary" adrenal insufficiency is caused by destruction of the adrenal glands themselves.) In secondary adrenal insufficiency, aldosterone secretion is normal. ("Secondary" adrenal insufficiency is caused by dysfunction of the corticotroph cells in the pituitary gland.) For this reason, acid and potassium levels are normal in secondary adrenal insufficiency.
2. Compare and contrast type 1 and type 2 diabetes mellitus with regard to the symptoms that are seen when the disease first develops.
Ideal Answer: The symptoms of type 1 and type 2 diabetes mellitus are the same. They are simply the symptoms of a high blood sugar: polyuria, polydipsia, blurred vision, and fatigue. Weight loss is a feature in the presentation of most type 1 diabetics and some type 2 diabetics, but this is simply a reflection of the severity of the insulin deficiency. In general, symptoms tend to present more explosively in type 1 than in type 2 diabetes mellitus. One other distinguishing feature in the mode of presentation is that patients with type 1 diabetes mellitus frequently present in a severe state of metabolic derangement called "diabetic ketoacidosis" due to the increased hepatic synthesis of ketoacids brought on by absolute insulin deficiency. Additional Information: Often it is possible to state with some certainty how long the symptoms have been going on in type 1 diabetes mellitus. Type 2 diabetes mellitus can have a much more insidious onset and it is often difficult to say exactly when the symptoms began. The symptoms in type 2 diabetes mellitus may also have been present for a much longer period of time than in type 1 at the time of diagnosis. Type 2 diabetics are rarely in a crisis situation from their high blood sugar when the diagnosis is first made.
Because Ms. Long's child has an abdominal wall defect, he or she will be at an increased risk for future abdominal wall injuries - namely, ventral hernias. What are the two major types of hernias that occur in the region of the groin? How are they differentiated? Which is most common in a previously healthy male and which in a female? What are the deep and superficial inguinal rings?
Ideal Answer: The two most common types of groin hernias are inguinal hernias and femoral hernias. Protrusion of abdominal contents through the anterior abdominal wall inferiorly may occur through the inguinal canal or through the femoral canal. The inguinal canal permits structures to pass between the abdominopelvic cavity and the scrotum/labium majorum; the femoral canal allows structures to pass between the abdominopelvic cavity and the thigh. Inguinal hernias occur above the inguinal ligament and femoral hernias occur below the inguinal ligament. Femoral hernias are always "acquired" hernias and constitute only about 4% of all groin hernias; they are more common in females. Inguinal hernias may be congenital (present at birth) or acquired and are more common in males, mainly because the descent of the testes creates a "larger" inguinal canal. The external iliac artery passes beneath the inguinal ligament to become the femoral artery and the femoral vein ascends behind the inguinal ligament to become the external iliac vein. As these vessels pass beneath the inguinal ligament they are invested in a somewhat tubular arrangement of fascia (derived from the transversalis fascia), only about 1.5 cm in length. This is known as the femoral sheath. Just medial to the sheath is the femoral canal, a potential space into which the femoral vein can expand when the venous return through it increases. The mouth (proximal end) of the femoral canal, just over 1 cm in diameter, represents a potential weakness through which a herniating portion of intestine/peritoneum can descend beneath the inguinal ligament and into the thigh. Femoral hernias occur through the femoral canal. A femoral hernia is particularly likely to obstruct and strangulate. The inguinal canal is a normal "defect" in the inferior portion of the anterolateral abdominal wall. It is created during development by the process of gonadal descent. It lies entirely above the inguinal ligament. The deep inguinal ring is at the lateral extremity of the canal and is the point of communication of the inguinal canal with the abdominopelvic cavity. The superficial inguinal ring is at the medial extent of the canal and is the point of communication of the inguinal canal with the scrotum/labium majorum. Inguinal hernias may protrude through either ring. Hernias can be extremely painful and carry risk for incarceration of the bowel. They are usually diagnosed with the help of imaging (CT, MRI, etc.) and most are ultimately treated with surgery.
5. Describe the histopathologic changes in the pancreas seen in patients with type 2 diabetes mellitus and compare this to the pathology seen in a patient with type 1 diabetes. Please identify the images in Figures 1, 2 and 3 as a pancreas tissue section from a normal patient, a type 1 diabetic patient, or a type 2 diabetic patient.
Ideal Answer: Type 1: Insulitis early, marked atrophy & fibrosis, B-cell depletion and Type 2: No insulitis, focal atrophy & amyloid deposits, mild B-cell depletion. Figure 1 shows Type II diabetes with amyloidosis, Figure 2 shows Normal Pancreas and Figure 3 shows Type I diabetes with insulitis. Additional Information: Pancreatic lesions in Type 1 and Type 2 diabetes depend on the stage of disease. In early Type 1 diabetes, leukocytic infiltration of the islets is present (insulitis). This is predominantly an infiltrate of T lymphocytes (CD 4+ T cells and CD 8+ cytotoxic T cells), reflective of the underlying autoimmune disorder. With time, there is beta cell depletion, atrophy and loss of islets. In Type 2 diabetes, the pathologic findings are subtle and nonspecific. Early in the disease course, the islets are essentially normal. As the disease progresses, there may be a subtle reduction in islet cell mass. Amyloid deposition appears as pink, amorphous material deposited in and around capillaries and between islet cells. At advanced stages, islets may be obliterated. Similar findings are present in nondiabetics, apparently part of normal aging.
6. Compare and contrast how environmental factors may influence the susceptibility in the development of Type 1 and Type 2 diabetes mellitus.
Ideal Answer:Although Type 1 diabetes is an autoimmune disorder with a genetic predisposition, there are indications that environmental factors play a role in the pathogenesis both in triggering and potentiating the destruction of pancreaticβ-cells. Some environmental factors may include geographic location (i.e. highest rate of incidence in Finland compared to other parts of Europe), a seasonal pattern during cold months - fall and winter, viral infections with research indicating that enterovirus is the likely trigger ofβ-cells autoimmunity, and the possibility that early exposure to cow's milk may boost the immune response to bovine insulin in infants. Type 2 diabetes risk factors include obesity, family history, reduced physical activity and aging, but there has been increasing evidence that environmental factors and epigenetics may play a role in the development of Type 2 diabetes. There remains some limits on the knowledge of factors related to environment/gene interaction but studies that have shown the association of environmental factors that may increase the risk for Type 2 diabetes include arsenic, air pollutants (particulate matter -PM-influencing epigenetic changes, including DNA methylation as well as up- or down-regulation of miRNAs) and endocrine-disrupting chemicals (EDCs) (dioxin, DDT and plasticizers such as bsiphenol-A and phthalates).
2. A second ultrasound showed a fetus with bowel outside the abdomen consistent with an omphalocele. In addition, the fetus was found to be large for gestational age. Should an amniocentesis be recommended for this patient? Why or why not?
Ideal Answer:An amniocentesis should be offered to this expectant mother. Fetuses with omphalocele are at an increased risk of having other malformations, and have a 30% risk of having a chromosome abnormality such as Trisomy 18. Amniocentesis could be performed and the sample sent for karyotype analysis to assess for chromosome abnormalities. Omphalocele may also be seen in connection with other conditions such as Beckwith-Wiedeman syndrome.
3. What course of action, if any, should be taken for each condition? If action should be taken describe why.
Ideal Answer:In 5-alpha-reductase deficiency, gender assignment will dictate course of treatment. If female gender is assigned, then gonadectomy is necessary to avoid neoplasia and virilization that is certain to appear at puberty. If a male gender is assigned with a possibility of a functional penis as an adult, then testosterone or dihydrotestosterone therapy should be considered. In androgen insensitivity syndrome, gonadectomy is performed after puberty, allowing growth to be completed since no virilization occurs and this allows for a slow transition into puberty. Since gonadal cancers happen much later in life (20-30's) gonadectomy can be delayed until growth is completed. In SRY deletion/mutation, gonadectomy is necessary to avoid neoplasia, and hormone replacement is necessary.
How would the above clinical scenario be different from a patient with isolated ACTH deficiency? What would you expect blood levels of cortisol (glucocorticoids) and ACTH (adrenocorticotrophic hormone) to be? What would you expect the levels of corticotropin releasing hormone (CRH) to be in the hypophyseal portal system?
Ideal Answer:In isolated ACTH deficiency, there is destruction of the pituitary corticotroph cells, so blood ACTH levels will be low. Because of the lack of ACTH stimulation on the cells of the adrenal cortical zona fasciculata there will be little cortisol secretion. Adrenal cortex would atrophy after sometime and blood cortisol levels will be low. Because of the lack of negative feedback inhibition from cortisol on the hypothalamus, CRH levels in the hypophyseal portal system will be elevated. ACTH also exerts a "short loop" feedback inhibition on CRH secretion, so the absence of ACTH is another reason for the increased CRH levels in the hypophyseal portal system. So in isolate ACTH deficiency, CRH level would be high; it would be suppressed when hypothalamus is suppressed by exogenous steroid intake.
At birth, the infant was noted to have an enlarged tongue. Over time, it was noted that the infant's growth rate was greater than normal, and he had hemihyperplasia (asymmetric overgrowth). Genetic testing revealed that the infant was mosaic for a duplicate paternal segment of 11p15 (without a maternal copy), confirming a diagnosis of Beckwith-Wiedeman syndrome. Define mosaicism and speculate how genetic mosaicism may be related to hemihyperplasia.
Ideal Answer:Mosaicism is defined as the occurrence of two or more cell lines with different genetic or chromosomal constitutions in a single individual or tissue. Thus, for this infant, one cell line should have a normal male karyotype (46,XY), and the other cell line showing 11p15 duplication. The body part which exhibit hyperplasia or enlargement might have more cells with the 11p15 duplication than tissues that appear to have normal growth. For example, the cell line with the 11p15 duplication might be in the growth plates of the bones in an enlarged limb, and the normal limb might have normal karyotype.
What would a radioactive iodine uptake and radioactive iodine scan reveal?
Ideal Answer:Since the thyroid gland is inactive when it is not exposed to thyroid stimulating hormone, and iodine uptake by thyroid gland is TSH dependent, the radioactive iodine uptake will be very low. The thyroid scan would show homogeneous but barely detectable uptake in the thyroid gland.
3. Compare and contrast type 1 and type 2 diabetes mellitus with regard to how the diagnosis is made.
Ideal Answer:The diagnosis of diabetes is made in the same way whether you are talking about type 1 or type 2. There are four criteria for making a diagnosis of diabetes mellitus. These are: (1) A random plasma glucose ≥ 200mg/dL plus typical symptoms of diabetes; (2) A fasting plasma glucose ≥ 126mg/dL; (3) A 75 gm oral glucose tolerance test in which the 2 hour blood sugar is ≥ 200mg/dL; (4) A hemoglobin A1c > 6.5%. In the absence of hyperglycemic symptoms, an abnormal plasma glucose is repeated to confirm the diagnosis.
9. The patient is concerned about his shaking and jittery spells. You explain to him the normal response to low glucose levels and how it can cause his symptoms. In your answer, list the normal hormonal response to hypoglycemia and discuss how this response causes his symptoms.
Ideal Answer:The hormones secreted in response to hypoglycemia are called "counter-regulatory" hormones. The first or immediate hormone response is an increase in serum epinephrine and glucagon levels. A delayed response is seen in increased level of serum cortisol and serum growth hormone. All these hormones act to increase blood glucose levels and thus "counter" and correct the occurrence of hypoglycemia. The symptoms of hypoglycemia are therefore broadly classified as adrenergic and neurologic. The adrenergic symptoms occur as a result of increase in adrenergic hormone epinephrine. Symptoms include palpitation, hunger, increased sweating and shakiness. These symptoms serve as warning to the individual that the blood glucose is too low and therefore the individual should eat something. The neurogenic symptoms or neuroglycopenic symptoms can result if the hypoglycemia persists which deprives the central nervous system of glucose. These symptoms include headache, slow response, drowsiness, confusion and coma.
Describe normal mid-gut herniation, rotation and retraction during embryonic development. In your description, include the germ layer origins of the cells of the mid-gut, and the gestational age at the major steps.
Ideal Answer:The midgut lining is derived from the endoderm, the midgut smooth muscle and connective tissue derive from the splanchnic mesoderm and the enteric nervous system derives from the neural crest. At 6 weeks, a midgut loop herniates into the umbilicus. From 7 to 9 weeks the midgut undergoes a ninety degree rotation and at 10 weeks the midgut retracts into the abdomen.
4. Compare and contrast type 1 and type 2 diabetes mellitus with regard to treatment.
Ideal Answer:The treatment of type 1 diabetes mellitus always includes insulin. With type 2 diabetes, however, there are more options. One can elect to treat type 2 diabetes mellitus either by decreasing the insulin resistance or by increasing the amount of insulin in the body. Insulin resistance can be decreased non-pharmacologically by a combination of weight loss and regular exercise. Insulin resistance can also be decreased by the use of the drug metformin, and drugs of the glitazone class such as pioglitazone and rosiglitazone. The amount of insulin in the body can be increased by taking drugs of the sulfonylurea and meglitinide class (which stimulate the pancreas to secrete more insulin), by injections of exenatide (which also stimulates the pancreas to secrete more insulin, as well as having other hypoglycemic actions), by DDP-4 inhibitor sitagliptin (increases the action of GLP1) or by injections of insulin itself. Another class of medications, SGLT-2 inhibitors, decrease plasma glucose by increasing glucose excretion in urine.
What is causing his symptoms?
Ideal Answer:These symptoms suggest presence of secondary adrenal insufficiency, resulting from the suppression of hypothamalo-pituitary-adrenal (HAP) axis from chronic steroid use. Since there was exogenous steroid intake by the patient, it would suppress the secretion of corticotropin releasing hormone (CRH) from the hypothalamus and ACTH from the pituitary. The patient's own adrenal glands would become atrophic. So when the patient stops exogenous steroid, the adrenal gland is not able to make glucocorticoid, and this results in adrenal insufficiency.
You find a 2003 paper that describes 93 infants with an omphalocele and abnormal karyotypes all with a partial trisomy of chromsome 3q. The authors suggest a hypothesis for the genetics of the developmental defect. From your knowledge of chromosome structure and function, propose a general mechanism that explains the potential association of omphalocele to chromosome 3q. (Yatsenko SA, Mendoza-Londono R, Belmont JW, Shaffer LG. Omphalocele in trisomy 3q: further delineation of phenotype. Clin Genet. 2003 Nov;64(5):404-13)
Ideal Answer:This study discusses an association between omphaocele and a specific karyotype abnormality of the long arm of chromosome 3. This is a type of aneuploidy, which refers to the addition or loss of a part or an entire chromosome. Thus, the infants in the study all have a trisomic region of chromosome 3. If each of the three alleles in the trisomic region is normally expressed, the amount of protein product is increased, which may disrupt the normal regulatory mechanisms important during mid-gut formation. Alternatively, the trisomic region may harbor a single gene, that when over expressed may cause the phenotype. Further mapping and correlative studies will need to be done before any of these hypotheses are proved to be correct.
MY answer
In T1DM, once about 80-90% of beta cells are destroyed, symptoms appear suddenly. In T2DM, the disease occurs gradually over time and the adult may be asymptomatic. Classic symptoms of type 1 and 2 diabetes are polyuria, (increased urination), polydipsia (increased thirst), and polyphagia (increased hunger). Late symptoms are microvascular complications such as retinopathy, nephropathy, and neuropathy. Other late symptoms are macrovascular complications such as stroke and cardiovascular disease.
My answer
In type 1 DM, the patient needs insulin therapy. In type 2 DM there may be stages to treatment depending on how severe their disease has progressed (prediabetes vs diabetes). Treatment in type 2 may begin with lifestyle changes and monitoring, followed by oral antidiabetic drugs, and then insulin therapy
W4 SEQ Vignette 1
Jennifer Jones is a 28-year-old woman who is 16 weeks pregnant. Her obstetrician requested an ultrasound examination to evaluate her baby because on examination her uterus was larger than would have been expected based on her last menstrual period. The ultrasound examination revealed a normal female fetus with no congenital anomalies. Since Ms. Jones has two cousins with Down syndrome, she felt very strongly about having an amniocentesis to exclude the possibility of Down syndrome in this pregnancy. An amniocentesis was done at the time of the ultrasound. Approximately two weeks later she received a call from her obstetrician, congratulating her that the baby had a normal male karyotype. This immediately triggered some confusion since she was told previously that she was going to have a baby girl. In fact, she had already picked a name for her. A repeat ultrasound was immediately arranged, now at 20 weeks gestation. After a very detailed examination, the ultrasonographer continued to report a normal female intrauterine gestation based on a detailed ultrasound visualization of the external genitalia. Ms. Jones' family history was explored in more detail. She has a brother who was born with hypospadias which was surgically corrected.
Week 5 SEQs Vignette 1
Karen Long is a 32-year-old G1P0 woman, who presented for prenatal care. She had no significant past medical history. She underwent a dating ultrasound and gestational age was determined to be 8 weeks and 1 day. The fetal cord insertion appeared slightly thickened with bowel extending 8mm into the cord. The patient declined first trimester screening for fetal trisomies, but did desire screening for neural tube defects, so an AFP was performed at 16 weeks gestation. The AFP returned at 4.2 MOM.
my answer
Mosaicism is a genetic abnormality that occurs during mitosis in early stages of embryogenesis leading two different cell populations: one that is normal and one that carries an mutation or genetic abnormality. This may manifest as hemihyperlasia when one side of the body receives the normal cell line and the other side of the body may receive the mutated cell line that results in overgrowth and enlargement of bones and tissues on that side.
W3 SEQ - Vignette 1
T3 (tri-iodothyronine) is available commercially under the brand name "Cytomel." Occasionally a patient will present to an endocrinologist with a puzzling form of thyrotoxicosis that turns out to be due to the patient's secret ingestion of excessive amounts of thyroid hormone pills. This is a psychiatric illness. The patient takes the excessive thyroid hormone for the secondary gain of having people worry over them and take care of them because they are sick. It is called "thyrotoxicosis factitia."
my answer
Two major types of groin hernias are inguinal and femoral. An inguinal hernia is a protrusion of intra-abdominal contents through the deep (internal) inguinal ring, superficial (external) inguinal ring, and into the scrotum (called indirect inguinal hernia). Or an inguinal hernia could be protrusion through the peritoneum and into the superficial/external inguinal ring (called indirect direct inguinal hernia). These are most common in males. Direct inguinal hernias are usually due to structural weakness in the transversalis fascia whereas indirect inguinal hernia is usually noticed when the patient is a baby and it is due to failure of the processus vaginalis to close properly. A femoral hernia is due to protrusion of intra-abdominal contents through the femoral ring in the femoral canal. It is more common in females. However, inguinal hernias are more common overall with femoral hernias representing just 5% of all hernia cases.
My answer
Type 1 DM is associated with autoimmune destruction of Beta cells in the pancreas. Type 1 DM is associated with an individual being positive for human leukocyte antigen. In contrast, type 2 DM has a strong hereditary and genetic component and is associated with metabolic syndrome, obesity, and a sedentary lifestyle. T2DM is a product of insulin resistance combined with the eventual reduction in the function of the pancreatic beta cells. At first the beta cells produce more insulin to try to compensate for consistently high blood glucose levels. But over time, they become overworked and beta cell function is lost. In both types of diabetes, blood glucose levels are high due to insufficient presence of insulin
1. Compare and contrast type 1 and type 2 diabetes mellitus with regard to etiology.
Type 1 diabetes mellitus is an autoimmune disorder in which the body's own immune system attacks and destroys the beta cells in the islets of Langerhans in the pancreas. These are the cells that make insulin. It appears that an individual inherits a genetic predisposition toward developing this autoimmune attack on the beta cells, which is then triggered by something in the environment. The etiology of type 2 diabetes mellitus is much less clear. It appears to begin with the development of insulin resistance that gradually gets worse and worse. Initially the pancreas is able to overcome this insulin resistance by simply making more insulin. Additional Information: The best candidate available for this trigger right now is a viral infection of the pancreas. Such an infection might trigger an autoimmune attack either by releasing individual islet cell proteins that can then serve as antigens or by making proteins that cross react with normal islet cell constituents, thus stimulating an immune response against self antigens. As time goes on, the pancreas falls behind. Although it is often making supra-physiologic amounts of insulin, it still does not make enough insulin to overcome the insulin resistance. The exact cause of the insulin resistance and the reason why the pancreas cannot make more insulin and overcome the insulin resistance indefinitely is not known.
My answer
Type 1 is associated with onset during childhood whereas type 2 is associated with adult onset and the individual may have other concurrent medical conditions such as sedentary lifestyle, obesity, hypertension, or an immediate family member with the disease. To diagnose diabetes, a single random blood sample can be taken. If it is over 200mg/dl it is indicative of DM. The clinician should also run additional tests such as HbA1C, urine analysis, anti-GAD, and C-peptide. C peptide will indicate how much insulin is being produced by the body and anti-GAD will determine if there are antibodies to insulin. Both of these tests will help specifically narrow it down to T1DM.