Medical Physiology: Principles for Clinical Medicine, 3e Ancillary Case Studies Page 1 of 21

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Part IX

Endocrine Physiology

Case 9.1 Growth Hormone Deficiency

A 6-year-old boy is brought to the endocrine clinic to be evaluated for growth hormone (GH)

deficiency. The boy’s height is between 2 to 3 standard deviations below the average height for

his age. Initial physical examination rules out head trauma, chronic illness, and malnutrition.

Family history does not suggest similar short stature in immediate relatives. Thyroid hormones

are normal.

Questions

1. Why would you order a blood test for levels of IGFBP3 and IGF-1?

2. The levels of IGFBP3 and IGF-1 are below the normal range in your patient. What does

this finding suggest?

3. What is GH resistance, and what test would you order to rule out that the patient does not

have this syndrome?

4. Why is it important to treat GH deficiency and short stature prior to the onset of puberty?

5. Why is resistance to insulin action a potential side effect of giving extremely high

pharmacologic doses of GH for long periods of time?

Answers

1. GH is released in a pulsatile manner, and between pulses of GH secretion, the

concentration in the blood may be undetectable in normal individuals. GH induces the synthesis

and secretion of IGF-1 and IGFBP3, both of which are easily detectable in the serum. Low IGF-1

and IGFBP3 would indicate insufficient GH secretion.

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2. GH stimulates the synthesis and secretion of IGF-1 and IGFBP3. In most cases, low

levels of these molecules in the blood would indicate insufficient GH release. However, low

levels of IGF-1 and IGFBP3 could also be a result of a defect in the GH receptor resulting in GH

resistance.

3. GH resistance is characterized by impaired growth resulting from low levels of IGF-1

and IGFBP3 in the blood. However, the concentration of GH in the blood is high. Defects in the

GH receptor, which prevent GH from stimulating the production of IGF-1 and IGFBP3, are a

common cause of GH resistance. Measurement of a GH in the blood should detect the extremely

high levels of the hormone to confirm diagnosis.

4. GH and IGF-1 stimulate the epiphyseal growth plate of the long bones to grow. The

epiphyseal plate fuses several years after puberty, at which time GH and IGF-1 can no longer

stimulate the growth of the bone. Therefore, the earlier GH therapy is initiated, the greater

chance of achieving normal adult height before long bone growth stops.

5. GH has diabetogenic actions that oppose the actions of insulin. Thus, chronic, high doses

of GH can impair the actions of insulin. Insulin resistance is a condition in which tissues in the

body do not respond well to insulin.

Reference

Reiter EO, Rosenfeld RG. Normal and aberrant growth. In: Larson PR, Kronenberg HM,

Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th Ed. Philadelphia:

Saunders, 2003.

Case 9.2: Hypothalamic Diabetes Insipidus

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A 7-year-old girl is seen by her pediatrician because she has started “wetting the bed” at night.

Her mother explains that this has been going on now for several weeks and that she has tried to

limit fluid intake after dinner, but that her daughter complains of constant thirst. The mother

notes that her daughter usually consumes a half-liter or more of soda after dinner. Upon physical

examination it is noted that the girl is at the 95th percentile for weight. The patient has normal

serum sodium levels and does not exhibit signs of dehydration. Family history indicates that both

maternal grandparents have type 2 diabetes mellitus.

Questions

1. What are two possible initial diagnoses for this patient?

2. What clinical finding can easily rule out one of the two initial diagnoses?

3. Why is the serum sodium level normal and there are no signs of dehydration despite the

polyuria?

4. A dehydration test followed by administration of vasopressin or its analogue

desmopressin is performed. To perform this test, the weight of the patient is obtained and serum

sodium is determined. The subject is allowed no fluid intake. Voided urine is recorded and

osmolality determined. When the subject has lost 2% of the body weight, a plasma sample is

taken for quantitation of sodium, osmolality, and vasopressin. The patient then receives an

injection of vasopressin or desmopressin. If the subject has severe hypothalamic diabetes

mellitus, what would you expect the urine osmolality to be when the subject has lost 2% body

weight? What will urine osmolality be following injection of vasopressin?

5. At the end of the dehydration test in a subject with nephrogenic diabetes insipidus, urine

osmolality will not be increased. What distinguishing feature allows the differentiation of

nephrogenic from hypothalamic diabetes insipidus?

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6. In addition to diagnosing and treating this girl’s diabetes insipidus, what other

recommendations should you make?

Answers

1. The child presents with polyuria, which can be indicative of diabetes insipidus or diabetes

mellitus. The fact that the child is at the 95th percentile for weight indicates that she is obese.

Type 2 diabetes mellitus is increasingly common in obese children.

2. Polyuria can be the result of glucose excretion in patients with type 2 diabetes mellitus

resulting from hyperglycemia. Absence of glucose in the urine indicates that the polyuria is

probably not resulting from an osmotic effect of glucose resulting from diabetes mellitus. A

measurement of fasting blood glucose in the normal range also rules out diabetes mellitus.

3. If the patient is ambulatory and the thirst mechanism is intact, sufficient fluid intake will

maintain normal sodium and prevent dehydration.

4. A dehydration test is performed because fluid intake must be limited to diagnose diabetes

insipidus. When the subject has lost 2% body weight, urine osmolality will not be different or

only slightly higher than that obtained at baseline. Following vasopressin administration, urine

osmolality will increase a minimum of 50% and often up to 200% to 400%.

5. At the end of the dehydration test the subject with hypothalamic diabetes insipidus will

have undetectable to low levels of serum vasopressin. Subjects with nephrogenic diabetes

insipidus will have high levels of serum vasopressin with dehydration.

6. The patient is extremely obese and should be counseled on a proper diet and exercise

plan. In particular, the patient should be encouraged to reduce the amount of soda consumption.

Reference
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Robinson AG, Verbalis JG. Posterior pituitary. In: Larson PR, Kronenberg HM, Melmed S,

Polonsky KS, eds. Williams Textbook of Endocrinology. 10th Ed. Philadelphia: Saunders, 2003.

Case 9.3: Thyrotoxicosis

A 35-year-old woman is seen in the endocrine clinic for evaluation of thyroid disease. The

patient complains of weight loss, irritability, and restlessness. Physical examination reveals

enlargement of the thyroid gland, weakness in maintaining the leg in an extended position, warm

moist skin, and tachycardia. Family history identifies the patient’s mother as exhibiting

hypothyroidism after the birth of the patient’s brother and an aunt with Hashimoto disease.

Questions

1. Based on the history and physical examination, what would be a reasonable initial

diagnosis?

2. From a blood sample, what hormone concentrations would you ask the laboratory to

measure and what would you expect the results to be?

3. What antibody titers would you request the laboratory to determine? Which antibody titer

is the most useful in the diagnosis of Graves disease?

4. What would an increase in antibodies to thyroid peroxidase (TPO) indicate?

5. The antibody titers indicate that the patient has Graves disease. What treatment would be

appropriate for this patient?

Answers

1. The physical findings including the presence of goiter suggest that the patient may be

hyperthyroid. However, goiter can also occur in hypothyroidism. Because autoimmune thyroid

disease “runs in families,” the family history of postpartum thyroiditis suggests that the
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thyroiditis might be resulting from an autoimmune response. The patient may have Graves

disease.

2. The laboratory should determine the levels of thyroid hormone (T4 and T3) and thyroid-

stimulating hormone (TSH). Thyroid hormones should be increased. TSH may be increased if it

is early in the progression of Hashimoto disease or decreased if the patient has Graves disease.

3. Antibodies to TSH receptor, thyroid peroxidase, and thyroglobulin can all be elevated in

Graves disease. However the presence of TSH receptor antibodies is diagnostic.

4. Antibodies to thyroid peroxidase (TPO) are elevated to the greatest extent in Hashimoto

disease.

5. A thionmide compound should first be used to inhibit thyroid hormone synthesis. This

treatment will relieve the symptoms of hyperthyroidism and may result in a reduction in immune

response. The drug may be withdrawn after several months of treatment to determine if the

disease is in remission. If thyroid hormones increase with cessation of the drug, surgical

intervention to remove the thyroid would be indicated.

References

Davies TF, Larson PR. Thyrotoxicosis. In: Larson PR, Kronenberg HM, Melmed S, Polonsky

KS, eds. Williams Textbook of Endocrinology. 10th Ed. Philadelphia: Saunders, 2003.

Larson PR, Davies TF, Schlumberg M-J, Hay ID. Thyroid physiology and diagnostic evaluation

of patients with thyroid disorders. In: Larson PR, Kronenberg HM, Melmed S, Polonsky KS, eds.

Williams Textbook of Endocrinology. 10th Ed. Philadelphia: Saunders, 2003.

Case 9.4: Hypothyroidism

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A 55-year-old male construction worker is seen by his family practice physician in December

complaining of fatigue, weight gain, and poor appetite. The patient comments that he is always

cold when working outside and that this has never been a problem before. He has also noticed

that small cuts on his hands seem to take a long time to heal. Physical examination reveals that

the patient is obese, with a body mass index (BMI) of 35 kg/m2. Skin is dry, hair is course,

complexion is sallow (pale yellowish), and heart rate is slow. The physician suspects

hypothyroidism.

Questions

1. What laboratory tests should be ordered to support a diagnosis of hypothyroidism, and

what would be the expected finding?

2. The blood work indicates an elevated thyroid-stimulating hormone (TSH) with reduced

free T4. What is the most likely cause of such a finding, and what test should be ordered to

confirm the diagnosis?

3. Thyroid peroxidase (TPO) antibodies results come back negative, ruling out a diagnosis

of Hashimoto disease. The patient is referred to an endocrinologist who, after confirming the

laboratory findings, suggests that this may be a case of postviral thyroiditis, which is often

transient. The endocrinologist prescribes replacement therapy with levothyroxine (T4). What

physical and biochemical changes can be expected with this treatment?

4. What is the physiologic advantage to treatment with levothyroxine (T4)?

5. At 4 months following initiation of treatment, the endocrinologist reduces the

levothyroxine dose by 50% and asks the patient to return in 6 weeks to check his TSH levels.

What is the expected TSH level at 6 weeks following the reduction in therapy if the diagnosis of

transient postviral thyroiditis is correct and why?

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Answers

1. TSH levels should be measured. In 99% of patients with hypothyroidism there is a

significant increase in basal TSH with reduced T4 levels.

2. The most likely cause of hypothyroidism is Hashimoto disease; therefore, antibodies to

thyroid peroxidase (TPO) should be evaluated. A positive finding would support a diagnosis of

Hashimoto disease.

3. The patient should begin to feel better overall; heart rate will return to normal, as will

appetite and skin. The patient may lose a little weight. TSH levels should be reduced if the

patient is compliant with treatment.

4. By providing therapy with T4, the peripheral deiodination mechanisms can provide the

amount of T3 required under physiologic control for each tissue. Thus hormone replacement

therapy in this way replicates the natural state.

5. If the patient had postviral thyroiditis, TSH levels would be normal when measured 6

weeks after the reduction in levothyroxine therapy. This is because the function of the thyroid

gland has recovered and it is secreting T. Thus with sufficient T there is no stimulus to increase

TSH release. If TSH is elevated, then the patient has a permanent hypothyroidism (antibodies

and other tests can be re-evaluated), but levothyroxine therapy must be continued and increased

to appropriate levels.

Reference

Larson PR, Davies TF. Hypothyroidism and thyroiditis. In: Larson PR, Kronenberg HM,

Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th Ed. Philadelphia:

Saunders, 2003.
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Case 9.5: Congenital Adrenal Hyperplasia

The pediatric endocrinologist is called in to consult on the case of a 1-week-old female neonate.

The baby was born at home and is now being seen in the emergency room because she appears

listless and has not nursed at all during the last 24 hours. The parents report that the baby has

become increasing listless and less willing to nurse since birth. Upon physical examination the

baby exhibits signs of virilization (growth of pubic hair) and hyponatremia (low plasma sodium),

hyperkalemia (high plasma potassium), and volume depletion.

Questions

1. Based on the physical examination, history, and what you know about adrenal

steroidogenesis, what would be a reasonable initial hypothesis?

2. What are the two most likely congenital defects in adrenal steroidogenic enzymes that

could explain the findings in this child?

3. From a blood sample, what hormones and metabolites would you ask the laboratory to

measure and what would you expect the results to be?

4. From the hormone and metabolite analysis, how would you distinguish between the two

most likely causes for this case of congenital adrenal hyperplasia?

5. A genetic screen using DNA from the baby’s white cells identifies an inactivating

mutation in the gene (CYP21A2) for 21-hydroxylase. What would be appropriate hormone

replacement for this patient?

Answers

1. A reasonable initial hypothesis is that the baby has a form of congenital adrenal

hyperplasia. The virilization (appearance of pubic hair) suggests the presence of excess androgen

production by the adrenal gland. The hyponatremia, hyperkalemia, and volume depletion suggest
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a “salt wasting” syndrome.

2. Mutations in CYP21A2, which encodes 21-hydroxylase, account for more than 90% of all

cases of adrenal hyperplasia associated with excess androgen production. Mutations in

CYP11B1, which encodes 11B-hydroxylase, would also result in excess adrenal androgen

production.

3. Adrenal androgens would be significantly elevated in patients with virilizing forms of

congenital adrenal hyperplasia. Adrenal hyperplasia is usually a result of defects in cortisol

production. Therefore, the serum concentrations of precursors of cortisol biosynthesis such as

progesterone, 17α-hydroxyprogesterone, and 11-deoxycortisol could be elevated. In addition,

serum adrenocorticotropic hormone (ACTH) would be elevated as a result of the lack of negative

feedback from the absent cortisol.

4. Genetic defects in the gene for 11B-hydroxylase resulting in a reduction in the activity of

this enzyme would result in increased 11-deoxycortisol. Defects in the gene for 21-hydroxylase,

which impairs the activity of the enzyme, would not lead to the production of 11-deoxycortisol.

Because 11-deoxycortisol has significant mineralocorticoid activity, excess production of this

steroid is usually associated with hypertension, rather than volume depletion and hypotension as

is observed in this patient.

5. Treatment would be directed toward replacement of glucocorticoids and

mineralocorticoids. Glucocorticoids would replace the missing cortisol and also suppress ACTH

secretion. With less ACTH stimulation of steroid production from the adrenal gland, the

hyperandrogenism should be reduced. Mineralocorticoids are given to treat the “salt wasting,”

which occurs in the absence of aldosterone.

Reference
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Stewart PM. The adrenal cortex. In: Larson PR, Kronenberg HM, Melmed S, Polonsky KS, eds.

Williams Textbook of Endocrinology. 10th Ed. Philadelphia: Saunders, 2003.

Case 9.6: Endocrine Hypertension

A 45-year-old man is seen by his physician because during the past week he has experienced

severe headaches with palpitations and sweating. The patient also reports that he occasionally

feels lightheaded when he stands up quickly. Upon physical examination the patient has a body

mass index of 45 kg/m2, heart rate is increased (82 beats/min), and blood pressure is 160/95 mm

Hg. The doctor orders a 24-hour urine collection and blood work for suspicion of

pheochromocytoma.

Questions

1. What is a pheochromocytoma and what symptoms support the initial diagnosis?

2. What measure in the urine or blood supports a diagnosis of pheochromocytoma? What is

the potential advantage of a 24-hour urine collection for this measure?

3. The amount of urinary metanephrine (a catecholamine metabolite) in the 24-hour urine

collection is at the high limit of normal (two to three times normal is diagnostic for

pheochromocytoma). The patient is referred to an endocrinologist, and after evaluation of the

previous clinical workup, a clonidine suppression test and glucagon stimulation test are ordered.

Clonidine is a centrally acting α2-adrenoreceptor agonist that suppresses release of

catecholamines from neurons but not from neoplasm. Glucagon stimulates release of

catecholamines. If the patient has a pheochromocytoma, what is the expected outcome of the

dynamic testing with clonidine and glucagon?

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4. Clonidine and glucagon testing are positive for pheochromocytoma. What testing should

now be ordered?

5. Two weeks following surgical removal of the pheochromocytoma, catecholamine levels

were normal but hypertension persisted. What possibilities could explain the persistent

hypertension?

Answers

1. Pheochromocytomas are tumors of neuroectodermal origin arising from chromaffin cells

of the adrenal gland. Tumors arising in paraganglia are termed extra-adrenal

pheochromocytomas. Patients with pheochromocytoma frequently present with a classic triad of

severe headaches, palpitations, and diaphoresis (sweating). Pheochromocytoma is a rare cause of

hypertension, estimated to occur in fewer than 1% of patients evaluated for hypertension.

2. Diagnosis of pheochromocytoma is made by demonstration of elevated urinary or

circulating catecholamines or their metabolites. Because catecholamines are secreted

episodically and have short half-lives, a random plasma measure may miss the peak

catecholamine level. The 24-hour urine collection thus provides an integration of catecholamine

release over time. Urinary catecholamines or metabolites two or three times the upper limit of

normal is considered diagnostic.

3. If the patient has a pheochromocytoma, suppression of plasma catecholamines will be

attenuated to approximately 50% compared with that in normal subjects. Glucagon stimulation

will result in an increase in catecholamine three times normal in subjects with

pheochromocytoma.
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4. After biochemical testing confirms the diagnosis of pheochromocytoma, a magnetic

resonance imaging or computed tomography scan to locate the tumor should be ordered.

Approximately 90% of pheochromocytomas originate within the adrenal gland.

5. The patient could harbor another pheochromocytoma or have metastatic disease and

should be evaluated to rule this out. Alternatively, the patient may have essential or primary

hypertension as a comorbidity of his obesity. A number of pharmacologic treatments for

essential hypertension are available. The patient should receive a diet and exercise plan to lose

weight and increase physical activity.

Reference

Dluhy RG, Lawrence JE, Williams GH. Endocrine hypertension. In: Larson PR, Kronenberg

HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 10th Ed. Philadelphia:

Saunders, 2003.

Case 9.7: Insulin and C-Peptide

An 8-year-old girl was diagnosed with type 1 diabetes. Nausea and vomiting, symptoms of

ketoacidosis, which is not uncommon, were accompanied by polyuria, polydipsia, polyphagia,

weight loss, and blurred vision. The patient’s parents also became concerned with changes in the

child’s mental status, ranging from slight drowsiness to profound lethargy. Upon visiting her

pediatrician, the patient had slipped into a diabetic coma and was admitted to the hospital.

Plasma glucose concentrations at presentation were elevated (620 mg/dL) and, consistent with

diabetic ketoacidosis, fluid and electrolyte measurements reflected the presence of acidosis.

Plasma insulin (5 mU/mL) and C-peptide (0.6 ng/mL) were reduced. The patient was placed on

an insulin pump and basal insulin rates and bolus meal dosages were determined. Following the
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hospital treatment, the patient and her parents worked closely with a health care team including a

physician, diabetes nurse educator, nutritionist, and other health care professionals as appropriate

to adjust insulin pump parameters to achieve blood glucose concentrations as close to normal as

possible. Data from her 1-year visit are as follows: fasting blood glucose was 120 mg/dL and C-

peptide was 0.1 ng/mL.

Questions

1. What might be the reason for the decrease in this girl’s C-peptide values after 1 year?

2. Why were the patient’s plasma insulin values not measured at the 1-year examination?

Answers

1. The decrease in C-peptide reflects further destruction of the patient’s insulin-producing

pancreatic beta cells and indicates a further impairment in her own insulin production capacity.

2. Because the patient is on an insulin pump, measurement of circulating insulin levels

would not have provided any information about insulin secretion. This information is inferred

from the C-peptide data.

Case 9.8: Recurrent Hypoglycemia

A 64-year-old man with a 15-year history of type 2 diabetes started to experience low back pain

and saw his family physician. His diabetes was well controlled with 35 units of insulin a day, and

he had had no hypoglycemic episodes in the past 2 years. He had no history of hypertension,

retinopathy, or nephropathy. He was compliant with his diet, insulin therapy, and exercise

program. He was prescribed a nonsteroidal anti-inflammatory drug, diclofenac, to manage the

pain, and his back pain improved.

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Two weeks later, he started to experience headache and irritability with periods of sweating. His

wife brought him to the emergency department on three occasions—16, 19, and 23 days after

starting diclofenac. He was noted to be hypoglycemic, with blood glucose concentrations of 1.2

to 2.5 mmol/L. At each visit his symptoms responded to intravenous glucose and feeding. No

investigations were done at his first two visits to the emergency department.

At his third visit, a physical examination taken after correction of hypoglycemia showed the

patient had developed a decline in renal function with a four-fold increase in serum creatinine

after starting diclofenac treatment. Diclofenac was immediately stopped, and his insulin dosage

was decreased. Two weeks later, his serum creatinine concentration returned to baseline and he

resumed his usual insulin dosage, with no further episodes of hypoglycemia and with reasonable

glucose control.

Questions

1. Why was the patient’s endocrine status influenced by diclofenac?

2. If renal function was not compromised, what might be considered?

Answers

1. The kidney plays an important role in endocrine status including glucose homoeostasis.

In addition to metabolizing between 30% and 40% of insulin, it provides up to 45% of

endogenous glucose through gluconeogenesis. In renal failure, it cannot metabolize insulin or

generate glucose, thereby increasing the risk of hypoglycemia. In the general population, the

frequency of acute renal failure from nonsteroidal anti-inflammatory drugs is not known but is

probably less than 1% a year.

2. For most hormones, the liver is quantitatively the most important site of degradation. So,

a liver abnormality might be a consideration. Hypoglycemia is a well-documented systemic

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effect that accompanies hepatoma. Although hypoglycemia as a sole presentation is rare, a case

of poorly differentiated hepatoma with multiple lung metastases presenting with recurrent

hypoglycemic seizures as the only manifestation 4 months before the diagnosis of the tumor has

been reported.

Case 9.9: Transient Neonatal Diabetes

A 21-day-old male infant was referred to a specialized children’s hospital for management of

hyperglycemia. Hyperglycemia had been noted on day one of life with an initial blood glucose

value of 16 mmol/L. At diagnosis, both the plasma immunoreactive insulin (IRI) and

immunoreactive glucagon (IRG) were below the reference range for normal neonates. The IRG,

but not the IRI, normalized within the first month. A regimen of daily insulin was begun.

Interestingly, from day 41 to day 47, the infant did not receive insulin and a crude control of the

blood glucose was demonstrated. Peak levels of blood glucose in excess of 20 mmol/L were

followed by drops to levels less than 2 mmol/L without insulin administration. However, because

of unsatisfactory glucose levels, administration of daily insulin was reintroduced. The infant was

discharged from the hospital on day 50, and administration of insulin was discontinued

uneventfully at 9 months. At 1 year, glycemic control was normal.

Questions

1. What might be the basis for the infant’s reversible bout of hyperglycemia?

2. In addition to hyperglycemia, the patient probably presented with what?

3. Do people with poorly controlled type 1 diabetes display inappropriate IRG?

Answers
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1. The findings indicate an immature function of both beta-cells and alpha-cells at the

diagnosis, with the alpha-cells maturing within the first month and the beta-cells recovering later.

The exact mechanism to explain this entity is not known, but there are several postulates

including transient hypothalamic imbalance, infection, adrenocortical disturbance, insulin

resistance, and immaturity of hepatic gluconeogenetic enzymes. However, the most accepted

ones are hypoinsulinism with ß-cell hypoplasia and temporary delay in ß-cell maturity.

2. The infant (even though he was full term) might be expected to be small for gestational

age with features of dehydration and wasting in presence of normal intake and absence of

vomiting and loose motions.

3. Type 1 diabetes is a consequence of an inappropriate autoimmune (type 1A) or, to a

lesser extent, nonimmune (type 1B) destruction of the beta-cell. As insulin is also necessary for

alpha-cells to sense blood glucose appropriately, in the absence of insulin or an insufficient

insulin therapy regime, the secretion of glucagon is inappropriately elevated. The result is an

imbalance in the insulin/glucagon ratio and an accentuation of glucagon effects well above what

would be seen in normal states of low insulin, such as in fasting.

Case 9.10: Nodular Glomerulosclerosis

A 57-year-old man presents with a typical diabetic nodular glomerulosclerosis without other

apparent clinical findings of diabetes mellitus (DM), except for impaired glucose tolerance. The

man had a family history but no personal history of DM. In an extensive examination for DM,

the results of funduscopy and a daily profile of serum glucose and hemoglobin Alc were entirely

within normal limits. However, an oral glucose tolerance test (OGTT) was abnormal. A renal

biopsy showed typical nodular lesions.

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Questions

1. Why were the back of the eyes (fundus) visualized via an ophthalmoscopy examination?

2. What most likely were the abnormal OGTT findings and the diagnosis that resulted?

3. What other undiagnosed pathologies might this 57-year-old man currently have or

develop?

Answers

1. Associated with DM is a spectrum of chronic secondary complications. It is rare that

patients with DM will not suffer from some of the chronic secondary complications of the

disease. Most lesions occur in the circulatory system, although the nervous system is also often

affected. Both small and large blood vessels are damaged, producing what are known,

respectively, as microvascular and macrovascular complications in both type 1 and type 2

diabetes. The common finding in affected vessels is a thickening of the basement membrane. An

early site of this complication is the small blood vessels of the retina of the eye, causing

retinopathy, which would be visualized by funduscopy.

2. In the OGTT test, a person's blood glucose level is measured after a fast and 2 hours after

drinking a glucose-rich beverage. If the 2-hour blood glucose level is between 140 and 199

mg/dL, the person tested has prediabetes. If the 2-hour blood glucose level is at 200 mg/dL or

higher, the person tested has diabetes. Based on the family history of DM and lack of apparent

clinical findings of DM, the abnormal OGTT measured blood glucose value was between 140

and 199 mg/dL, and prediabetes is the diagnosis.

3. Additional lurking pathologies may include deterioration of blood flow to the extremities,

hypertension, high triglycerides, and low high-density lipoprotein cholesterol. These would

increase this patient’s susceptibility to foot or leg amputation, myocardial infarction, stroke, and
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cardiovascular disease. Patients displaying a constellation of these derangements have been

designated as having metabolic syndrome.

Case 9.11: Back Pain

Two siblings presented with a history of back pain. Radiographs showed decreased lumbar bone

density and multiple compression fractures throughout the thoracic and lumbar spines of both

patients. One child has moderate short stature and mild neurosensory hearing loss. Protein

studies demonstrated electrophoretically abnormal type I collagen in samples from both children.

Enzymatic cleavage of RNA:RNA hybrids identified a mismatch in type I collagen alpha2

(COL1A2) mRNA. DNA sequencing of COL1A2 cDNA subclones defined the mismatch as a

single-base mutation (1715G --> A) in both children. This mutation predicts the substitution of

arginine for glycine at position 436 (G436R) in the helical domain of the α2(I) chain. Analysis of

genomic DNA identified the mutation in the asymptomatic father, who is presumably a germ-

line mosaic carrier.

Questions

1. What most likely is the disorder?

2. How might these siblings be treated?

Answers

1. Mutations in the type I collagen genes have been identified as the cause of all four types

of osteogenesis imperfecta (OI). Type I OI is the most common and mildest form, resulting from

decreased collagen production but normal molecular structure. The more severe forms, type II

and type III, involve mutations in the collagen molecule that prevent normal assembly. Type II

OI is frequently lethal at or shortly after birth, often as a result of respiratory problems. These
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patients have numerous fractures, severe bone deformity, and small stature. Type III patients

feature progressively deforming bones, usually with moderate deformity at birth. Type IV OI

falls between type I and type III in severity. Microscopic analyses revealed that some people who

are clinically within the Type IV group had a distinct pattern to their bone yet do not have

evidence of having mutations in the type I collagen genes. These individuals have been

designated as types V and VI OI. Based on the clinical, biochemical, and molecular findings,

these siblings might have type III OI or a new variation with only spine manifestations and

variable short stature into adolescence.

2. Treatment is directed toward preventing or controlling the symptoms, maximizing

independent mobility, and developing optimal bone mass and muscle strength. Care of fractures,

extensive surgical and dental procedures, and physical therapy are often recommended for

people with OI. Use of wheelchairs, braces, and other mobility aids is common, particularly

(although not exclusively) among people with more severe types of OI. A surgical procedure

called “rodding” is frequently considered. This treatment involves inserting metal rods through

the length of the long bones to strengthen them and prevent and/or correct deformities. Several

medications and other treatments are being explored for their potential use to treat OI. For

example, antiresorptive therapy with intravenous pamidronate has been shown to decrease

fractures in children with severe OI, even before 3 years of age.

Case 9.12: Gastrectomy

Polya partial gastrectomy was performed for peptic ulcer in a previously healthy woman aged 28

years. She complained afterwards of a variety of nonspecific symptoms including weakness,

tiredness, debility, slowness of walking, poor appetite, and constipation. Within 10 years, her
Medical Physiology: Principles for Clinical Medicine, 3e Ancillary Case Studies Page 21 of 21
Rhoades & Bell
back became bent. She was treated for intercurrent hypertension and epilepsy. Bone fractures on

low-impact trauma occurred in her fifties. At 57 years, she was unable to care for herself and had

to be admitted to a nursing home. She could still walk slowly with the aid of a stick. For 3

months at the age of 65 years, she was unable to rise from her chair. Investigations disclosed

severe postgastrectomy bone disease.

Questions

1. What undiagnosed postgastrectomy bone disease has plagued this woman for 40 years?

2. How could the peptic ulcer treatment set the stage for this bone disorder?

3. What other pathology might have promoted the progression or worsening of bone failure?

Answers

1. Osteomalacia

2. Osteomalacia is a result of calcium and vitamin D malabsorption, a well-defined

consequence of gastrectomy. As for this patient, the diversity of its presentation, however, can be

misleading, resulting in delayed diagnosis or a thorough investigation for possible underlying

neoplasias being undertaken.

3. Epilepsy, in particular, might have promoted the progression of bone failure, as some

anticonvulsants used in the treatment of epilepsy may produce osteomalacia with prolonged

treatment.