Sweet
A 12-year-old boy presents to his local emergency department with a three week history of weight loss, increased thirst, and increased urine output. He has also been vomiting for the last 3 days. His weight is 40 kg. Initial laboratory results at presentation include a sodium of 128 mmol/L, potassium of 4.2 mmol/L, chloride of 103 mEq/L (103 mmol/L), bicarbonate of 6 mEq/L (6 mmol/L), BUN of 16 mg/dL (5.7 mmol/L), creatinine of 1.03 mg/dL (91.1 µmol/L), and glucose of 991 mg/dL. His venous blood gas reveals a pH of 7.11. The local physician gave him an IV bolus of one-half liter of normal saline and then began an IV infusion of normal saline with 20 mmol/L of KCl at a rate of 120 mL/hour and an IV insulin drip at a rate of 4 units/hour. He was managed at the local hospital overnight and then transferred to your facility. Upon arrival, he is awake and alert but he feels tired and has symmetric weakness on examination.
Of the following, the patient would be MOST at risk for complications resulting from:
A. Hypocalcemia
B. Hypochloremia
C. Hypokalemia
D. Hyponatremia
C. Hypokalemia
The patient in the vignette presented with new-onset type 1 diabetes mellitus (T1D) and diabetic ketoacidosis (DKA). Up to two-thirds of new-onset T1D patients in Europe and North America present with DKA at diagnosis. Fluid and electrolyte management and insulin administration are the critical components in the treatment of DKA, and close attention must be paid to avoid complications.
Most children with DKA are estimated to be 7% to 10% dehydrated at diagnosis. The first step in management is a bolus (or boluses) of isotonic fluid. After initial fluid resuscitation, insulin administration is warranted and should be given as a continuous infusion in an acidotic patient as described in the vignette. Acidosis takes a longer period of time to correct than the hyperglycemia. Dextrose should be added to the IV fluids when the serum glucose falls below 200 to 300 mg/dL. As the acidosis improves with fluid and insulin therapy, electrolyte changes may occur if not monitored closely.
Serum potassium levels at diagnosis of DKA can be low, normal, or elevated. All patients in DKA are considered to have total body potassium depletion (ranging from 3-5 mEq/kg), regardless of their serum value. In an acidotic state, hydrogen ions enter cells and displace potassium ions into the extracellular compartment. Insulin drives potassium back into the cell by correcting the acidosis and by stimulating the Na+/K+ ATPase pump. Consensus statements for the treatment of DKA advise adding 40 mmol/L of potassium to the IV fluids after the initial isotonic saline bolus.
The patient in the vignette has been receiving IV fluids with 20 mmol/L of potassium chloride, an insufficient amount given his degree of acidosis. His initial serum potassium level was 4.2 mmol/L, which is inappropriately normal in the setting of severe acidosis. He is potassium deplete and is in danger of marked hypokalemia with insulin therapy and resolution of his acidosis. His fatigue and symmetric weakness on examination may be evidence for hypokalemia. Other symptoms may include muscle cramping and constipation. Severe hypokalemia can lead to a potentially life-threatening arrhythmia.
Potassium replacement in DKA can be accomplished with potassium chloride, potassium acetate, or potassium phosphate. When added to normal saline, potassium chloride may result in hyperchloremic metabolic acidosis. This is not harmful, but may delay resolution of the acidosis and transition to subcutaneous insulin therapy. To avoid this complication, many providers will use potassium acetate and/or potassium phosphate instead of potassium chloride.
Hypophosphatemia in DKA occurs as a result of osmotic diuresis and is exacerbated with insulin therapy (which drives phosphate into the cell). Studies have not shown any clinical benefit in empiric phosphate replacement during DKA treatment, however. Furthermore, adding potassium phosphate to the IV fluids may lead to hypocalcemia through phosphate-binding to calcium. Hypocalcemia would not be expected in the patient described in this vignette, who received normal saline and potassium chloride.
Hyponatremia in DKA may result from osmotic diuresis or from fluid treatment with hypotonic solution. In addition, serum sodium levels are low due to the presence of markedly elevated glucose levels in the extracellular compartment (termed pseudohyponatremia).
An 11 year old girl presents with a 3 month history of polyuria and polydipsia. A water deprivation test reveals an elevation of serum osmolality to 307 mOsm/L and a urine osmolality of 107 mOsm/L. She recently saw her primary care NP for ear pain with purulent discharge as well as occasional leg pains. you note a rash on her wrists and groin. Based on the findings, you diagnose diabetes insipidus. A trial of DDAVP results in great relief of her increased thirst and urination.
Which of the following would confirm the cause of the diabetes insipidus?
a) MRI of the pituitary showing a thickened stalk and an absent bright spot
b) Biopsy of the groin and/or wrist rash showing an accumulation of macrophages
c) CT showing calcification in the region of the sella
d) Fluorescent in situ hybridization (FISH) test revealing a V2 receptor defect
e) Bone biopsy revealing a sarcoma
b) Biopsy of the groin and/or wrist rash showing an accumulation of macrophages
One of the most common causes of diabetes insipidus in children is histiocytosis. Manifestations include drainage of infected ears, pathologic fractures of the long bones, and skin rash which may be petechial or hemorrhagic. Hepatosplenomegaly occurs in 20% of affected persons. Pituitary dysfunction may result in growth retardation as well as panhypopituitarism. The pituitary dysfunction can develop slowly over the course of years. DI is common. Rarely, primary hypothyroidism due to thyroid gland infiltration may also be present. A biopsy of the rash can confirm histiocytosis, so answer B is correct. In this patient, examination of the biopsy specimen revealed an accumulation of histiocytes - macrophages that have distinct dendritic features and resemble neurons. It is true that in histiocytosis, as in option A, there would be a thickened stalk and an absent bright spot; however, these findings are not specific for histiocytosis, because other diagnosis such as a germinoma and hypophysitis, would also demonstrate them. Therefore, option A is incorrect. MRI of the pituitary in any infiltrative condition may reveal thickening of the stalk, but in DI there is no ectopic posterior pituitary, but rather an absent posterior pituitary bright spot. Calcifications in the region of the sella that are observed on CT are most commonly due to a craniopharyngioma; thus option C is incorrect. Option D, defects in V2 receptors, would cause a form of nephrogenic DI, not central DI. A bone biopsy would reveal histiocytosis. Other infiltrative disorders are possible, such as sarcoidosis, but sarcoma is not one of the common cancers that cause DI, and option E is incorrect.
A 12-year-old boy diagnosed with inflammatory bowel disease 2 years ago is referred to you for growth failure after recently moving to the area. You review his growth chart (Figure 1). Physical examination reveals scant pubic hair and his testes are 5 mL bilaterally. The rest of his physical examination is normal. You plot his current height on the prior growth curve. His parents indicate that he started a new therapy about 1 year ago (blue arrow).
Of the following, the therapy that is MOST likely to be responsible for the improvement in his growth is:
A. Growth Hormone
B. Infliximab
C. Prednisone
D. Testosterone
B. Infliximab
The child in the vignette had evidence of growth failure that predated his diagnosis of IBD. The initiation of therapy to control his disease symptomatically correlates with improvements in his growth pattern. The most likely therapy to have such a dramatic improvement on linear growth would be an agent that controls inflammation without having adverse effects on the GH-IGF-1-growth plate axis. Biologics are novel agents designed to target specific proteins; most are monoclonal antibodies that target disease promoting cytokines or immune cells. Infliximab is a monoclonal antibody against TNF-α that is approved for treatment of pediatric IBD. By lowering the TNF-α levels, the drug targets the inflammatory process, while also having positive effects on appetite and growth. Treating this child with growth hormone without concomitantly addressing the inflammatory process would not be expected to improve linear growth. Linear growth improvement would not be as likely with prednisone treatment. Finally, while many children with IBD have delayed puberty, addition of testosterone would not improve linear growth in this scenario because GH action is negatively impacted by inflammation.
A full term infant born by C-section to a mother with type 2 diabetes has a seizure 2 weeks after birth. The child has been formula fed. Glucose was slightly low on initial testing, but it was normal for subsequent tests, including during the seizure. Family history is negative for calcium problems. On exam, the patient has a broad nasal bridge, small ears, and a narrow chin. A loud murmur is audible. Laboratory values after the seizure include:
Glucose 69 mg/dL
Total Calcium 5.2 mg/dL
Phosphorus 9.5 mg/dL
Creatinine 0.6 mg/dL
Parathyroid hormone 16 pg/mL
Which of the following is the most likely cause of hypocalcemia in this patient?
a) High phosphate content of formula
b) Williams syndrome
c) Hypoparathyroidism
d) Vitamin D deficiency
e) Maternal diabetes
c) Hypoparathyroidism
This newborn has hypocalcemia and hyperphosphatemia, with an inappropriately low-normal PTH consistent with hypoparathyroidism. The murmur and dysmorphic features suggest DiGeorge syndrome as the cause of the hypoparathyroidism. DiGeorge syndrome is an important diagnosis because other evaluations (especially cardiac) are necessary. Excessive oral phosphate load due to some infant formulas can cause neonatal hypocalcemia, but the PTH should be elevated. The typical response to vitamin D deficiency involves elevation of PTH, and low-normal or low phosphorus. Maternal DM, perinatal asphyxia, and prematurity are also associated with transient neonatal hypocalcemia, but it typically occurs during the first few days. Magnesium deficiency can also cause neonatal hypocalcemia in infants of a diabetic mother. Williams syndrome is a contiguous gene deletion syndrome associated with supravalvar aortic stenosis, cognitive delay, and hypercalcemia in infancy.
Due to concern about fetal size, a mother has ultrasonography performed at 38 weeks. The fetus is noted to have a goiter, and the ossification center of the distal femur is absent. There is no family history of thyroid disease.
Of the following, the MOST accurate statement about the fetus is:
A. T4 level was undetectable at 12 weeks gestation
B. Thyroperoxidase activity is impaired
C. TSH level is 7 mIU/L
D. TSH receptor stimulating antibodies are present
B. Thyroperoxidase activity is impaired
Normally, calcification of the skeleton begins at 8 or 9 weeks of gestation. By week 13, most primary centers of the tubular bones are well developed into diaphyses. At birth, all diaphyses are completely ossified, while most of the epiphyses are still cartilaginous. Ossification of the distal femoral epiphysis normally begins during the last 2 months of gestation and increases progressively (Table).
Babies born with congenital hypothyroidism may have delayed skeletal maturation, while those born with congenital hyperthyroidism may have accelerated skeletal maturation. As this baby does not have a visible ossification center of the distal femur, he has delayed skeletal maturation consistent with congenital hypothyroidism.
Fetal goiters due to congenital hypothyroidism are present in 1 out of 30,000 to 50,000 live births and may be due to transplacental passage of antithyroid drugs or due to fetal thyroid dyshormonogenesis. Mutations in thyroperoxidase are the most common cause of thyroid dyshormonogenesis. The incidence of fetal goiters due to hyperthyroidism is unknown. These goiters are caused by transplacental passage of stimulating antibodies against the thyroid-stimulating hormone receptor.
At 10 to 12 weeks of gestation, thyroid embryogenesis is largely complete: the follicular architecture is present, the sodium-iodine symporter is expressed, iodine binding can be identified, and thyroglobulin can be detected in follicular spaces. While both T4 and T3 are detectable in fetal serum by 11 to 12 weeks of gestation, this is likely maternal in origin due to transplacental transfer.
TSH is detectable at levels of 3 to 4 mIU/L at 12 weeks of gestation and starts increasing as early as 18 to 20 weeks, continuing to rise over the last 2 trimesters to a peak of approximately 6 to 10 mIU/L at term. During the second half of gestation, the thyroid gland grows and thyroid hormone increases due to the increasing serum TSH level. The maturation of the negative feedback control of thyroid hormone synthesis occurs at approximately mid-gestation.
At 18 to 20 weeks of gestation, total serum T4 and TBG concentrations start to increase steadily until the final weeks of pregnancy. Serum T3 remains low until 30 weeks of gestation because the low activity of type 1 iodothyronine deiodinase (D1) results in relatively low rates of T4 to T3 conversion and increased production of the inactive metabolites reverse T3 (rT3) and T3 sulfate in fetal tissues; type 3 deiodinase (D3) in the placenta and selected fetal tissues degrades T3 to T2. The low circulating T3 concentrations may prevent tissue thermogenesis and potentiate the anabolic state of the rapidly growing fetus. Both type 2 deiodinase (D2; converts T4 to T3) and D3 (converts T4 to reverse T3) are present in fetal brain and pituitary as early as 7 weeks of gestation. The highest concentrations of D2 are found in the brain, pituitary, placenta, and brown adipose tissue. Despite the low circulating T3 concentration, the amount of T3 in the fetal brain is 60% to 80% of the adult as early as 20 to 26 weeks of gestation due to local generation of T3 from T4 by D2. Type 3 deiodinase is present in many fetal tissues, most prominently the brain, uteroplacental unit, skin, and gastrointestinal tract, and may protect fetal tissues against high maternal T4 concentrations in the placenta or amniotic fluid. After 30 weeks, there is progressive maturation of liver type 1 deiodinase activity and decreased placental T3 degradation leading to a slow increase in serum T3 until birth.
After delivery, TSH rises acutely in response to exposure to the cold extrauterine environment, with a peak at 30 minutes to approximately 70 mU/L. In response, serum T3 and T4 concentrations increase 2- to 6-fold within the first few hours and peak on the second day of life. Levels then gradually decline over the first 4 to 5 weeks of life and reach a new equilibrium. During infancy and childhood, the T4 secretion rate progressively declines, which correlates with a decrease in metabolic rate.
In premature infants born before 30 to 32 weeks, there are low circulating levels of T4 and free T4, normal or low concentrations of TSH, and a normal or prolonged TSH response to thyrotropin-releasing hormone suggesting relative hypothalamic (tertiary) hypothyroidism (relative immaturity of the hypothalamic-pituitary-thyroid axis). Following delivery, there is a surge in TSH and T4 similar to that in term infants, but with a decreased magnitude. During the first 1 to 2 postnatal weeks, the T4 levels may not increase and may even fall in infants born before 31 weeks of gestation. In most cases, the total T4 is more affected than the free T4 due to abnormal protein binding or due to decreased TBG due to immature liver function. However, thyroglobulin (the storage form of T4) concentrations are higher in the preterm than in the term infant, especially in those who are sick. TSH is not significantly elevated in most preterm infants, and an elevated TSH level may reflect recovery from acute illness rather than true hypothyroidism. Normal escape from the Wolff-Chaikoff effect (reduction of iodide trapping in response to excess iodide) does not appear until 36 to 40 weeks of gestation, so the premature infant is more sensitive than the full term neonate to the thyroid-suppressive effects of iodine exposure.
You are evaluating a left-handed 16-year-old adolescent girl with a 4-year history of poorly controlled type 2 diabetes in your clinic. She receives a total daily dose of insulin of 1.4 units/kg per day, and 1,000 mg of metformin per day. Her physical examination reveals a body mass index of 38 kg/m2 (> 95th percentile) and hypertrophy of the skin over her abdomen and the back of her right arm.
You counsel the family about adverse effects of insulin therapy.
Of the following, the MOST likely cause of the swelling over her right arm is:
A. Adverse immunologic effect
B. Concomitant use of metformin and insulin
C. Lipogenic action of insulin
D. Lipotoxicity
C. Lipogenic action
Repeated insulin injection in the same site may result in hypertrophy or atrophy of fatty tissue at the site. Metformin use does not exacerbate lipohypertrophy or lipoatrophy. Lipohypertrophy is one of the most common complications of insulin therapy and refers to localized swelling of fatty tissue at the injection site as a result of the lipogenic action of insulin. Injection of insulin into hypertrophic sites results in erratic absorption of insulin, variability in glycemia, and difficulty in achieving optimal metabolic control. In contrast, lipoatrophy is due to an adverse immunological effect of insulin therapy. Insulin lipoatrophy has largely disappeared since the introduction of recombinant human insulin and analog insulin.
Insulin is an anabolic hormone produced by the β cells of the pancreas. Insulin stimulates glycogen synthesis, lipogenesis, and protein synthesis. Insulin promotes the entry of glucose into muscle cells, adipocytes and several other tissues through the activation of the GLUT4 glucose transporters, which are insulin-dependent. Insulin stimulates hepatic storage of glucose in the form of glycogen by several enzymatic steps. These involve the simultaneous activation of hexokinase, which phosphorylates glucose and traps it within the hepatocytes, and the inhibition of glucose-6- phosphatase. Insulin further activates enzymes involved in glycogen synthesis such as phosphofructokinase and glycogen synthase. As the liver reaches its saturation point for glycogen, glucose is then shunted into pathways for the hepatic synthesis of fatty acids, which are exported from the liver as lipoproteins.
Insulin promotes lipogenesis in adipocytes by facilitating the entry of glucose into adipocytes where it is used to synthesize glycerol. Fatty acids from the liver and glycerol from adipocytes are used in the synthesis of triglyceride within the adipocytes.
Insulin inhibits lipolysis by inhibiting an intracellular lipase that hydrolyzes triglycerides to release fatty acids. In addition to promoting glycogen synthesis and lipogenesis, insulin also facilitates protein synthesis through stimulating the uptake of amino acids and suppressing proteolysis.
In states of insulin deficiency, the secretion of counterregulatory hormones is enhanced, with increased glycogenolysis, gluconeogenesis, lipolysis, and proteolysis.
Studies have shown that persistently elevated serum concentrations of glucose (glucotoxicity) and free fatty acids (lipotoxicity) may lead to β-cell dysfunction, insulin resistance, and progression to type 2 diabetes. The effectiveness of the individual’s β-cell response to glucose and/or free fatty acids is genetically determined, and in predisposed individuals, the β-cells are unable to produce insulin at a sufficient rate to maintain euglycemia. This results in β-cell death and a predisposition to type 2 diabetes. The effect of glucolipotoxicity on β-cell function in individuals with established diabetes mellitus is unclear. Lipotoxicity would not be expected to cause lipohypertrophy.
You consult on a 10 year old girl with a history of diabetes insipidus. She is maintained on DDAVP with perfect compliance. DDAVP was started by a pediatric endocrinologist on the opposite coast, from which the girl and her family recently moved. You check the girl's sodium, which is 152 mEq/L. you then read about a novel medication being developed for children with DI and you wish to understand its mechanism of action.
Which of the following is true regarding the physiology of vasopressin?
a) Vasopressin binds to V1 receptors on the collecting tubules, which results in increased urine concentration.
b) Baroreceptors in the hypothalamus signal the release of vasopressin
c) Vasopressin binds to V1 receptors, which results in vasodilation, which in turn causes aquaporin 1-induced urinary concentration
d) Vasopressin binds to V2 receptors, which results in migration of aquaporin 2, thus leading to concentration of the urine
e) Vasopressin binds to V2 receptors, which leads to platelet aggregation, and V1 receptors, which leads to increased urinary concentration
d) Vasopressin binds to V2 receptors, which results in migration of aquaporin 2, thus leading to concentration of the urine
The arginine vasopressin receptor 2 (V2) is a protein in the G class, which stimulates adenylate cyclase activity. V2 is expressed in renal tubular distal collecting ducts. After vasopressin activation of V2 receptors, aquaporin 2 migrates in vesicles to the renal collecting tubule surface and allows the kidneys to concentrate the urine; thus, answer D is correct. V1 receptors are located on blood vessels, where they function in the vasoconstriction induced by vasopressin; therefore, options A and C are incorrect. The platelet activation effects of vasopressin also seem to occur via the V1 receptor, so option E is incorrect. Volume receptors are located in the cardiac atria, and the baroreceptors are located in the carotid arteries and the aortic arch, so option B is incorrect. In the hypothalamus, a cluster of cells function as osmoreceptors and signal thirst.
You are seeing an 8-year-2-month-old girl in your office for evaluation of short stature. Growth records from her pediatrician are shown in the Figure. She is in the third grade and does well in school. Her only medical problem is moderate persistent asthma. Her mother reports that the asthma has been well controlled for the last couple of years, and she has not been hospitalized for an asthma exacerbation in over 3 years. She has been compliant taking her asthma medications for the last few years, including montelukast (5 mg by mouth once per day), fluticasone propionate nasal spray (50 mcg/spray, 1 spray in each nostril twice per day), fluticasone dipropionate inhaler (250 mcg per inhalation, 1 inhalation twice a day), and albuterol inhaler as needed. Her physical examination is normal for her age and she is prepubertal. A bone radiograph is read as 2 years delayed.
Of the following, the laboratory test that MOST likely will be abnormal in this patient is:
A. Cortisol
B. Free T4
C. IGF-1
D. Karyotype
A. Cortisol
Inhaled corticosteroids (ICS) have been considered safe and effective agents in the daily treatment of asthma in children. As ICS have become the mainstay in asthma treatment, reports of potential adverse effects have emerged, including effects on linear growth, the hypothalamic-pituitary-adrenal axis, bone mineral density, and glucose metabolism. Although adverse effects are uncommon, predicting which child may have unwanted effects is impossible. Therefore, a high index of suspicion is needed to detect problems before a child becomes symptomatic or has an adverse event.
Several prospective studies have demonstrated a transient impairment in linear growth in children on ICS. This impairment is usually mild and occurs during the initial 12 months of treatment, and is less pronounced in subsequent years of treatment. Few studies have followed children taking ICS to final adult height and outcome data are conflicting. Some studies have found a minor reduction in final height of about 1 cm, which represents approximately a 0.7% reduction compared to those who did not use ICS, while other studies have found no significant change in height outcome. These data are difficult to apply to all ICS, as each agent can differ in particle size, protein binding capacity, clearance, and lipophilicity. Inhaled corticosteroids can also differ based on the mode of delivery and dose. Patients at greater risk for adverse effects of ICS include those with lower body mass index and those with great daily adherence to medications (like the patient in the vignette).
The girl in the vignette is on both intranasal and ICS, placing her at risk of unwanted adverse effects from cumulative doses of glucocorticoids. Fluticasone has increased lipophilicity leading to a greater risk of systemic side effects due to wider body distribution and slower clearance. Her asthma is well controlled, but the glucocorticoid doses have not been adjusted or decreased over the last few years. As shown in the Figure, her growth velocity has declined over this same time period.
Growth failure is a late finding in children on ICS, and when it occurs, suppression of the hypothalamic-pituitary-adrenal axis is nearly universally present. Children receiving medium to high doses of ICS can exhibit growth failure, hypothalamic-pituitary axis suppression, and hypoglycemia without developing Cushingoid features. Therefore, the most likely abnormal test for the patient in the vignette is a low cortisol level. A morning, basal cortisol may be falsely reassuring, and dynamic adrenal testing would be the best test to see if the patient can mount a cortisol response in times of stress. IGF-1 measurements can be elevated, normal, or low in children receiving systemic glucocorticoids. Corticosteroids may impair linear growth through a variety of mechanisms, including downregulation of growth hormone receptors, reduction of growth hormone secretion, reduction of IGF-1 activity, and reduction of collagen synthesis. Patients with profound primary hypothyroidism or Turner syndrome may also present with linear growth arrest without excessive weight gain. The patient in the vignette does not have any symptoms of hypothyroidism or any stigmata of Turner syndrome and these diagnoses would be less likely in this scenario.
A 17 year old girl had surgery for thyroid cancer last year, resulting in hypoparathyroidism. Despite prescriptions for calcium and calcitriol, she occasionally has had total serum calcium levels less than 7 mg/dL. She comes to her late afternoon appointment with her mother. She complains of intermittent muscle cramps and perioral numbness. During the visit she starts arguing with her mother about missing doses of medication and has an anxiety attack, hyperventilating. She then develops a painful spasm in her hand.
What precipitated this finding?
a) Her morning dose of calcitriol has worn off, causing low calcium that was not present earlier in the visit
b) The patient is faking the exam finding to upset her mother
c) Phosphate release from cell lysis is binding free calcium
d) Hyperventilation is increasing protein binding of calcium
e) She has hypoalbuminemia due to under-replacement of her thyroid hormone
d) Hyperventilation is increasing protein binding of calcium
Clinical findings of hypocalcemia include parasthesias, carpal-pedal spasms, other muscle cramps, tetany, seizures, and prolonged QT interval. Exam findings include Chvostek and Trousseau signs. All of these findings are the result of neuromuscular excitability, which is increased with low extracellular calcium. Cell lysis does cause hyperphosphatemia and consequent hypocalcemia, typically as part of tumor lysis syndrome, hemolysis or rhabdomyolysis, but the history is not suggestive of this. hypoalbuminemia could cause low total calcium, but a change in free (ionized) calcium is responsible for her symptoms. Hyperventilation causes respiratory alkalosis. Protein binding of calcium is increased by alkalosis and decreased by acidosis. Thus, ionized calcium changes in response to changes in acid-base balance. In clinical situation in which acid-base abnormalities or hypoalbuminemia are present (such as the intensive care unit), it may be useful to measure ionized calcium rather than total calcium.
A 2 week old, breast feeding infant presents for a routine check-up. She was born at 38 weeks gestation after an uncomplicated pregnancy and delivery. The baby is reported to sleep up to 6 hr at a time and has to be woken for feeds. On exam, she has a large posterior fontanelle, is jaundiced to the chest, has an umbilical hernia, and has normal capillary refill. The newborn screen done at 28 hr of life revealed a TSH of 3.2 mIU/L (normal <25 mIU/L).
Which of the following will establish the cause of this patient's symptoms?
a) Direct and indirect bilirubin levels
b) Lumbar puncture
c) TSH and Free T4 levels
d) Head ultrasound
c) TSH and Free T4
The infant has signs and symptoms of congenital hypothyroidism. Given that the initial TSH was not elevated, the concern is that she has central hypothyroidism, which necessitates measurement of free T4 since the TSH may be low, normal, or even slightly elevated in this setting. The diagnosis may be missed on newborn screens solely measuring TSH, so option D, repeating the newborn screen, will not make the diagnosis. Signs of congenital hypothyroidism include a large (>1 cm) posterior fontanelle, prolonged hyperbilirubinemia (>7 days), umbilical hernia, hoarse cry, macroglossia, and hypotonia. It is not uncommon for breastfed infants to have a more prolonged course of jaundice, but the infant should not be excessively somnolent. It is important to recognize prolonged jaundice as a sign of an underlying problem and to endeavor to determine why the infant is jaundiced, so checking bilirubin levels, option A, is not a sufficient evaluation. Meningitis is unlikely given that the infant has been somnolent since discharge and has normal capillary refill, so option B is not indicated. This infant was not born prematurely and had an uneventful delivery, making intra-ventricular hemorrhage unlikely, so option E would not be the appropriate next step.
A 22-year-old patient with type 1 diabetes for 11 years presents to clinic. She manages her diabetes with multiple daily injection therapy. Her control was optimal until 3 years ago when she had to leave college to support herself financially. Her BMI is 32 kg/m2 and her blood pressure is 110/72 mm Hg. She had her annual profile performed prior to visiting your clinic, which showed:
Of the following, the risk of microvascular complications for this patient is:
A. Higher than if she were diagnosed with Type 2 Diabetes
B. Increased as a result of her obesity
C. Lower than an individual with long-standing poor diabetes control
D. Not affected by her history of optimal glycemic control
C. Lower than an individual with long-standing poor diabetes control
Only 30% of individuals with diabetes meet glycemic targets as set forth by professional societies. The resulting hyperglycemia may cause chronic inflammation, oxidative stress, and the formation of abnormal glycation products contributing to the well-described micro- and macrovascular complications. Historical cohort studies demonstrate that any increase in HbA1c above normal increases the risk of these complications, and that the overall risk is higher for individuals with type 2 diabetes than type 1 diabetes.
The landmark Diabetes Control and Complications Trial (DCCT) randomized approximately 1,500 patients (200 adolescents) with type 1 diabetes to either standard care or multiple daily injection therapy. Those randomized to intensive therapy had a lower mean HbA1c that was associated with reductions in retinopathy, nephropathy, and neuropathy compared to the standard group. In addition, the rate of major cardiovascular disease was reduced by 42% in the intensive cohort years after the study was discontinued, despite the HbA1c being similar between the groups after the study was complete. Similar findings were also seen related to nephropathy and retinopathy, suggesting that glycemic control provides metabolic memory as related to complication risk. The benefits related to decreases in microvascular complications also translated to the pediatric population.
The recommendations related to screening for diabetes related complications in children and adolescents are summarized in the Table. For patients with type 1 diabetes diagnosed in childhood, screening for diabetes complications generally does not need to be initiated until 3 to 5 years after diagnosis and/or once the child has reached age 10 years or has entered puberty. The recommendations suggest that screening for complications should occur at diagnosis for patients with type 2 diabetes. This is based on the observation in adults that type 2 diabetes has a protracted presentation history, with many patients having abnormal glucose levels prior to diagnosis in the presence of other comorbidities. Individuals with type 2 diabetes have a higher risk for microvascular complications compared to those with type 1. It is hypothesized that the inflammatory metabolic milieu as well as the protracted history from onset to diagnosis of the disease contributes to this increased risk. After the initial screening, the guidelines parallel those for type 1 diabetes.
The patient in the vignette has several factors that increase her risk of diabetes complications: current poor glycemic control, elevated total cholesterol, obesity, and elevated albumin excretion. However, her history of optimal diabetes control is a protective factor, and may delay the likelihood of progression to significant micro- or macrovascular complications. Thus, her risk of retinopathy is lower than an individual with continued poor control. While she does have evidence of early diabetic renal disease, her normal blood pressure is reassuring given that hypertension is a major risk factor for diabetic kidney disease. Obesity is a risk factor for hypertension, but not for microvascular complications and she is currently normotensive; she should be counselled regarding this risk and blood pressure should be monitored at each visit.
In the clinic, you see an obese 16 year old boy with a 5 month history of polyuria and polydipsia. He has a strong family history of diabetes mellitus in his grandparents. He has several fasting tests for hyperglycemia, with the highest value 101 mg/dL. A hemoglobin A1c performed 6 months earlier was normal at 5.6%. His growth curve is unremarkable, and he reports no headaches or change in vision. He describes his frustration with the necessity of drinking and urinating twice during the overnight hours, as well as requiring liquids by his side during school. Physical examination reveals height at the 60th percentile and weight at the 95th percentile. His BMI is at the 98th percentile. His skin has mild acanthosis nigricans and no rashes. He has normal visual fields to confrontation. His lungs are clear. Sexual development is Tanner stage 5 and he has no gynecomastia. Findings from his neurologic examination are unremarkable. Laboratory test results taken at 8 am, 4 hours after his last drink of water (no calories since 12 hours prior to the test), are:
Sodium 148 mEq/L
Potassium 5.6 mEq/L
Chloride 103 mEq/L
Carbon dioxide 25 mEq/L
Serum urea nitrogen 28 mg/dL
Creatinine 0.7 mg/dL
glucose 102 mg/dL
Urine osmolality 220 mOsm/kg
Urine specific gravity 1.004, negative for glucose and ketones.
Which of the following should be the next step in the diagnostic evaluation of this patient's polyuria and polydipsia?
a) An MRI, because he has primary polydipsia
b) Admit him to the hospital and perform a water deprivation study
c) Perform a glucose tolerance test and a hemoglobin A1c
d) Inform the family that he has definitive diabetes insipidus and institute a trial of DDAVP to see if it can concentrate his urine
e) Quantify precise intake and urine output over 24 hours
d) Inform the family that he has definitive diabetes insipidus and institute a trial of DDAVP to see if it can concentrate his urine
The first diagnosis to consider in this patient is diabetes mellitus, especially with his acanthosis nigricans and strong family history of diabetes. His fasting blood sugars are slightly elevated, but certainly not in the diabetic range of above 125 mg/dL. His blood glucose levels need to be followed but are not the cause of his polyuria, especially with a urine negative for glucose. The diagnosis of DI requires having dilute urine with serum osmolality higher than 300 mOsm/kg. The serum osmolality in this case can be estimated as follows: 2Na + (BUN/2.8) + (glucose/18) which equals 312. The urine was dilute at an osmolality of 220 mOsm/kg, which gives the diagnosis of DI and dismisses the need for a formal water deprivation study, so option B is incorrect. Since the patient already has the diagnosis of DI, he does not have primary polydipsia, and option A is incorrect. he is at risk for type 2 diabetes and will need to have his hemoglobin A1c re-measured, but diabetes mellitus is not the reason for his 6 months of polyuria and polydipsia, and option C is incorrect. Option E, quantifying the precise intake and urine output over 24 hours is useful in understanding the degree of his symptoms, and it will prove the patient had true polyuria and polydipsia but it will not establish the cause. The diagnosis of primary polydipsia requires establishing marked polydipsia and urine that , after prolonged water deprivation, can concentrate. Although a child without DI may concentrate the urine to 800 mOm/kg or higher, a child with primary polydipsia may not concentrate to this degree but will generally concentrate the urine above 500 mOm/kg. After determining that the diagnostic criteria for DI are met, determining whether he has central or nephrogenic DI is the next step. Option D, a trial of DDAVP, not only will prove that the diagnosis is central DI, but also will have therapeutic implications. Finally, if the diagnosis of central DI is confirmed with the DDAVP, an MRI of the pituitary with contrast is necessary.
A 14 year old boy with growth failure presents to your clinic. Review of his growth curve reveals that his height has fallen from the 50th to the 5th percentile over the past 4 years while his weight has remained relatively stable (Figure 3). His tests measure 2 cc in volume and he has no pubic hair. Testing of his visual fields reveals bitemporal hemianopsia.
Which of the following diagnoses is most likely?
a) Nasopharyngeal carcinoma
b) Rathke cleft cyst
c) Pituitary adenoma
d) Craniopharyngioma
e) Autoimmune hypophysitis
In this case, the boy has at least GH and gonadotropin deficiencies. Craniopharyngioma is the most common cause of acquired hypopituitarism, although many other CNS tumors and lesions can be responsible, including Rathke cleft cyst, pituitary adenoma, and autoimmune hypophysitis. Hypopituitarism with nasopharyngeal carcinoma typically occurs as the result of radiation therapy. Vision loss is common with craniopharyngiomas and Rathke cleft cysts.
A 7 year old boy with hypoparathyroidism, who is taking calcitriol twice a day and calcium three doses daily, complains of periodic tingling (parasthesias) and muscle cramps. Routine laboratory testing reveals:
Total Calcium: 6.7 mg/dL
Phosphorus: 6.5 mg/dL
Creatinine 0.3 mg/dL
Which is the most appropriate next step in management for this patient?
a) Increase the calcitriol dose
b) Decrease the calcitriol dose
c) Change the calcium to once a day
d) Increase the calcium dose
e) Take the calcium dose separately from meals
d) Increase the calcium dose
Treatment of hypoparathyroidism is primarily with active analogs of vitamin D (such as calcitriol or 1,25-OH Vit D) and calcium. At the current doses, the patient's calcium remains low and his phosphorus is high, consistent with the effects of hypoparathyroidism. At the current calcium level he needs a dose increase in calcitriol or calcium. Increasing the calctriol dose will increase intestinal absorption of both calcium and phosphorus. Since his serum phosphorus is already high, raising it further is undesirable. Oral calcium intake serves to increase the net absorbed calcium and oral calcium is more effective at maintaining serum calcium in safe ranges if given in divided doses through the day. Calcium is also taken with meals in this situation to allow it to double as a phosphate binder, and to help lower the serum phosphorus concentration. Thus, increasing the calcium dose addresses both mineral abnormalities. Conversely, decreasing the calcitriol will decrease both serum phosphorus and serum calcium. However, treatment to increase serum calcium also increases total urine calcium excretion. In fact, at any given serum calcium a hypoparathyroid patient will excrete more calcium than someone with normal parathyroid function, resulting in increased risk of nephrocalcinosis during treatment. Thus, target calcium levels for treatment are in the low end of the normal range or even slightly low levels if the patient remains without symptoms of hypocalcemia.
A 19 year old G1P0 woman is diagnosed with Graves' disease in her third trimester of pregnancy. At 36 weeks gestation, she is on no medication and delivers a female infant. The baby's birth weight is 2585 g, birth length is 47 cm, and head circumference is 32 cm. She has no dysmorphism and does not have a goiter. Serial thyroid tests revealed the following:
Day of Life 1: TSH 0.02, Total T4 normal, Free T4 normal
Day of Life 4: TSH 0.7, Total T4 low, Free T4 low
Day of Life 6: TSH 2.5, Total T4 lower than DOL4, Free T4 lower than DOL4
During her nursery stay, the infant is not tachycardic, jaundiced, or jittery. She is discharged at age 7 days, weighing 2660 g.
What are the next best tests to perform to explain this child's thyroid test results?
a) TSH receptor stimulating antibodies
b) Thyroglobulin and thyroid peroxidase antibody titers
c) Thyroid ultrasound
d) Radionuclide uptake and scan
e) Growth hormone and cortisol level
a) TSH receptor stimulating antibodies
Infants born to mothers with Graves disease are at risk for transplacental transmission of maternal TSH receptor stimulating antibodies (which include thyroid stimulating immunoglobulin and thyrotropin-binding inhibitory immunoglobulin). In cases in which both stimulating and blocking antibodies cross the placenta, the blocking antibodies may predominate and block the effect of the stimulating antibody initially, but, over subsequent weeks, the infant may transition to a hyperthyroid state/late-onset neonatal Graves disease. This infant had a low TSH at birth, suggesting neonatal Graves disease, but over ensuing days had declining thyroid hormone levels and a minimal TSH response, suggesting predominance of blocking antibodies. The antibodies in option B, thyroglobulin and thyroid peroxidase antibodies are not associated with pronounced effects on neonatal thyroid function. Option C, ultrasound of the thyroid, is technically more difficult in the neonate. This baby does not have a goiter; if the thyroid is not visualized by ultrasound it may be a function of the gland's being small and the limitations of the study in this age group. A radionuclide scan, option D, would be expected to show high uptake if the infant is biochemically hyperthyroid or low or no uptake if blocking antibodies are prevalent. If the scan showed no uptake, one would not be able to differentiate between the presence of blocking antibodies and thyroid agenesis, although in the latter diagnosis, one would expect an elevated TSH. Given the relatively low TSH in the face of declining thyroid hormone levels, one might consider the possibility of central hypothyroidism, which is possible when a mother has uncontrolled hyperthyroidism during pregnancy (and the infant has been exposed to higher levels of T4). Normally, central congenital hypothyroidism is diagnosed in conjunction with other pituitary hormone deficiencies. However, this infant had no history of hypoglycemia or jaundice and no physical exam findings suggestive of multiple pituitary hormone deficiencies, so the tests in options E are unlikely to be revealing.
A 6-day-old healthy neonate born to a 31-year-old woman is on treatment with antibiotics for management of suspected sepsis. His delivery was complicated by nuchal cord, and his Apgar scores were 3 and 6 at 1 and 5 min, respectively. He developed respiratory distress requiring supplemental oxygen. On day of life 4, he developed an episode of jitteriness. His point-of-care glucose was 37 mg/dL (2.1 mmol/L). He was started on intravenous fluids with dextrose 10% in water at a glucose infusion rate (GIR) of 9 mg/kg per minute because of persistent low glucose levels.
Following the detection of intermittent blood glucose levels of 40 mg/dL (2.2 mmol/L) and 37 mg/dL (2.1 mmol/L), his GIR was increased to 12 mg/kg per minute to maintain normoglycemia.
Following an endocrine consultation, a critical sample was obtained at point-of-care glucose level of 37 mg/dL (2.1 mmol/L).
The result of his critical sample showed a plasma glucose of 36 mg/dL, an insulin level of 0.1 µU/mL, plasma free fatty acid level of 1.2 mmol/L, plasma β-hydroxybutyrate of 1.1 mmol/L, cortisol of 25 µg/dL, and GH of 15 ng/mL.
A second critical sample, drawn 2 days later, showed similar results. The repeat critical sample was followed by a glucagon challenge test at serum glucose of 31 mg/dL (1.7 mmol/L). Glucose levels at 10, 20, and 30 minutes following glucagon injection were 43 mg/dL (2.4 mmol/L), 52 mg/dL (2.9 mmol/L), and 63 mg/dL (3.5 mmol/L), respectively.
Of the following, the MOST likely cause for the hypoglycemia in this newborn is:
A. A fatty acid oxidation defect
B. Glycogen storage disease
C. Hyperinsulinism
D. Mitochondrial disease
C. Hyperinsulinism
The newborn in the vignette most likely experienced hypoglycemic episodes as a result of transient hyperinsulinism from sepsis and perinatal stress. Hyperinsulinism (HI) can be congenital or transient. Congenital HI arises from mutations of genes responsible for insulin secretion from beta cells of the pancreas. The most common of these mutations affect the genes (ABCC8 and KCNJ11) that encode the ATP-sensitive potassium channels. Transient HI is commonly seen with neonates of diabetic mothers, but can also be associated with perinatal stress acting through an unknown mechanism.
The diagnostic evaluation of hypoglycemia is based on the assessment of the fasting systems which work to ensure fuel supply to the brain. These include glycogenolysis, gluconeogenesis and ketogenesis, and are influenced by the endocrine system. Insulin suppresses all 3 systems, while counterregulatory hormones enhance them. Specifically, GH increases ketogenesis by augmenting lipolysis; cortisol enhances gluconeogenesis; glucagon increases glycogenolysis; and epinephrine activates glycogenolysis, gluconeogenesis, and ketogenesis.
When samples are obtained during hypoglycemia, HI is indicated by the following serum studies:
- Detectable insulin on the assay
- β-hydroxybutyrate less than 2 mmol/L
- Free fatty acids less than 1.5 mmol/L
- Low IGFBP-1 (from insulin-mediated suppression of hepatic IGFBP-1 secretion)
- Glucose rise greater than or equal to 30 mg/dL (> 1.7 mmol/L) within 30 minutes of receiving glucagon
Hyperinsulinism is the only condition with vigorous response to glucagon at the time of hypoglycemia, and this is therefore a very useful test when HI is suspected. Hyperinsulinism is not always defined by measurable hyperinsulinemia. Insulin levels fluctuate due to its short half-life (4-5 minutes) and due to its rapid clearance by hepatocytes before reaching the peripheral circulation.
The presence of acidemia during hypoglycemia may be due to accumulation of lactate. Disorders associated with deficient gluconeogenesis may lead to elevated lactate levels at the time of hypoglycemia, due to accumulation of substrate for glucose synthesis. Elevated lactate levels can also be seen on the first day of life in normal neonates after a difficult delivery. This is thought to result from birth asphyxia, poor perfusion, impaired aerobic metabolism, and accumulation of lactic acid. Ketone production during hypoglycemia may also lead to acidosis. Ketotic hypoglycemia may be seen with growth hormone and/or cortisol deficiency, with glycogen storage disease (GSD types 3, 6, 9), or in normal young children with low metabolic reserve. Low serum alanine concentration is associated with GSD type 3. This results from excessive turnover of alanine for gluconeogenesis. Patients with this disorder often have severe hepatomegaly. Low serum alanine may also be seen in patients with low metabolic reserve. In contrast to patients with GSD type 3, these patients have low alanine from reduced muscle mass and do not have hepatomegaly.
Elevated free fatty acids and suppressed ketones at the time of hypoglycemia are features of genetic defects of fatty acid oxidation and ketogenesis. The most common form of this defect is medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. These children may experience symptomatic hypoglycemia during an intercurrent illness. The biochemical profile shows hypoketotic hypoglycemia with low serum carnitine. Liver enzymes, uric acid, and ammonia levels are elevated. Elevated ammonia levels may also be seen in 1 form of congenital HI, in disorders if the urea cycle, and in organic acidemias. Organic acidemias result from defective enzyme functioning in intermediary metabolism. Hypoglycemia results from increased glucose use and from impaired gluconeogenesis. Testing for urinary organic acids may be diagnostic if organic acidemias are suspected, as it may reveal elevation of metabolites upstream of the enzymatic deficiency.
Mitochondrial diseases are rare causes of hypoglycemia. Episodes usually follow a long fast or during times of stress. No consistent mechanism has been elucidated for the hypoglycemia, though impairments in gluconeogenesis (with elevated lactate and alanine levels), fatty acid oxidation (with elevated serum free fatty acids), and glycogenolysis have been described.
A 2 year old girl with a 4 day history of vomiting and diarrhea presents to the emergency department with lethargy. Three days earlier, she was placed on a form of tetracycline by her primary care physician. On physical examination, she is fatigued, but she has a moist tongue and her eyes are not considerably sunken. Capillary refill is appropriate. She has no edema. A chest x-ray shows pneumonia. her laboratory test results are:
Sodium 125 mEq/L
Potassium 4.5 mEq/L
Chloride 81 mEq/L
CO2 30 mEq/L
Serum urea nitrogen 7 mg/dL
Creatinine 0.2 mg/dL
Serum osmolality 258 mOm/kg
Urine osmolality 129 mOsm/kg
Which of the following explanations best accounts for her clinical status?
a) Pneumonia is causing SIADH
b) Cerebral salt wasting
c) Medication-induced SIADH
d) Adrenal insufficiency
e) Water intoxication
e) Water intoxication
This girl has clinically significant hyponatremia. The first step is to determine whether she is indeed in a true hypo-osmolar state. Marked hyperglycemia, for example, can cause an extracellular fluid shift that results in hyponatremia, but not hypo-osmolality. This patient has a serum osm of 258 mOsm/kg, which is quite low; thus there cannot be marked hyperglycemia. Option A, SIADH, would require concentrated urine, which is not present here. In fact, with almost every cause of hyponatremia, the urine is concentrated. The dilute urine in this patient suggests free water overload as the cause of hyponatremia, so answer E is the correct choice. Option B, cerebral salt wasting, requires the presence of a CNS lesion. Its features include high urinary salt loss in the face of hyponatremia and a failure to correct with fluid restriction. Answer D, adrenal insufficiency, can result in hyponatremia, even without the presence of mineralocorticoid deficiency. Thus, the patient's normal potassium level does not exclude adrenal insufficiency as the cause of hyponatremia. However, the urine concentration is increased in adrenal insufficiency, and the patient's normal capillary refill and lack of dehydration do not support this etiology as the cause of the hyponatremia. Tetracyclines, such as demeclocycline, have been used in treating patients with chronic SIADH because tetracycline can inhibit the actions of ADH, but this would result in hypernatremia, so option C is incorrect.
A 6 year old male has chronic renal failure, with a GFR of 23 mL/min per 1.73 m2. Over the past 4 years, his height fell from the 50th percentile to the 10th percentile. Over the past year his growth velocity has been <2 SD below the mean.
Which of the following is most likely contributing to his growth failure?
a) Low IGF-1 and IGFBP-3
b) Low IGFBP-1 levels
c) Protein wasting
d) Excessive caloric intake
e) Metabolic alkalosis
c) Protein wasting
In chronic renal failure, protein wasting, decreased caloric intake, metabolic acidosis, chronic anemia, loss of electrolytes necessary for normal growth, inadequate formation of 1,25-dihydroxycholecalciferol, and insulin resistance can all contribute to growth failure. IGF-1 and IGFBP-3 levels tend to be normal, but increases in serum IGFBPs (especially IGFBP1) may lead to decreased IGF action.
A 4 year old girl undergoes resection of most of her distal duodenum and half of her jejunum due to volvulus.
Which of the following is most true regarding intestinal calcium absorption in this patient?
a) Passive calcium transport is regulated by Vitamin D
b) Vitamin D mediated calcium absorption is impaired
c) Vitamin D mediated calcium absorption is normal
d) Calcium absorption only occurs in the ileum, and thus is normal
e) Parathyroid hormone levels will increase and stimulate calcium absorption in the ileum
b) Vitamin D mediated calcium absorption is impaired
Calcium absorption involves both active transport and passive transport. Passive transport occurs throughout the small intestine, is not saturable, and is not regulated by Vitamin D. Thus it is possible to become hypercalcemic with excessive calcium intake, despite down-regulation of the active transport of calcium. Active transport occurs primarily in the duodenum and also in the jejunum. Active transport is regulated by 1,25-dihydroxyvitamin D through pathways involving up-regulation of genes involved in calcium transport. In this patient, the primary region for vitamin D mediated active calcium transport has been removed, impairing the response to vitamin D. The effects of PTH on intestinal calcium absorption are indirect. PTH stimulates production of 1,25-OH Vit D, which then increases active calcium absorption in the proximal intestine, rather than the ileum.
A 17 year old boy is referred for evaluation of a 4 cm mass in the left lobe of the thyroid. Fine-needle aspiration biopsy reveals papillary thyroid carcinoma.
What do you tell the family about the likely extent of disease and the general prognosis?
a) The cancer is likely confined to the thyroid gland and the 10 year mortality rate is 5%
b) The likelihood of lymph node metastases is >40% and the 10 year mortality rate is <2%
c) The likelihood of distant metastases to the lungs is >50% and the 10 year mortality rate is <2%
d) The likelihood of distant metastases to the brain is 10% and the mortality rate is <2%
e) The extent of disease can only be determined by surgery and the 10 year mortality rate is 10%
b) The likelihood of lymph node metastases is >40% and the 10 year mortality rate is <2%
Children and adolescents who present with PTC are very likely to have lymph node metastases at the time of diagnosis, yet their prognosis is excellent, with 10 year mortality rates <2%. It is likely this patient has lymph node metastases, given the large size of his nodule. Thus, it is unlikely the disease is confined to the gland, and a mortality rate of 5% is higher than reported in multiple series of PTC patients; therefore, option A is incorrect. Overall recurrence rates are on the order of 30% for patients who present with lymph node metastases. Lung metastases are reported in 10-30% of PTC patients at diagnosis, not >50% so option C is incorrect. Brain and bone metastases are reported, but distant spread is more common to the lungs; the chance this patient has brain metastases is not as high as 10%, and option D is incorrect. Preoperative staging can and should be performed using ultrasound; it is important that lateral lymph node involvement be assessed so that the appropriate lymph node surgery (central only versus central plus modified radical neck dissection) can be planned in advance, not determined at the time of the surgery; thus, option E is incorrect.
You are participating in a clinical trial to understand the risk factors associated with the development of diabetes. You are seeing a 6-year-old girl and her parents to review recent results of testing conducted as a part of the research protocol.
Of the following, the feature that is MOST predictive of the onset of type 1 diabetes is:
A. Autoantibodies
B. Family History
C. HLA Genotype
D. OGTT Results
D. OGTT Results
Autoimmune destruction of the pancreatic β cells causes type 1 diabetes. Models of the development of type 1 diabetes (Figure) aid in the understanding of the disease and separate the development of type 1 diabetes into stages, beginning with genetic susceptibility and ending with the clinical presentation of type 1 diabetes.
HLA genotypes confer most of the genetic risk associated with type 1 diabetes. In particular, the genotype DR3-DQ2/DR4-DQ8 is associated with a 20-fold higher risk for the development of type 1 diabetes compared with the general population. Specific HLA genotypes are protective for the development of type 1 diabetes, such as 0602. Genes outside the HLA are also associated with risk for type 1 diabetes, such as the variable number of tandem repeats (VNTR) in the insulin gene, which is associated with both risk and protection for type 1 diabetes.
These genetic influences on the development of diabetes provide clues to the pathogenesis of the disease. The HLA locus encodes proteins that are important for the presentation of antigens to the immune system. The VNTR of the insulin gene has been associated with levels of insulin protein produced in the thymus, with lower levels being associated with a higher risk for the development of type 1 diabetes. Potentially, this is the result of decreased destruction of autoreactive T-cells.
Most people at genetic risk for type 1 diabetes do not develop disease. Therefore, other factors must also play a role. The environmental factors associated with the development of type 1 diabetes have been extensively analyzed in prospective studies of infants at increased risk for the development of disease. Factors such as infant diet, infections, growth patterns, and the microbiome have all been studied, and it appears that there may be more than 1 environmental trigger for the development of the autoimmunity associated with type 1 diabetes.
Once autoimmunity is triggered, markers of the autoimmune process can be detected in the serum. The autoimmune process is largely T-cell mediated, and markers of this process are being developed. It has long been recognized that the autoimmunity is associated with autoantibodies, including antibodies to insulin, GAD65, ZnT8, and IA-2. Risk for diabetes is associated with the number of autoantibodies present (higher risk with more antibodies), the degree of positivity, and the persistence of positivity. Risk for the development of type 1 diabetes in patients with 4 positive autoantibodies is approximately 50% after 5 years of follow-up.
Once the autoimmune process is initiated, the β-cell mass declines over time. Prospective follow-up of individuals with autoantibodies suggests that the first sign of insulin deficiency is the loss of the first phase insulin response. A further decrease in β-cell mass results in a progressive loss of insulin with impaired glucose tolerance and impaired fasting glucose. Risk for symptomatic type 1 diabetes with abnormalities of glucose tolerance is approximately 75% after 5 years of follow-up. After 80% to 90% of the β-cell mass has been lost, glucotoxicity to the remaining β cells results in loss of the vast majority of insulin production, and frank hyperglycemia and symptoms of diabetes develop. Control of blood glucose with administration of insulin results in decreased blood glucose and improvement in glucotoxicity. Patients then produce insulin from the remaining β cells and enter the honeymoon phase. However, the autoimmune process continues, and the remaining β cells are destroyed, ending the honeymoon.
β-cell release of insulin is regulated by the concentration of blood glucose. Glucose enters the β cell through the GLUT2 transporter (which is not insulin regulated), and is subsequently phosphorylated by glucokinase. Metabolism of glucose within the β cell increases the ATP/ADP ratio, which closes the Kir6.2 potassium channel. This results in membrane depolarization, opening of the voltage-sensitive calcium channel, and release of preformed insulin. In the state of chronically high glucose, any remaining β cells have released most of their insulin and are unable to respond to hyperglycemia by increasing insulin release.
Insulin acts through the insulin receptor to cause glucose uptake by increasing the presence of GLUT4 transporter in the cell membrane. Insulin also inhibits hormone-sensitive lipase, decreasing the conversion of triglycerides to free fatty acids, the precursors to ketones. Conversely, lack of insulin results in hyperglycemia and ketone production. Hyperglycemia causes an osmotic diuresis, resulting in polyuria, polydipsia, dehydration, and weight loss due to loss of glucose in the urine. Accumulation of ketones can lead to diabetic ketoacidosis (DKA). The ketoacidosis of DKA is exacerbated by lactic acidosis from profound dehydration. Treatment of DKA requires both rehydration and insulin administration.
You are called to the ED to see a 10 year old boy. His parents had taken him to their family doctor 2 weeks earlier because of headaches, fatigue, and weight loss. The doctor obtained a CBC, CMP, TSH, and free T4. The CBC was normal, and the CMP was remarkable only for hyponatremia, with a sodium level of 134 mmol/L. The free T4 was low, 0.4 ng/dL and the TSH was 5.9 mU/L, slightly above the reference range of 0.5-5. The boy was diagnosed with primary hypothyroidism, and treatment with levothyroxine was initiated. One week later, he began to feel more tired and irritable. He has been vomiting for the last 3 days and he has been very lethargic today.
Which medication is most likely to help this patient?
a) Desmopressin
b) Glucagon
c) Hydrocortisone
d) Levothyroxine
e) Ondansetron
c) Hydrocortisone
Thyroid hormone has important effects on the metabolism of drugs and hormones. In particular, treatment of a previously hypothyroid patient may result in more rapid metabolism of cortisol, and initiation of levothyroxine therapy in a patient with concomitant adrenal insufficiency may provoke an adrenal crisis from increased cortisol clearance. For the patient described, administration of hydrocortisone is the best treatment option (after obtaining a diagnostic serum cortisol level). For this reason, it is recommended that the HPA axis be assessed in patients with central hypothyroidism before initiation of levothyroxine replacement therapy. The boy described here most likely has hypothalamic disease given his symptoms and lab results, because the TSH is less abnormal than would be expected given the significantly low serum T4 level. Treatment with the other medications listed would not likely be beneficial. Similarly, initiation of levothyroxine in a patient with known adrenal insufficiency may prompt a dose increase in hydrocortisone therapy if the hydrocortisone dose is relatively low. Patients with adrenal insufficiency are unable to adequately excrete a water load and are prone to hyponatremia. This state may partially mask diabetes insipidus, and correction of the adrenal insufficiency may increase water excretion, leading to polyuria and polydipsia and prompting initiation or increase of desmopressin therapy.
A 5 year old boy is referred to the clinic for excessive growth. His history is pertinent for a birth weight of 5000 g and developmental delay. His height is 3 SD above the mean. Physical examination reveals a high and bossed forehead, down-slanting palpebral fissures, and a pointed mandible. He has normal IGF-1 and IGF-BP3 levels.
Which of the following is the most likely diagnosis?
a) Weaver syndrome
b) GH excess
c) Klinefelter syndrome
d) Homocystinuria
e) Soto's syndrome
e) Soto syndrome
Patients with Soto syndrome (cerebral gigantism) are born large for gestational age, have large heads, and grow rapidly in infancy. Dysmorphic features include a prominent forehead, high-arched palate, hypertelorism, and pointed chin. Developmental delay is common. Children with Weaver syndrome also have large heads and rapid prenatal and postnatal growth. However, their facies include a round face, small chin, long philtrum, large ears, and hypertelorism. A 5 year old boy with GH excess and Klinefelter syndrome should not have dysmorphic features. The most common form of homocystinuria is characterized by tall stature, myopia, dislocation of the lens, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture. Mutation of the CBS gene, which encodes the enzyme cystathionine beta-synthase, is the most common cause of homocystinuria.
A premature infant is delivered to a diabetic mother after failure of tocolytics, including magnesium. During the first day in the neonatal intensive care unit, the newborn girl is hypocalcemic, with a total calcium of 6.3 mg/dL and ionized calcium of 3.2 mg/dL.
Which of the following is true about the interaction of magnesium and calcium metabolism?
a) Hypomagnesemia enhances the response of the PTH receptor to PTH
b) PTH inhibits renal calcium and magnesium reabsorption
c) High magnesium levels stimulate PTH release
d) Magnesium deficiency causes hypercalcemia
e) Both very low and very high magnesium levels inhibit PTH release
e) Both very low and very high magnesium levels inhibit PTH release
Maternal treatment with magnesium as a tocolytic can cause high neonatal serum magnesium levels. Magnesium interacts with calcium metabolism at multiple points. Both magnesium and calcium are able to activate the calcium-sensing receptor. Thus, at very high extracellular magnesium concentrations, PTH release is inhibited, as it is for high calcium concentrations. On the other hand, severe hypomagnesemia causes intracellular magnesium depletion, which impairs the intracellular second messenger systems and PTH secretory granule response to hypocalcemia. Magnesium deficiency also decreases the end-organ response of the PTH receptor. PTH stimulates renal calcium and magnesium reabsorption in the distal renal tubule.
An 11 year old girl presents with a complaint of abdominal pain and severe constipation. Review of her growth curve reveals that her height has dropped from the 50th to the 3rd percentile over the past 4 years. Her heart rate is 61 beats/min and her blood pressure is 988/69 mmHg.
Which of the following findings would you expect on physical exam?
a) An enlarged, bosselated thyroid and brisk deep tendon reflexes
b) Dry skin, a small thyroid, and deep tendon reflexes with a delayed relaxation phase
c) A normal sized thyroid and diminished deep tendon reflexes
d) A small thyroid, erupted wisdom teeth, and diminished deep tendon reflexes
e) Hyperpigmentation of the buccal mucosa, an enlarged bosselated thyroid, and pretibial edema
b) Dry skin, a small thyroid, and deep tendon reflexes with a delayed relaxation phase
The patient's severe growth failure is the most important clue that she may have severe acquired primary hypothyroidism. In this situation, the thyroid may be enlarged due to chronic TSH stimulation or it may be small if the hypothyroidism is long-standing and the gland has atrophied and burned out. The gland may feel bosselated if the child has underlying Hashimoto thyroiditis, the most likely etiology. The skin may appear sallow due to carotenemia. A hypothyroid patient would not be expected to have brisk deep tendon reflexes; rather, the relaxation phase may be delayed so option A is incorrect. The child would be expected to have delayed loss of primary teeth and delayed eruption of permanent teeth, not accelerated dental maturation, so option D is incorrect. The hyperpigmentation in option E suggests adrenal insufficiency, which should be considered in a child with severe acquired primary hypothyroidism, but pretibial edema is typically seen more commonly in adults with severe hypothyroidism, not children.