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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=[[User:Gonzalo Romero|Gonzalo A. Romero, M.D.]] [mailto:gromero@wikidoc.org]
|QuestionAuthor=[[User:Gonzalo Romero|Gonzalo A. Romero, M.D.]] [mailto:gromero@wikidoc.org] (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Pathology, Pathophysiology, Physiology
|MainCategory=Pathology, Pathophysiology, Physiology
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|MainCategory=Pathology, Pathophysiology, Physiology
|MainCategory=Pathology, Pathophysiology, Physiology
|SubCategory=Endocrine
|SubCategory=Endocrine
|MainCategory=Pathology, Pathophysiology, Physiology
|MainCategory=Pathology, Pathophysiology, Physiology
|MainCategory=Pathology, Pathophysiology, Physiology
|MainCategory=Pathology, Pathophysiology, Physiology
|MainCategory=Pathology, Pathophysiology, Physiology
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|MainCategory=Pathology, Pathophysiology, Physiology
|MainCategory=Pathology, Pathophysiology, Physiology
|SubCategory=Endocrine
|SubCategory=Endocrine
|Prompt=A 46-year-old woman presents to the outpatient rural clinic complaining of a 2-year history of constipation. She has taken over the counter fiber tablets which were not helping much. Her husband convinced her to go to the clinic after he entered the restroom and saw red bright blood in the toilet following the patient's defecation.  She is allergic to penicillin, for which she had a severe allergic reaction 4 years ago. She stopped going to the doctor for a yearly checkup ever since; she is afraid of medications and their complications.  She has a history of bilateral lower back abdominal pain  radiated to the groin, which has resolved partially after taking lots of water; she states that "water is the best medicine".   On review of systems she communicates that she has been feeling nauseated, urinating more than usual, has had bone and muscle aches. Upon physical examination she looks fatigued and her vitals are WNL.   The mucous membranes are moist and without abnormalities. The neck is supple without any thyroid or lymph nodes enlargement, the rest of HEENT is normal.  Lungs are clear to auscultation bilaterally without rales, wheezes or crackles.  S1S2 RRR without murmurs, rubs or gallops.  Abdomen is NT/ND, BS 3 per minute, CVA tenderness bilaterally, without organomegaly. Neuro is grossly intact. Her primary physician, which she has not seen in a long time, is thinking that a non-palpable benign tumor is most likely causing her symptoms.  He decides to order a blood test to check for Calcium and PTH serum levels in order to confirm his suspicioun. Which of the following most likely correlates with this patient's serum findings?
|Prompt=A 46-year-old woman presents to the outpatient clinic for a long history of constipation. She states that her symptoms did not improve despite the use of over-the-counter fiber tablets. Her past medical history is significant for recurrent kidney stones. The patient denies any family history of similar symptoms. Upon review of systems, the patient also reports increased thirst, frequent urination, and easy fatigability. Her temperature is 37.1 °C (98.6 °F), blood pressure is 142/88 mmHg, and heart rate is 70/min. Physical examination in the clinic is unremarkable. Work-up reveals decreased bone mineral density in the distal third of the forearm. Urine work-up is remarkable for hypercalciuria and elevated cAMP. Which of the following set of serum lab results is most likely present in this patient?
<br>
<br>
[[File:PTHCa.png|center|500px]]
[[File:PTHCa.png|500px]]
|Explanation=This patient is presenting with constipation, kidney stones, nausea, polydypsia, polyuria, muscle and bone pains, which is the typical presentation of primary hyperparathyroidism. The constipated habit of the patient made her bleed when defecating. [[Hyperparathyroidism]] courses with elevated [[PTH]] levels which increase the [[Calcium]] levels in blood.
|Explanation=Primary hyperparathyroidism is the most common cause of hypercalcemia. The most common cause of primary hyperparathyroidism is a single adenoma, which accounts for more than 80% of cases. Less commonly, primary hyperparathyroidism is caused by hyperplasia of the parathyroid glands or hereditary syndromes, such as multiple endocrine neoplasia (MEN) syndromes types 1 and 2A. Although the diagnosis of primary hyperparathyroidism is usually incidental since the majority of patients remain asymptomatic, manifestations of the disorder are primarily due to hypercalcemia. The classical clinical features of hypercalcemia may be summarized as: Stones, bones, groans, and psychiatric overtones.
*Stones: Nephrolithiasis and nephrocalcinosis
*Bones: Low bone mineral density (characteristically at the distal third of the radius as observed in this patient), vertebral fractures, and bone pain
*Groans: Constipation
*Psychiatric overtones: Cognitive impairment, anxiety,  
 
Other features may include polyuria and polydypsia, easy fatigability, high blood pressure, insulin resistance, hyperglycemia, and dyslipidemia.
Typically, initial laboratory findings of patients with primary hyperparathyroidism reveal hypercalcemia on routine work-up. Total serum calcium level should always be differentiated from free and albumin-bound circulating calcium. Accordingly, calcium levels should be corrected and calculated as follows: Corrected serum calcium (mg/dL) = Measured total calcium (mg/dL) + [0.8 x (4.0 - serum albumin (g/dL)]. Patients with hypercalcemia should undergo testing for serum PTH, which is often elevated or inappropriately normal in patients with primary hyperparathyroidism. The definitive diagnosis of primary hyperparathyroidism cannot be made until other diseases that also cause hypercalcemia and/or elevated serum PTH are excluded, such as thiazide or lithium intake, tertiary hyperparathyroidism due to end-stage renal disease (ESRD), familial hypocalciuric hypercalcemia, and PTHrp-secreting malignancies. Of note, PTH and PTHrp are measured separately during laboratory work-up, and patients with PTHrp-secreting tumors usually have low PTH and elevated PTHrp levels). Patients with primary hyperparathyroidism usually have decreased 25-hydroxyvitamin D levels due to the increased conversion to 1,25-dihydroxyvitamin D. Urinary creatinine and calcium levels should be measured to differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcemia (mutation in calcium-sensing receptor gene). In patients with primary hyperparathyroidism, the urinary calcium:creatinine clearance ratio is typically > 0.01. Other urinary findings also include elevated cAMP levels. Parathyroidectomy is often required to treat patients with symptomatic disease.


<font color="MediumBlue">'''PTH has many functions:'''</font>
Physiologically, PTH has many functions:
# Increases the production of macrophage colony-stimulating factor and RANK-L, which binds RANK on osteoblasts and consequently stimulate osteoclasts
# Net increase in serum calcium levels and net decrease in serum phosphate levels
# Increases bone resorption of both calcium and phosphate
# Increases bone resorption of both calcium and phosphate
# Increases renal reabsorption of calcium in the distal convoluted tubule
# Increases the activity of Ca<sup>2+</sup>/Na<sup>+</sup> exchange and increases the reabsorption of calcium in the early distal convoluted tubule in the kidneys
# Inhibits renal phosphate reabsorption
# Inhibits the activity of Na<sup>+</sup>/PO4<sup>3-</sup> cotransport in the proximal convoluted tubule in the kidneys and facilitates that renal excretion of phosphate  
# Stimulates 1-alfa hydroxylase which converts Vit D 25-(OH) form into its active form (Vit D 1,25-0H or calcitriol)
# Stimulates 1-α hydroxylase, which converts 25-hydroxyvitamin D into its active form, 1,25-dihydroxyvitamin D
Calcium levels vary from 8.5 to 10.2 mg/dL and PTH levels vary from 15-65 pg/mL.
[[File:PTH & Ca pathology.png|center|700px]]
<font color="MediumBlue"><font size="4">'''Educational Objective:''' </font></font>
# Hyperparathyroidism is frequently caused by a hyperfunctioning adenoma in a parathyroid gland
# PTH increases Calcium and Phosphorus levels
# Frequently it is symptomatic, unless the calcium serum level is extremely high
# '''WikiDoc Mnemonics:''' Hyperparathyroidism causes '''Stones, bones, and groans''' (kidney stones, bone pains and constipation).
<br>
<br>
'''References:''' First Aid for STEP 1 2013, Endocrinology Chapter.
[[File:PTH & Ca pathology.png|700px]]
|AnswerA=A
|AnswerA=A
|AnswerAExp=<font color="red">'''Incorrect.'''</font> This represents the normal range of Calcium and PTH values in serum;   Calcium levels vary from 8.5 to 10.2 mg/dL and PTH levels vary from 15-65 pg/mL. PTH increases when the ionized calcium level drops.
|AnswerAExp=This represents the normal range of calcium and PTH values in serum; calcium levels vary from 8.5 to 10.2 mg/dL and PTH levels vary from 15-65 pg/mL. PTH increases when the ionized calcium level decreases.
|AnswerB=B
|AnswerB=B
|AnswerBExp=<font color="red">'''Incorrect.'''</font> [[Hypoparathyroidism]] can be caused by surgical removal of the parathyroids (i.e. thyroid surgery), or due to an autoinmune destruction of the glands. The lab values reveal low PTH and low Calcium levels.
|AnswerBExp=[[Hypoparathyroidism]] is commonly caused by incidental parathyroidectomy duruing thyroid surgery. Other causes of hypoparathyroidism include autoimmune destruction of the glands. The lab values reveal low PTH and low calcium levels.
|AnswerC=C
|AnswerC=C
|AnswerCExp=<font color="red">'''Incorrect.'''</font> [[Hyperparathyroidism|Secondary hyperparathyroidism]] is characterized by elevated PTH due to decreased levels of calcium. The most common causes are chronic renal insufficiency (due to impaired vitamin D hydroxylation towards its active form) and intestinal malabsorption of calcium.
|AnswerCExp=[[Secondary hyperparathyroidism]] is characterized by elevated serum [[PTH]] due to decreased levels of calcium. The most common causes are chronic renal insufficiency (due to impaired [[vitamin D]] hydroxylation towards its active form) and intestinal malabsorption of calcium.
|AnswerD=D
|AnswerD=D
|AnswerDExp=<font color="Green">'''Correct.'''</font>  [[Hyperparathyroidism]] can be caused by an adenoma, hyperplasia or carcinoma in the parathyroid glands.  The increased levels of PTH increase the Calcium levels above 10, therefore it corresponds to upper right corner on the graph.
|AnswerDExp=[[Primary hyperparathyroidism]] is most commonly caused by an adenoma, hyperplasia, or carcinoma of the parathyroid glands.  
|AnswerE=E
|AnswerE=E
|AnswerEExp=<font color="red">'''Incorrect.'''</font>  This option corresponds to [[hypercalcemia]] independent of PTH, for example seen in metastatasis or excess calcium ingestion
|AnswerEExp=This option corresponds to [[hypercalcemia]] independent of PTH, as observed in malignancies with paraneoplastic syndromes in PTHrp-secreting tumors.
|EducationalObjectives=[[Primary hyperparathyroidism]] is most commonly caused by an adenoma, hyperplasia, or carcinoma of the parathyroid glands. Although the diagnosis of primary hyperparathyroidism is usually incidental since the majority of patients remain asymptomatic, manifestations of the disorder are primarily due to hypercalcemia. The classical clinical features of hypercalcemia may be summarized as: Stones, bones, groans, and psychiatric overtones. Typically, patients with primary hyperparathyroidism have elevated serum calcium levels and elevated or inappropriately normal serum PTH levels.
|References=Marcocci C, Cetani F. Primary hyperparathyroidism. N Engl J Med. 2011;365(25):2389-97.<br>
First Aid 2014 page 323, 324
|RightAnswer=D
|RightAnswer=D
|WBRKeyword=PTH, Primary hyperparathyroidism, Hyperparathyroidism, Hypercalcemia, Constipation, Polyuria, Polydypsia, Calcium, Phosphate, Vitamin D, Kidney stones, Nephroplithiasis, Hypercalciuria,
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 00:01, 28 October 2020

 
Author [[PageAuthor::Gonzalo A. Romero, M.D. [1] (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Pathology, MainCategory::Pathophysiology, MainCategory::Physiology
Sub Category SubCategory::Endocrine
Prompt [[Prompt::A 46-year-old woman presents to the outpatient clinic for a long history of constipation. She states that her symptoms did not improve despite the use of over-the-counter fiber tablets. Her past medical history is significant for recurrent kidney stones. The patient denies any family history of similar symptoms. Upon review of systems, the patient also reports increased thirst, frequent urination, and easy fatigability. Her temperature is 37.1 °C (98.6 °F), blood pressure is 142/88 mmHg, and heart rate is 70/min. Physical examination in the clinic is unremarkable. Work-up reveals decreased bone mineral density in the distal third of the forearm. Urine work-up is remarkable for hypercalciuria and elevated cAMP. Which of the following set of serum lab results is most likely present in this patient?


]]

Answer A AnswerA::A
Answer A Explanation AnswerAExp::This represents the normal range of calcium and PTH values in serum; calcium levels vary from 8.5 to 10.2 mg/dL and PTH levels vary from 15-65 pg/mL. PTH increases when the ionized calcium level decreases.
Answer B AnswerB::B
Answer B Explanation [[AnswerBExp::Hypoparathyroidism is commonly caused by incidental parathyroidectomy duruing thyroid surgery. Other causes of hypoparathyroidism include autoimmune destruction of the glands. The lab values reveal low PTH and low calcium levels.]]
Answer C AnswerC::C
Answer C Explanation [[AnswerCExp::Secondary hyperparathyroidism is characterized by elevated serum PTH due to decreased levels of calcium. The most common causes are chronic renal insufficiency (due to impaired vitamin D hydroxylation towards its active form) and intestinal malabsorption of calcium.]]
Answer D AnswerD::D
Answer D Explanation [[AnswerDExp::Primary hyperparathyroidism is most commonly caused by an adenoma, hyperplasia, or carcinoma of the parathyroid glands.]]
Answer E AnswerE::E
Answer E Explanation [[AnswerEExp::This option corresponds to hypercalcemia independent of PTH, as observed in malignancies with paraneoplastic syndromes in PTHrp-secreting tumors.]]
Right Answer RightAnswer::D
Explanation [[Explanation::Primary hyperparathyroidism is the most common cause of hypercalcemia. The most common cause of primary hyperparathyroidism is a single adenoma, which accounts for more than 80% of cases. Less commonly, primary hyperparathyroidism is caused by hyperplasia of the parathyroid glands or hereditary syndromes, such as multiple endocrine neoplasia (MEN) syndromes types 1 and 2A. Although the diagnosis of primary hyperparathyroidism is usually incidental since the majority of patients remain asymptomatic, manifestations of the disorder are primarily due to hypercalcemia. The classical clinical features of hypercalcemia may be summarized as: Stones, bones, groans, and psychiatric overtones.
  • Stones: Nephrolithiasis and nephrocalcinosis
  • Bones: Low bone mineral density (characteristically at the distal third of the radius as observed in this patient), vertebral fractures, and bone pain
  • Groans: Constipation
  • Psychiatric overtones: Cognitive impairment, anxiety,

Other features may include polyuria and polydypsia, easy fatigability, high blood pressure, insulin resistance, hyperglycemia, and dyslipidemia. Typically, initial laboratory findings of patients with primary hyperparathyroidism reveal hypercalcemia on routine work-up. Total serum calcium level should always be differentiated from free and albumin-bound circulating calcium. Accordingly, calcium levels should be corrected and calculated as follows: Corrected serum calcium (mg/dL) = Measured total calcium (mg/dL) + [0.8 x (4.0 - serum albumin (g/dL)]. Patients with hypercalcemia should undergo testing for serum PTH, which is often elevated or inappropriately normal in patients with primary hyperparathyroidism. The definitive diagnosis of primary hyperparathyroidism cannot be made until other diseases that also cause hypercalcemia and/or elevated serum PTH are excluded, such as thiazide or lithium intake, tertiary hyperparathyroidism due to end-stage renal disease (ESRD), familial hypocalciuric hypercalcemia, and PTHrp-secreting malignancies. Of note, PTH and PTHrp are measured separately during laboratory work-up, and patients with PTHrp-secreting tumors usually have low PTH and elevated PTHrp levels). Patients with primary hyperparathyroidism usually have decreased 25-hydroxyvitamin D levels due to the increased conversion to 1,25-dihydroxyvitamin D. Urinary creatinine and calcium levels should be measured to differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcemia (mutation in calcium-sensing receptor gene). In patients with primary hyperparathyroidism, the urinary calcium:creatinine clearance ratio is typically > 0.01. Other urinary findings also include elevated cAMP levels. Parathyroidectomy is often required to treat patients with symptomatic disease.

Physiologically, PTH has many functions:

  1. Increases the production of macrophage colony-stimulating factor and RANK-L, which binds RANK on osteoblasts and consequently stimulate osteoclasts
  2. Net increase in serum calcium levels and net decrease in serum phosphate levels
  3. Increases bone resorption of both calcium and phosphate
  4. Increases the activity of Ca2+/Na+ exchange and increases the reabsorption of calcium in the early distal convoluted tubule in the kidneys
  5. Inhibits the activity of Na+/PO43- cotransport in the proximal convoluted tubule in the kidneys and facilitates that renal excretion of phosphate
  6. Stimulates 1-α hydroxylase, which converts 25-hydroxyvitamin D into its active form, 1,25-dihydroxyvitamin D



Educational Objective: Primary hyperparathyroidism is most commonly caused by an adenoma, hyperplasia, or carcinoma of the parathyroid glands. Although the diagnosis of primary hyperparathyroidism is usually incidental since the majority of patients remain asymptomatic, manifestations of the disorder are primarily due to hypercalcemia. The classical clinical features of hypercalcemia may be summarized as: Stones, bones, groans, and psychiatric overtones. Typically, patients with primary hyperparathyroidism have elevated serum calcium levels and elevated or inappropriately normal serum PTH levels.
References: Marcocci C, Cetani F. Primary hyperparathyroidism. N Engl J Med. 2011;365(25):2389-97.
First Aid 2014 page 323, 324]]

Approved Approved::Yes
Keyword WBRKeyword::PTH, WBRKeyword::Primary hyperparathyroidism, WBRKeyword::Hyperparathyroidism, WBRKeyword::Hypercalcemia, WBRKeyword::Constipation, WBRKeyword::Polyuria, WBRKeyword::Polydypsia, WBRKeyword::Calcium, WBRKeyword::Phosphate, WBRKeyword::Vitamin D, WBRKeyword::Kidney stones, WBRKeyword::Nephroplithiasis, WBRKeyword::Hypercalciuria
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