VA Resident Report: Review of pheochromocytoma and imaging

The Bottom Line: Imaging studies are important for tumor localization and lineation of its extent. They are also important in diagnosing multiple primary tumors and/or metastatic lesions in patients with various genetic disorders. The approach to surgical removal may depend considerably on the location, extent, and the association of the tumor with nearby anatomical structures. Imaging studies, especially functional studies are also useful adjuncts in confirming diagnosis of the tumor when biochemical investigations are ambiguous or not available in patients with clinical suspicion of the tumor. Computed tomography, contrast enhanced CT, and magnetic resonance imaging are now routinely complemented by functional imaging using various radiotracers such as 123I-metaiodobenzylguanidine and 111In-DTPA-pentetreotide.

References: Ramachandran, R., & Rewari, V. (n.d.). Current perioperative management of pheochromocytomas. Indian Journal of Urology : IJU : Journal of the Urological Society of India., 33(1), 19-25.

Summary: Surgical removal of PCC and PGL alleviates the signs, symptoms and probable end organ damage due to catecholamine hypersecretion. Preoperative optimization has played an important role in decreasing the high incidence of perioperative morbidity and mortality historically associated with these surgical procedures. Alpha-receptors blockade, especially with selective alpha-1 receptor antagonists, is thus vital in these patients preoperatively


EUHM Resident Report: What is the incidence of muscle twitch in hypercalcemia

The novel family of genetically encoded calcium indicators, named ‘Twitch’ sensors, fulfill the majority of criteria and represent a major improvement over most existing indicators. The name of the indicators originates from the fact that their calcium sensor is derived from troponin C, a calcium-binding protein found in skeletal and cardiac muscle (but not neurons) that regulates muscle twitching.

Wilms, C., & Häusser, M. (n.d.). Twitching towards the ideal calcium sensor. Nature Methods., 11(2), 139-140.

Calcium is an exquisitely versatile signaling molecule, determining both cell differentiation and death as well as triggering neurotransmission and regulating synaptic plasticity. Consequently, determining the spatial and temporal dynamics of intracellular calcium concentration, [Ca2+], is crucial not only in cell biology but also for understanding immune physiology and brain function. Unsurprisingly, measuring [Ca2+] dynamics is one of the main uses of fluorescence microscopy and has spurred the development of new indicators for many decades

VA Resident Report: Treatment of insulinoma

The Bottom Line: Treatment of insulinoma consists of controlling symptoms of hypoglycemia, followed by tumor localization.

Neuroendocrine Tumors
Jensen, Robert T., Norton, Jeffrey A., Oberg, Kjell
Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 33, Pages 501-541.e15
Copyright © 2016 by Saunders, an imprint of Elsevier Inc.!/content/3-s2.0-B9781455746927000338 (click on “Treatment” in the menu on the left)

Hypoglycemia is controlled in most insulinoma patients by a combination of dietary and pharmacologic therapy. Snack intake should not be restricted to rapidly absorbed carbohydrates, because their ingestion may occasionally stimulate insulin secretion from the tumor.

If liver metastases are not present on imaging studies (>90% of cases), surgical exploration and resection (if possible) are indicated in patients with insulinomas. Anywhere from 70% to 97% of patients are cured by surgery.

VA Resident Report: What is the association of hyperprolactinemia in association with hypothyroidism?

The Bottom Line This study showed prevalence of hyperprolactinemia in subclinical hypothyroidism is notable and this disorder is more common in female subclinical
hypothyroidism than the men.

Bahar, Adele, et al. “Hyperprolactinemia in association with subclinical hypothyroidism.” Caspian journal of internal medicine 2.2 (2011):229-33.

Hyperprolactinemia is the most prevalent endocrine disorder in hypothalamicpituitary axis. Pathologic hyperprolactinemia is generally applied for the situation in which prolactin level increases because of some reasons other than physiologic causes. Prolactin secretion is controlled by prolactin inhibitor factor that is secreted from hypothalamus, other factors like vaso active inhibitory peptide and Thyroid releasing hormone cause to increase prolactin secretion. In fact, TRH in addition to increasing TSH causes to rise prolactin level . In patients with primary hypothyroidism, increased levels of TRH can cause to rise prolactin levels and these patients may have galactorrhea. Different increased level of serum prolactin has been reported in 30% of patients with primary hypothyroidism. Subclinical hypothyroidism is defined by high TSH and normal thyroid hormones.

Is there sufficient evidence for the subcutaneous administration of insulin for diabetic ketoacidosis?

The Bottom Line: In patients with mild-to-moderate DKA, subcutaneous injections of insulin lispro every 1-2h offer a feasible alternative to continuous intravenous infusions of regular insulin, and should now be evaluated in larger, more appropriately powered studies.

Reference: Vincent M, Nobécourt E.  Treatment of diabetic ketoacidosis with subcutaneous insulin lispro: a review of the current evidence from clinical studies.  Diabetes Metab. 2013 Sep;39(4):299-305.  

 Summary: The data presented in this review have several limitations. First, all four studies were only exploratory and included small patient numbers of 20–50 patients per study. Also, the studies offered a mean time to resolution of DKA only; median values would have been more representative as the time to event data are almost always skewed. In addition, a wide variety of patients was included in each of the studies, and no information regarding the presence of concomitant complications was provided. Patients with severe complications such as hypovolaemic shock or serious acidosis were excluded from all of these studies, so no data were available for these patient populations. However, patients with severe DKA and those who are critically ill or mentally obtunded, or who have severe complications such as hypotension, anasarca or cerebral oedema, require ICU admission anyway to ensure adequate nursing care and quick turnaround of laboratory test results. Replacing i.v. insulin infusions with s.c. injections would offer no advantages in such cases.

Correction of serum sodium [Na+] in hyponatremia

Bottom line: Verbalis states that the goal is a minimum correction of 4-8 mmol/L per day; if the risk of osmotic demyelination syndrome (ODS) is high then a lower goal of 4-6 mmol/L is recommended. Recommended limits not to exceed are 8 mmol/L per day for those at high risk of ODS and 10-12 mmol/L per day (or 18 mmol/L in any 48-hour period) for those at normal risk of ODS. Overcorrection risks iatrogenic brain damage.

How and why recommendations for sodium serum correction have changed over time are covered in the following sources.

Verbalis, Joseph G, et al. “Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.” The American journal of medicine 126.10 Suppl 1 (2013):S1-42.

Sterns, Richard H, Sagar UNigwekar, and John KevinHix. “The treatment of hyponatremia.” Seminars in nephrology 29.3 (2009):282-99.
This review article states, “A 4- to 6-mmol/L increase in serum sodium concentration is adequate in the most seriously ill patients…Virtually all investigators now agree that overcorrection of hyponatremia (which we define as 10 mmol/L in 24 hours, 18 mmol/L in 48 hours, and 20 mmol/L in 72 hours) risks iatrogenic brain damage….Accordingly, we suggest therapeutic goals of 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours.”

Adrogué, H J, and N EMadias. “Hyponatremia.” The New England journal of medicine 342.21 (2000):1581-9.
This review article states, “Most reported cases of osmotic demyelination occurred after rates of correction that exceeded 12 mmol per liter per day were used, but isolated cases occurred after corrections of only 9 to 10 mmol per liter in 24 hours or 19 mmol per liter in 48 hours.”

Sterns, R H, et al. “Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective.” Journal of the American Society of Nephrology 4.8 (1994):1522-30.
In this analysis of data for 56 patients, “no neurologic complications were observed among patients corrected by <12 mmol/L per 24 h or by <18 mmol/L per 48 h or in whom the average rate of correction to a serum sodum of 120 mmol/L was ≤0.55 mmol/L per hour.”

Karp, B I, and RLaureno. “Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia.” Medicine 72.6 (1993):359-73.
This was a review of records for 20 patients who experienced neurologic dysfuntion after hyponatremia correction. Six patients were eliminated from further analysis, leaving 14 who experienced severe hyponatremia. Because of the development of neurologic disorders in the patients, the study concluded that the rate of correction should be kept below 10 mEq/L/24 hours and 21 mEq/L/48 hours.

Diagnostic tests for pheochromocytoma and paraganglioma

Endocrine Society guideline states, “plasma metanephrines or urinary fractionated metanephrines are considered tests of choice.” See tables 4 and 5 in the guideline for data on sensitivity and specificity for the tests of choice.

DynaMed states, “Medications that may cause false positive results in biochemical catecholamine tests of plasma or urine include

  • acetaminophen
  • labetalol
  • sotalol
  • buspirone
  • paracetamol
  • phenoxybenzamine
  • tricyclic antidepressants
  • monoamine oxidase inhibitors
  • drugs containing catecholamines (for example decongestants)
  • levodopa
  • methyldopa
  • stimulants (such as caffeine, nicotine, or cocaine)
  • sympathomimetics (including amphetamines, ephedrine)
  • calcium-channel blockers such as dihydropyridines
  • sulphasalazine”

Figure 1 in New England Journal of Medicine article by Neary, King, and Pacak provides an illustration of pharmacologic interference with catecholamines and metanephrines. Acetaminophen doesn’t actually effect serum/urine levels of catecholamines but can interfere with lab assays used to measure them.

Lenders, Jacques W M, et al. “Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.” The Journal of clinical endocrinology and metabolism 99.6 (2014):1915-42.

Other references:
Donckier, J E, and LMichel. “Phaeochromocytoma: state-of-the-art.” Acta chirurgica Belgica 110.2 (2010):140-8.
Lenders, Jacques W M, et al. “Phaeochromocytoma.” Lancet (London, England) 366.9486 (2005):665-75.
Neary, Nicola M, Kathryn SKing, and KarelPacak. “Drugs and pheochromocytoma–don’t be fooled by every elevated metanephrine.” The New England journal of medicine 364.23 (2011):2268-70.

What is the mechanism of metformin-induced lactic acidosis ?

Lactic acid, the product of anaerobic glycolysis, is primarily produced and is fully dissociated into lactate and protons in both extracellular and intracellular fluids. Several studies have reported a small but significant increase in lactic acid levels with metformin use, in particular after meals. Metformin raises lactic acid levels by affecting the redox potential and promoting anaerobic metabolism. It interferes with complex I of the respiratory chain, leading to an inhibition of mitochondrial respiration. In the presence of hypoxia or tissue hypoperfusion, it can block mitochondrial oxidative phosphorylation inhibiting adenosine triphosphate synthesis, leading to a decrease in the ATP:ADP ratio and an increase in the NADH:NAD ratio. This can result in an accumulation of pyruvate that is later converted into lactate. This conversion allows for the regeneration of NAD+, enabling the production of ATP by anaerobic glycolysis, a much less efficient pathway. Increasing evidence indicates genetic differences that may explain interindividual variation in clinical response as well as renal clearance and bioavailability of the drug. Drug transporters, including plasma membrane monoamine transporter, organic cation transporters and multidrug and toxin extrusion transporter 1, have been recognized to play a major role in the absorption, distribution and elimination of metformin.46,47 In animal models, it was recently reported that MATE-1 dysfunction can lead to lactic acidosis after metformin treatment

Metformin-associated lactic acidosis.” The American journal of the medical sciences 349.3 (2015):263-267.

Metformin is a safe drug when correctly used in properly selected patients. In real life, however, associated lactic acidosis has been repeatedly, although rarely, reported. The term metformin-induced lactic acidosis refers to cases that cannot be explained by any major risk factor other than drug accumulation, usually due to renal failure. Treatment consists of vital function support and drug removal, mainly achieved by renal replacement therapy. Despite dramatic clinical presentation, the prognosis of metformin-induced lactic acidosis is usually surprisingly good.

The pharmacodynamics of levothyroxine (specifically synthroid) with regard to change in TSH level

Bottom line: No evidence exists that states how quickly TSH levels change after one begins taking levothyroxine. Recommendations for when to check TSH levels for those taking levothyroxine vary from 4-12 weeks depending on the circumstances.


The following pieces of the DynaMed entry for levothyroxine include the following quotes.

    • Overview: “Bioequivalence established for several brand and generic forms of levothyroxine, but consider measuring TSH level 6-8 weeks after change in formulation used”
    • Dosage and Administration/General: “Due to narrow therapeutic index, American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE) recommend not to use levothyroxine sodium preparations interchangeably.157 163 When switching preparations (e.g., from brand to generic), pharmacists should notify the patient and prescriber.162 163 In addition, clinicians should measure serum TSH concentration about 4–8 weeks after starting the new preparation and adjust dosage if needed.162 163
    • Dosage and Administration/General: “Initially, monitor response to therapy about every 6–8 weeks.135 140 141 142 Once normalization of thyroid function and serum TSH concentrations has been achieved, patients may be evaluated less frequently (i.e., every 6–12 months) 135 However, if dosage of levothyroxine is changed, measure serum TSH concentrations after 8–12 weeks.135 140 141 142 160
    • Dosage and Administration/Special Populations/Geriatric Patients/Hypothyroidism
      “Initiate therapy at lower doses than those recommended in younger patients.140 141 142 161 160 In geriatric patients with underlying cardiovascular disease, usual initial dosage is 12.5–25 mcg daily; increase dosage by increments of 12.5–25 mcg at intervals of 4–6 weeks until patient becomes euthyroid and serum TSH concentrations return to normal.140 141 142 160 If cardiac symptoms develop or worsen, reduce dosage or withhold therapy for 1 week and then cautiously restart therapy at a lower dose.140 141 142 161 160

The American Thyroid Association (ATA) website at states:
“Conclusion: Best Physician Practices: “Patients should be maintained on the same brand name levothyroxine product. If the brand of levothyroxine medication is changed, either from one brand to another brand, from a brand to a generic product, or from a generic product to another generic product, patients should be retested by measuring serum TSH in six (6) weeks, and the drug reiterated as needed. Since small changes in levothyroxine administration can cause significant changes in TSH serum concentrations, precise and accurate TSH control is necessary to avoid potential adverse iatrogenic effects.”

What is the correlation of hypertension and pheochromocytoma and anesthesia induction?

Pheochromocytomas are rare neuroendocrine tumors with a highly variable clinical presentation, but they most commonly present as spells of headaches, sweating, palpitations, and hypertension. Patients with pheochromocytoma may develop complicated and potentially lethal cardiovascular and other complications, especially in the setting of diagnostic or interventional procedures (e.g. upon induction of anesthesia or during surgery.

Karel Pacak Preoperative Management of the Pheochromocytoma Patient The Journal of clinical endocrinology and metabolism 92 (11) , pp. 4069–4079 2013/07/2/

to ensure ideal preoperative preparation of patients with pheochromocytoma, very close communication between the endocrine, surgical, medical, cardiology, pediatric, oncology, radiology, and anesthesia teams is essential. Such teamwork should be directed to meet the three most essential goals: treat hypertension and tachyarrhythmias, restore the vascular volume, and treat any tumor or catecholamine excess-associated medical problems