Hyponatremia due to secondary adrenal insufficiency

Thanks to Jess for presenting the fascinating case of a middle-aged woman with family history of autoimmune disease who presented with acute onset of fatigue and abdominal pain, found to have vitiligo on exam.  Work up revealed hyponatremia due to a secondary adrenal insufficiency, pancytopenia, and panhypopituitarism possibly due to a yet to be diagnosed autoimmune disorder!


Clinical pearls

  • Remember that hyponatremia is a problem of water regulation that can be compounded by low solute intake.
  • Primary adrenal insufficiency is disorder at the level of the adrenal glands and manifests with low sodium and high serum potassium levels.
  • Secondary adrenal insufficiency is disorder at the level of the pituitary and manifests with low/normal sodium and normal potassium levels (because low cortisol leads to high ADH levels and hyponatremia).
    • Make sure to do work up to rule out panhypopituitarism.  Keep in mind that the most sensitive test for HPA access integrity is LH/FSH.
  • Tertiary adrenal insufficiency is disorder at the level of the hypothalamus and presents similarly to secondary AI.
  • Test for adrenal insufficiency with a cort-stim test and/or AM cortisol and ACTH levels.

Hyponatremia

Remember these three steps to working up hyponatremia:

  1. Is there a sodium problem? check serum osm
  2. Are the kidneys responding appropriately? check urine osm
  3. Is ADH revved up for a hemodynamic reason? check urine Na 

Capture

Adrenal insufficiency

Adrenal insufficiency
Source: NIDDK.gov

Primary AI:

  • Failure of adrenal glands
  • Causes: Addison’s (most common in the US), infiltrative processes (TB, sarcoid), hemorrhage, toxins
  • Labs would show ↓Na and ↑potassium (b/c aldosterone is gone)

Secondary AI:

  • Failure of pituitary (low ACTH)
  • Causes: pituitary lesions, surgeries, TBI, drugs
  • Clinically may present with loss of other anterior pituitary hormones
  • Labs would show ↓Na (because low cortisol leads to high ADH levels) but normal potassium levels (b/c aldosterone is active)

Tertiary AI:

  • Failure of hypothalamus (low CRH)
  • Causes: more commonly iatrogenic (cessation of high dose glucocorticoid therapy without taper) or post surgical interventions.

Hypopituitarism

Capture

Hypophysitis:

  • Inflammation of the pituitary
  • Four categories based on histologic findings:
    • Lymphocytic
      • Most common form
      • Seen in late pregnancy and post-partum period
      • Also associated with CTLA4 inhibitors like ipilimumab
    • Granulomatous
      • Idiopathic or secondary to GPA, sarcoid, TB
    • Plasmacytic (IgG4-related)
    • Xanthomatous (most rare)
  • Clinical presentation
    • Headache out of proportion to exam findings
    • Preferential decrease in ACTH and TSH ⇒ adrenal insufficiency and hypothyroidism
  • Prognosis:
    • Pituitary size eventually normalizes but pituitary loss of function is often permanent.

 

Hypercalcemia

Today, we discussed the case of a middle-aged woman with no significant medical history who presented to PCP with a month of nausea, vomiting, weakness, and 30 pound weight loss, found to have severe hypercalcemia likely secondary to a granulomatous disease.  Final diagnosis pending biopsy results.


Clinical Pearls

  • The first step in working up hypercalcemia is correcting for albumin.  Keep in mind that patients with hypoalbuminemia may have a falsely low serum calcium level.  Conversely, patients with multiple myeloma who have a high paraprotein serum concentration may have a falsely elevated total serum calcium level.  When in doubt, check an ionized serum calcium to confirm true hypercalcemia.
  • Think of hypercalcemia in two broad categories of PTH dependent disorders and PTH independent disorders (see below).
  • 25-OH vitamin D has a long half life and is the best laboratory test to determine adequate nutritional intake of vitamin D.  In contrast, 1,25OH vitamin D has a short half life.

Calcium homeostasis:

  • Remember that bone is the largest reservoir of calcium in the body.

calcium homeostasis

Source: this NEJM case

Work up of hypercalcemia

  • Remember to confirm true hypercalcemia by correcting for albumin and/or measuring ionized calcium for people with conditions such as multiple myeloma who may have a falsely elevated total serum calcium due to increased paraprotein binding.
  • Check out this super awesome previous post on hypercalcemia on our blog for more details.  Here is the simplified diagnostic algorithm we went over today:

Hypercalcemia algorithm

Treatment

  • Ca <12
    • No treatment if asymptomatic
    • Avoid exacerbating factors
  • Ca 12-14
    • If chronic/asymptomatic ⇒ same treatment as Ca <12
    • If acute/symptomatic ⇒ same treatment as Ca 14-18
  • Ca 14-18
    • IVF – LOTS!
    • Lasix only if the patient has concurrent renal/heart failure
    • Calcitonin
    • Bisphosphobates
      • Zoledronic acid >> pamidronate for patients with malignancy
      • Do not use in patients with Cr >4.5
    • Denosumab (RANKL) if refractory to zoledronic acid or in patients with severe renal impairment
  • Ca >18
    • Same treatment as Ca 14-18 PLUS
    • Hemodialysis

Treatment options: (table adapted from UpToDate)

 

Treatment of hypercalcemia

* Only used in patients with renal insufficiency or heart failure, judicious use of loop diuretics may be required to prevent fluid overload during saline hydration.

Vitamin D metabolism

  • Remember the following simplified pathway of vitamin D metabolism

Vitamin D

Source: Hepatitis B Foundation

  • 25-OH vitamin D has a long half-life and the best laboratory test to perform to determine adequacy of nutritional intake
  • In work up of hypercalcemia, it is also important to check 1,25-dihydroxyvitamin D levels.  Why?
    • Remember that 1-alpha hydroxylase is an enzyme in the kidney that converts 25-OH vitamin D into its metabolically active form ⇒ 1,25-dihydroxyvitamin D
    • It turns out that in certain granulomatous diseases and lymphoma, activated monocytes in affected tissues start to express 1-alpha hydroxylase as well, resulting in overproduction of 1,25-dihydroxyvitamin D.
    • So, in work up of hypercalcemia that is PTH-independent, if you notice elevated 1,25-dihydroxyvitamin D with normal 25-OH vitamin D levels, suspect granulomatous disease or lymphoma causing exogenous 1,25-dihydroxyvitamin D  production.

Hypothermia and Myxedema Coma – 11/13/18

Thanks to Austin for presenting the case of an elderly woman with h/o psychiatric disorder who presented with acute/subacute onset of AMS, severe hypothermia, sinus bradycardia, and hypotension with work up revealing hypothyroidism suspicious for myxedema coma!


Clinical Pearls

  • Exam findings for hypothermia change depending on severity of hypothermia (see below).
  • It is crucial to measure core body temperature for accuracy especially when you are rewarming the patient (esophageal is the best, rectal/bladder are ok prior to rewarming but can remain low in spite of increasing core body temp so do not rely on these metrics alone)
  • Think of etiologies of hypothermia broadly within the categories of increased loss or decreased heat generation.
  • The most common causes of hypothermia are sepsis, exposure, and hypoglycemia.
  • The hallmarks of myxedema coma are AMS, hypothermia, and a precipitating event (i.e. infection, exposure, meds, etc.)
  • Myxedema coma is a medical emergency with a high mortality rate.  So consult endocrine early when you are suspecting it.
  • Always treat myxedema coma with levothyroxine AND steroids until you have ruled out a concurrent adrenal insufficiency.

HYPOTHERMIA

Types:

  • Mild (32-35°C)
    • Clinical manifestations
      • Shivering, rigors
      • ↑ HR, ↑ RR, ↑ BP, hyperventilation
      • Cold diuresis
        • Body’s attempt to preserve heat.  When peripheral vasoconstriction occurs to keep blood closer to vital organs, BP rises.  Kidneys see this rise in BP and act to correct it by dumping fluid! (Oh kidneys…)
    • Treatment
      • Passive, external
        • Blankets
        • Humidified inspired air
  • Moderate (28-32°C)
    • Clinical manifestations
      • ↓ shivering
      • Confusion, slurred speech
      • ↓ HR, hypoventilation
      • Can also start to notice other cardiac manifestations such as prolonged QTc, QRS, osborn (J) waves, ST elevations/depressions.
      • ↓ renal blood flow
    • Treatment
      • Passive, external (see above) PLUS
      • Active external
        • Forced heated air
        • Warm blankets
        • Warm water immersion
      • Active internal
        • Warm humidified air (42°C)
        • Warm IV fluids (42°C)
        • Body cavity lavage (in trauma patients only)
  • Severe (<28°C)
    • Clinical manifestations
      • NO shivering
      • Edema (due to poor renal blood flow) of extremities and lung
      • ↓ HR, ↓ BP (due to drop in cardiac output), hypoventilation, ventricular arrhythmias
      • Cardiac manifestations more common as with moderate hypothermia
      • AMS
      • Paradoxical undressing
        • mechanism is poorly understood but thought to be due to paralysis of the nerves regular vascular muscle tone leading to vasodilation and sensation of a heat flush which results in the patient wanting to take their clothes off.
    •  Treatment
      • Any of the above (passive external, active external, active internal) and/or
      • Extracorporeal
        • HD
        • ECMO

Etiologies of hypothermia:

Capture

Items in red above are the most common causes of hypothermia.

Lab findings:

  • Less reliable since labs have to be warmed prior to processing
    • ABG is often inaccurate
    • Coagulopathy may be masked
    • Hyperkalemia due to rewarming

Complications of rewarming:

  • Hypotension due to peripheral vasodilation
  • Ileus and urinary retention
  • Worsening coagulopathy
  • Arrhythmias
  • Hyperkalemia
  • Core temperature after-drop (a condition in which cold peripheral blood gets shunted to the core and results in further decline in temperature.  You can avoid this by active internal rewarming like warmed IV fluids)

MYXEDEMA COMA 

Learn all about it from our prior blog post here.

Metastatic… Insulinoma? 11/7/2018

Yonglu presented a middle age man with no medical history presenting with syncope. In the preceding months, he has been having non-specific fatigue, decreased exercise tolerance, dizziness, and diaphoresis. He was found to be hypoglycemic after this syncopal episode, and in the hospital his labs were consistent with hyperinsulinism when he was in a hypoglycemic state. CT revealed diffuse liver masses concerning for HCC, as well as a lesion on his left iliac crest appearing to be an osteosarcoma. He was also found to have a pancreatic mass as well…

Three malignant processes? Octreotide scan revealed increased uptake at these regions, and biopsy of the liver revealed a diagnosis of a neuroendocrine tumor!


Hypoglycemia

When we think about hypoglycemia, its pattern can actually give us a clue.

  • Fasting: Most common
  • Post-prandial: non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), post-bariatric surgery hyperinsulinemic hypoglycemia
  • Both: Insulin autoantibody, insulinoma

hypoglycemic-differential-hypoglycemia-malignancy-diagnosis-original

Source: grepmed


Insulinoma

Epidemiology

  • Rare, not enough data
  • Small cohort: median age 48 years, 77% men
  • MEN Type 1: Younger presentation, 20s

Pathophysiology

  • Pancreatic islet cell origin
  • Generally benign, single vs multiple
  • Rare to be malignant (10%)

Presentation

  • Pattern: fasting hypoglycemia mainly but can be both
  • May have some sympathoadrenal sx i.e. palpitations, diaphoresis (seen in this patient), tremulousness
  • Likes to spread to liver, rarely can have bony mets (~13%)

Whipple’s Triad: Presence of all three demonstrates “true” hypoglycemia

  • Symptoms of hypoglycemia
  • Low plasma glucose at time of symptoms
  • Relief of symptoms when glucose is back to normal

Diagnosis

  • Evidence of inappropriately high serum insulin during episode of hypoglycemia
  • 72 hour fasting plasma glucose test: Supervised fast in order to bring on hypoglycemia in order to evaluate etiology. If pt has underlying hyperinsulinism, 95-99% of the time they will be hypoglycemia within 48 hours of fasting.
    • Blood test is drawn when pt has sx of hypoglycemia
    • Test: Glucose, insulin, proinsulin, and c-peptide level.
    • Normal: suppression of endogenous insulin
    • Abnormal: Inappropriately elevated insulin, pro-insulin, and c-peptide in setting of hypoglycemia.
  • Octreotide scan: Increased uptake seen in tumors of neuroendocrine etiology, more sensitive than US, CT, or MRI for detection of somatostatin receptor positive tumors
  • Evidence of hyperinsulinism
    • Low BHB
    • High insulin level
    • High C-peptide
    • High pro-insulin
  • Chromogranin A: used to help diagnose carcinoid tumors (NET of the digestive tract and lungs). Nowadays carcinoid is generally used to refer to well differentiated NETs originating in the lungs. GI tract tumors are now termed NET.

Management

  • Localized lesion: Surgical resection is curative
  • Hypoglycemia
    • Somatostatin analogy
      • Octreotide: Inhibits growth hormone secretion, can switch to Q-monthly formulation
      • Lanreotide
    • Diazoxide: Diminishes insulin secretion, side effects include hirsutism and edema
  • Radiation therapy: Data also limited in utility but can be consider if evidence of bony mets (which is also rare for NET)
  • Chemo:
    • Minority of NET, namely high-grade, well differentiated with Ki67 index > 20%, are rare and there is no consensus on how to treat these patients. These patients generally respond poorly to platinum/etoposide based regimens used to treat most NETs.
    • Other options: Temozolomide, Sunitinib (RTK inhibitor), Everolimus (mTOR inhibitor)

Helpful table for hypoglycemia work up.

Beta-hydroxybutyrate (BHB) is by product of alternate metabolism (more specifically ketone bodies) in a fasting state, so it can be elevated in setting of prolonged fasting (not just DKA).

Also thanks to Arathi for pointing out that insulin has a negative feedback on this process, hence in a hyperinsulinemic state (despite concurrent hypoglycemia), beta hydroxybutyrate would be very low!

Insulinomas can appear like hypoglycemia secondary to oral glycemic agents, but the key is the oral glycemic agent screen would be positive in the latter case!

IGF-omas can cause s/sx hypoglycemia due to similarity with insulin. Expect IGF2 levels to be elevated in such cases and elevated BHB.

Capture.JPG

Please refer to this helpful review article if you want to know more about NETs!

Also please refer to this paper for a case report on AFP-producing pancreatic NET (AFP elevated in this patient!)

Adrenal insufficiency, lupus flare, and mixed AIHA- 9/6/18

Thanks to Becky for presenting the case of a middle-aged woman with h/o SLE and Evans syndrome who presenting with subacute onset of fatigue after her prednisone dose was reduced, found to have iatrogenic adrenal insufficiency, lupus flare, and mixed autoimmune hemolytic anemia!


Clinical Pearls:

  • Evans syndrome describes AIHA + ITP, a rare condition associated with SLE and often precedes the diagnosis of SLE by a few years.
  • Hematologic manifestations of SLE are many and include the following
    • Anemia (chronic disease, iron deficiency, medication-induced, warm AIHA>>cold AIHA, pure red cell aplasia, MAHA, and pernicious anemia)
    • Leukopenia
    • Thrombocytopenia
    • Pancytopenia
    • Evans syndrome
  • Smear findings can be very helpful in diagnosing different types of hemolytic anemiasSchistocytes are a very specific for MAHA, valve disorders, AVMs, APLS whereas AIHA would result in spherocytes. 
    • The negative predictive value of spherocytes is low.  So a smear without spherocytes does not rule out AIHA!
  • Lastly, the most common cause of adrenal insufficiency (AI) is iatrogenic.
    • General rule of thumb for when risk of AI is high and you should taper steroids slowly is if someone is on prednisone > 20 mg for > 3 weeks.  Keep in mind that people with smaller BSA would be more susceptible to AI and at risk with even lower doses.

Hemolytic anemia work up

Check smear

  • Schistocytes
    • MAHA: TTP, HUS, HELLP, DIC, HTN
    • Valve disorder
    • AVMs
    • APLS
  • No schistocytes (+ spherocytes)
    • Intrinsic RBC defect
      • Enzyme deficiency (G6PD)
      • Hemoglobinopathy (sickle cell)
      • Membrane defect (hereditary spherocytosis)
    • Extrinsic RBC defect
      • Liver disease
      • Splenic sequestration
      • Infections (clostridium perfringens, babesia, malaria, bartonella)
      • Meds/toxins (dapsone, nitrites, lead, copper, snake venom)
      • AIHA (warm and cold)
    • Intravascular
      • Transfusion reaction
      • Infections
      • PNH

Lab findings in AIHA: 

  • ↑ retic
  • ↑ indirect bili
  • ↑ LDH
  • ↓ haptoglobin
  • + DAT (but keep in mind that DAT can be negative in 3% of patients with WAIHA)
  • + spherocytes

Summary of AIHAs:

Picture1

 

Thyroid storm! Or is it?… 8/28/18

Thanks Hong for presenting the case of a middle-aged woman with recent diagnosis of Grave’s disease off methimazole who presented with A fib with RVR and congestive heart failure, raising a debate on thyroid storm!


Clinical Pearls:

  • Thyroid storm is an extremely rare (1 in 500,000) but life-threatening diagnosis (up to 30% mortality) that should not be missed.
  • Degree of thyroid hormone elevation or TSH suppression is not a criteria for diagnosing thyroid storm! In fact, levels are typically similar to those of patients with uncomplicated thyrotoxicosis.
  • Common clinical feature is cardiovascular symptoms (heart failure, arrhythmia, tachycardia) but more specific finding is AMS.
  • Scoring criteria to screen for thyroid storm include Burch/Wartofsky and the Akamizu criteria, but they have not been validated.
  • Consult endocrine early if you suspect thyroid storm!

Thyroid storm: 

Risk factors:

  • Longstanding untreated hyperthyroidism
  • Precipitants:
    • Thyroid/non-thyroidal surgery
    • Trauma
    • Infection
    • Acute iodine load
    • Parturition
    • Irregular use or discontinuation of antithyroid treatment

Etiology: not clearly understood, but possibly related to the following

  • Rapid rate of increase in thyroid hormone levels?
  • Increased responsiveness to catecholamines?
  • Enhanced cellular responses to thyroid hormone?
  • The degree of thyroid hormone elevation or TSH suppression is not typically more profound than uncomplicated thyrotoxicosis

Clinical features:

  • CV (>60% of cases)
    • Tachycardia
    • CHF
    • Arrhythmias
  • Hyperpyrexia
  • AMS (considered by many to be essential to diagnosis)
    • Agitation, anxiety, delirium, psychosis, stupor, coma
  • Features associated with worse outcomes?
    • AMS
    • Older age >60
    • Mechanical ventilation
    • Not using antithyroid drugs or beta blockers

Diagnosis: 

  • Clinical! No universally accepted criteria or validated clinical tools.  Degree of hyperthyroidism is not a criterion for diagnosis.  Some to know of that might be helpful:
    • Burch and Wartofsky (sensitive, not specific)
      • > 45: highly suggestive of thyroid storm
      • 25 – 44: impending storm
      • <25: thyroid storm unlikely
    • Akamizu (Japanese) system developed in 2012 (less sensitive but more specific)

Treatment

  • ICU admission!
  • Regimen
    • Beta blockers ⇒ control symptoms from increased adrenergic tone
    • Thionamide ⇒ block new hormone synthesis. PTU is preferred because it blocks peripheral conversion of T4 to T3.
    • Iodine solution ⇒ block release of thyroid hormone (saturated solution of potassium iodide)
    • Iodinated radiocontrast agent (not available anymore in most places) ⇒  inhibit peripheral conversion of T4 to T3
    • Glucocorticoids ⇒ reduce T4 to T3 conversion, promote vasomotor stability, and treat any associated relative adrenal insufficiency
    • Bile acid sequestrants ⇒ decrease enterohepatic recycling of thyroid hormones (only in very severe cases)
  • Principles
    • Start with beta blockers + PTU, and stress dose steroids
    • 1 hour later: start SSKI q6h (after hormone synthesis has been halted with PTU, otherwise SSKI can make thyroid storm worse)