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Primary Adrenal Failure in the Emergency Department
YAJEM-57046; No of Pages 3 American Journal of Emergency Medicine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
A case of primary adrenal failure in the emergency department Al Giwa ⁎ Manchester Memorial Hospital, Department of Emergency Medicine, Manchester, CT, USA
a r t i c l e
i n f o
Article history: Received 8 October 2017 Accepted 15 October 2017 Available online xxxx Keywords: Hyponatremia Altered mental status Primary adrenal insufficiency Hypovolemia Addison's disease
a b s t r a c t Background: Primary adrenal failure is considered to be an extremely rare disease presenting in the ED, with an incidence reported to be as low as 50 cases per 1,000,000 persons (Klauer, 2017). I would like to present a case of a young man who presented to the ED, with what I suspected to be this rare entity. Case report: A 26 year old otherwise healthy male presented to our ED with complaints of weakness, nausea, vomiting, and hiccups of 1.5-day duration. He also complained of lightheadedness, describing it as if he was going to pass out. Other than slight tachycardia (100) and darkened skin, his physical exam, ROS, PMH, Family and Social History, were all unremarkable. His sodium returned at 111, and he was later noted to become more confused in the ED prompting the emergent use of Hypertonic Saline. Why should an emergency physician be aware of this?: Albeit a rare disease entity, EPs need to keep this life threatening disease process in the back of their minds when presented with a patient with vague symptoms such as weakness or fatigue, electrolyte abnormalities and darkening of their skin. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Primary adrenal failure is considered to be an extremely rare disease, with an incidence reported to be as low as 50 cases per 1,000,000 persons [1]. Secondary adrenal failure on the other hand is commonly seen and is reported to be in higher incidence due to the increased and widespread use of exogenous steroids. Primary adrenocortical insufficiency is reported to have multiple possible etiologies, however ~80% of cases in the United States are caused by autoimmune adrenal destruction. The second most frequent cause is due to glandular infiltration by tuberculosis [2]. I would like to present a case of a young man who presented to the ED, with what I suspected to be this rare entity. 2. Case report A 26-year-old otherwise healthy male presented to our small community based ED with complaints of weakness, nausea, vomiting, and hiccups of 1.5-day duration. He also complained of lightheadedness, describing it as if he was going to pass out. He stated he had a similar presentation while backpacking with his sister in Europe during the spring, just a few weeks earlier. He said, while he was in France, he developed nausea, vomiting and while waiting to see a physician, passed out in
⁎ Emergency Medicine, Icahn School Of Medicine at Mount Sinai, One Gustave l. Levy Place, New York, NY 10128, USA. E-mail address: [email protected].
the triage area. He states he had severe electrolyte abnormalities and renal dysfunction (exact numbers are unknown) and they hydrated him with IV fluids. He said during his in-patient stay he had an ultrasound of his abdomen, which showed a mass on top of one of his kidneys. At this point, he wanted to return to the USA, and was discharged to the care of his PCP in Connecticut. Per the patient' father, his PCP ordered labs which were all within normal limits, and also ordered an MRI of his abdomen which as of the presentation to our ED tonight, had not yet been read. At tonight's presentation, patient denied any other constitutional symptoms such as fever, chills, sick contacts, hematemesis, hematochezia, diarrhea, dysuria, chest pain, sob, abdominal pain, headache, visual disturbances, or any other complaints. He did reiterate he felt very weak and felt like he was about to pass out. He denied taking any medications; he reported Acetaminophen gave him rashes and made him “sick”, and that he was lactose intolerant. He denied illicit drug use currently, but admitted to smoking marijuana a couple of times while in High School 10 years earlier. He denied cigarette use, and said he drank alcohol only occasionally. Of note, he went to Europe to chaperone his younger sister and as a result did not engage in any drug or alcohol use while in Europe, and has continued to remain a teetotaler. His initial vital signs were essentially normal except for a pulse of 100 (96.4, 22, 108/75, 98%). He appeared to be in no acute distress; Alert and oriented ×3, and other than looking somewhat more “tanned” than I would expect a Caucasian to be, the rest of his physical exam was completely unremarkable.
https://doi.org/10.1016/j.ajem.2017.10.043 0735-6757/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Giwa A, A case of primary adrenal failure in the emergency department, American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.10.043
2
A. Giwa / American Journal of Emergency Medicine xxx (2017) xxx–xxx
I ordered routine labs including lactate and urinalysis, as well as a CXR, CT Abdomen/Pelvis with IV contrast, and started him on a 2 liter NS bolus. He was also given IV Pepcid and Zofran, but within an hour, his father came out to the nurses' station and asked for more antinausea medicine due to his son's persistent symptoms. Upon reevaluation, I noticed the patient was pacing around his room and appeared very restless and somewhat agitated. He was very different from the person who just an hour earlier had calmly given me a very detailed history on his symptoms and recent travels to Europe and everything that since ensued. He continued to state he was feeling very nauseated, so I added Phenergan and Benadryl, in the hopes of giving him a little relaxation and somnolence. His CXR was read by me as No Acute Pulmonary Disease. Within a few minutes of leaving the patient's room, the lab called with a critical report. His Na+ was 111. His K + was 4.8, BUN/Cr was 25 and 0.89, CO2 was 21 and Cl- was 76. His lactate was 1.1. The lab called back again, this time stating they were having problems running his CBC, as it was “too thick”. His Unconjugated Bilirubin was 4.4 and conjugated was 0.3. The rest of his LFTs were essentially normal. The patient was sent for his CT Abdomen/Pelvis, but upon his return he started to complain of severe lower back pain of new onset. No other complaints, and no additional findings on reexamination. Due to the level of agony he appeared in, I gave him 50 ucg of Fentanyl IV and continued 0.9% NS. The CBC returned with a WBC of 7.2. Hct/Hgb of 18.2/51.2, and platelets of 269. A manual diff was performed and was all within normal limits. I reviewed the CT images of his abdomen, and saw nothing remarkable, but awaited the official read. The patient was reevaluated and gave me the thumbs up sign, stating his pain and nausea had all resolved. I told them about his hyponatremia and discussed the need to admit him and to start hypertonic saline. I discussed the case with the admitting team and awaited their evaluation. Approximately an hour later, his nurse observed that the patient was acting strange again, and called me back to the room. At this point, the hypertonic saline was infusing at 50 cm3/h. The admitting Family Medicine residents were at the bedside and were able to witness his changing mental status. They presented the case to their attending, but he asked for a urine toxicology, stating it sounded more like Ecstasy, Spice or K2, and discontinued the hypertonic saline. They said they would observe the patient in the ICU, and he was expeditiously moved out of the department. Initial Night Hawk Radiology read of his abdomen/pelvis CT was negative. A CT of his Head was ordered but patient was transferred out of the ED prior to it being performed. 3. Discussion According to Up-To-Date, “Adrenal insufficiency can be caused by diseases of the adrenal gland (primary), interference with corticotropin (ACTH) secretion by the pituitary gland (secondary), or interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus (tertiary)” [3]. For fear of losing my EM colleagues with an indepth analysis of the hypothalamic-pituitary axis, and the various components and regulatory mechanisms of the adrenocortical system, I will be providing only a cursory review of the role of the adrenals in primary adrenal insufficiency. In primary adrenocortical insufficiency, glucocorticoid and mineralocorticoid properties are lost. As you might recall, glucocorticoids are responsible for metabolism and immunologic function among many other postulated functions, whereas mineralocorticoids are primarily concerned with maintaining electrolyte and fluid balances [4]. Similarly, a discussion on the differential diagnosis of hyponatremia and altered mental status is beyond the scope of this paper, but the key causes of hyponatremia are as follows: • Pulmonary/Mediastinal Disease • Pseudo lowering due to a hyperosmolar agent
• • • •
CNS Disorders Water intoxication/SIADH Extreme activities causing profuse sweating Hormonal causes-Hypothyroid or Adrenal Insufficiency
Our patient had no pulmonary symptoms and had a completely unremarkable lung exam and chest X-ray. His neurological exam was completely normal, with an initial GCS of 15 and NIHSS of 0. He denied drug use and did not report excessive exercise or drinking large amounts of fluid (water or beer, as the latter has been reported to cause hyponatremia in a syndrome called Beer Potomania [5]). Lastly, his glucose and albumin were normal, and he was not spilling proteins in his urine to make me think of a pseudohyponatremia cause, which was traditionally defined as “a displacement of serum water by elevated concentrations of serum lipids or proteins” [6]. We have since, changed this definition to include all osmotically active substances, including but not limited to Glucose, proteins, lipids, etc. Hyponatremia is further characterized by the volume status of the patient in order to better elucidate a cause (and treatment). ACEP's online clinical management section discusses hyponatremia as follows: “Causes of hypovolemic hyponatremia may include excessive sodium losses from the kidneys, the skin, or the GI tract and also includes “third spacing” of fluids. Causes of euvolemic hyponatremia may include etiologies such as SIADH and psychogenic polydipsia. Many conditions stimulate ADH production including angiotensin release, hypovolemia, increased serum osmolality, hypotension, opiates, caffeine, and stress. ADH may be inappropriately secreted due to CNS or pulmonary infections and due to multiple medications including most diuretics. Causes of hypervolemic hyponatremia may include fluid overload states such as CHF, pregnancy, cirrhosis, and nephrotic syndrome. Serum sodium levels may also be artificially low with increased levels of plasma proteins or lipids and with increased serum concentration of osmotically active chemicals such as glucose and mannitol.” [7] I did not have an osmolality to determine the patient's volume status, but given his symptoms of vomiting and a prerenal azotemia on his labs, I presumed he was hypovolemic hyponatremia. Hence, given his hyponatremia, bronze-like skin, and the previously reported mass seen by the French, I suspected a primary Adrenal cause. He was not on any exogenous steroids (or any medications whatsoever) that could have caused a secondary or tertiary adrenal crisis. He denied any signs or symptoms of sepsis, with an initial qSOFA score of 0, and only 1 SIRS criterion (tachycardia), and hence an infectious etiology for adrenal failure was ruled out. According to the National Institute of Diabetes and Digestive and Kidney Diseases: “The most common symptoms of adrenal insufficiency are • • • • •
chronic, or long lasting, fatigue muscle weakness loss of appetite weight loss abdominal pain
Other symptoms of adrenal insufficiency can include • nausea • vomiting • diarrhea • low blood pressure that drops further when a person stands up, causing dizziness or fainting • irritability and depression • craving salty foods • hypoglycemia, or low blood sugar • headache
Please cite this article as: Giwa A, A case of primary adrenal failure in the emergency department, American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.10.043
A. Giwa / American Journal of Emergency Medicine xxx (2017) xxx–xxx
• sweating • irregular or absent menstrual periods • in women, loss of interest in sex Hyperpigmentation, or darkening of the skin, can occur in Addison's disease, although not in secondary adrenal insufficiency.” [8] Unfortunately, we see many of these symptoms in various disease processes, and as was in my case, many patients later found to have adrenal insufficiency may lack many of these symptoms or findings altogether. However, in the presence of some of these symptoms, with some electrolyte abnormalities and darkened skin, this should make the practitioner suspicious of a primary adrenal cause. In an attempt to determine the exact symptoms that cause Adrenal Crisis in patients with known Adrenal Insufficiency, Hahner et al. published the incidence of various presenting symptoms in their article “Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies” in 2010 [9], finding the following incidence of symptoms in their 444 datasets: • • • • • • • • •
Weakness (99%) Pigmentation of skin (98%) Weight loss (97%) Abdominal pain (34%) Salt craving (22%) Diarrhea (20%) Constipation (19%) Syncope (16%) Vitiligo (9%)
If there was a history of steroid use, and without skin changes, we would probably all recognize secondary adrenal insufficiency and treat accordingly. Of course, being told by a patient he had a history of a “mass above one of my kidneys” helps make one think of adrenal insufficiency as well. Presumably, his Acute Kidney Insufficiency (AKI) prompted the French to ultrasound his kidneys, otherwise this diagnosis might have never been entertained. I considered giving a stress dose of steroids, but was concerned about the affect on the cortisol stimulation test my admitting colleagues were sure to order. When I discussed this with the admitting attending, I was told to hold off on it, especially since he was convinced patient was just “high on something”, despite my insistence patient did not present with an illicit drug use prodrome. On follow-up, the patient's CT Abdomen/Pelvis was reread as showing a “suspicion of a subtle 2 cm mass in the lower pole of the L kidney. Further evaluation by ultrasound or MRI is recommended”. An ultrasound of his kidney failed to reveal a mass, with specific comments stating, “the suspicious mass found on CT scan in the medulla of the lower left kidney is most likely a prominent column of Bertin”. Further study shows the column of Bertin to be “the extension of renal cortical tissue which separates the pyramids, and as such are normal structures. They become of radiographic importance when they are unusually enlarged and may be mistaken for a renal mass” [10]. His Head CT was performed on his way to the ICU and showed possible areas of early infarction in the left parietal and temporal lobes, and MRI was recommended. The MRI showed no abnormalities and visualization of the pituitary was felt to be adequate and within normal limits. Interestingly, the radiologist felt the adrenals were well visualized on the CT Abdomen/Pelvis, and declined the admitting team's request to get an MRI of his abdomen to further look at his adrenals.
3
Patient had a cosyntropin test which was positive; levels were 6.57 to 6.73 at the 30-minute and 6.41 at the 1-hour mark. A diagnosis of primary adrenal insufficiency was made, and Endocrinology was consulted. Endocrine recommended special testing of ACTH plasma renin level activity and DHEA-S, but as of this writing the results are still pending. He was started on Solu-Cortef 100 mg TID and was eventually transitioned to hydrocortisone 20 mg po BID and Florinef 0.1 mg po QD. Nephrology was consulted later in the day, and they recommended that hypertonic saline be started, given the severe hyponatremia and altered mental status. His sodium eventually corrected to 133 on the day of his discharge. His bilirubin levels were also trended to normal without any intervention and further evaluation failed to reveal any obstructive process. It was thought patient might have Gilbert syndrome and he was referred for outpatient testing. Patient's Urine Toxicology was negative, including the send out for MDMA.
4. Why should an emergency physician be aware of this? As Emergency Medicine practitioners, we are all familiar with the need to aggressively identify and manage the patient presenting with hyponatremia, especially when associated with neurological symptoms. However, I think it would be fair to say that most EPs do not come across primary adrenal failure that often in their careers, and the knowledge of the intricacies of the adrenals production of glucocorticoid and mineralocorticoids may be lacking the further out we are from medical school. In the patient presenting with the aforementioned vague symptoms that is found to have severe electrolyte abnormalities, and darkening of their skin, one must consider primary adrenal failure, and admit the patient for urgent endocrine evaluation.
References [1] Klauer KM. Adrenal crisis in emergency medicine. Retrieved on August 23rd, 2017, from http://emedicine.medscape.com/article/765753-overview#a5; April 4th, 2017. (description of adrenal insufficiency). [2] Mayo Clinic Staff, et al. Retrieved on August 23rd, 2017, from http://www. mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/dxc20155757. (signs and sxs of primary adrenal insufficiency). [3] Nieman L. Causes of secondary and tertiary adrenal insufficiency in adults. Retrieved on August 23rd, 2017, from https://www.uptodate.com/contents/causes-ofsecondary-and-tertiary-adrenal-insufficiency-in-adults; September 2016. [4] Fuller PJ, et al. Specificity in mineralocorticoid versus glucocorticoid action. Retrieved on August 23rd, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/ 10760051; April 2000. (mineralocorticoids v glucocorticoids). [5] Craig S. Hyponatremia in emergency medicine clinical presentation. Retrieved on August 23rd, 2017, from http://emedicine.medscape.com/article/767624-clinical; February 17th, 2017. (beer potomania). [6] Awe TC, et al. Pseudohyponatremia. Am J Emerg Med May 1985;3(3):236–9 Retrieved on August 23rd, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/ 3994801. (pseudohyponatremia definition). [7] ACEP Case Reviews. Hyponatremia case review. Retrieved on August 23rd, 2017, from https://www.acep.org/Clinical—Practice-Management/Hyponatremia-CaseReview/#sm.0000hn7scjv3zcygsdu1pxpsxzprz. (ACEP Hyponatremia case). [8] National Institute of Diabetes and Digestive and Kidney Disease. Adrenal insufficiency and Addison's disease. Retrieved on August 23rd, 2017, from https://www.niddk. nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisonsdisease. (signs and sxs of adrenal failure). [9] Hahner S, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol Mar 2010;162(3):597–602 (Retrieved on August 23rd, 2017). [10] Gaillard F, et al. Hypertrophied column of Bertin. Retrieved on August 23rd, 2017, from https://radiopaedia.org/articles/hypertrophied-column-of-bertin. (column of Bertin).
Please cite this article as: Giwa A, A case of primary adrenal failure in the emergency department, American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.10.043
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
A case of primary adrenal failure in the emergency department Al Giwa ⁎ Manchester Memorial Hospital, Department of Emergency Medicine, Manchester, CT, USA
a r t i c l e
i n f o
Article history: Received 8 October 2017 Accepted 15 October 2017 Available online xxxx Keywords: Hyponatremia Altered mental status Primary adrenal insufficiency Hypovolemia Addison's disease
a b s t r a c t Background: Primary adrenal failure is considered to be an extremely rare disease presenting in the ED, with an incidence reported to be as low as 50 cases per 1,000,000 persons (Klauer, 2017). I would like to present a case of a young man who presented to the ED, with what I suspected to be this rare entity. Case report: A 26 year old otherwise healthy male presented to our ED with complaints of weakness, nausea, vomiting, and hiccups of 1.5-day duration. He also complained of lightheadedness, describing it as if he was going to pass out. Other than slight tachycardia (100) and darkened skin, his physical exam, ROS, PMH, Family and Social History, were all unremarkable. His sodium returned at 111, and he was later noted to become more confused in the ED prompting the emergent use of Hypertonic Saline. Why should an emergency physician be aware of this?: Albeit a rare disease entity, EPs need to keep this life threatening disease process in the back of their minds when presented with a patient with vague symptoms such as weakness or fatigue, electrolyte abnormalities and darkening of their skin. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Primary adrenal failure is considered to be an extremely rare disease, with an incidence reported to be as low as 50 cases per 1,000,000 persons [1]. Secondary adrenal failure on the other hand is commonly seen and is reported to be in higher incidence due to the increased and widespread use of exogenous steroids. Primary adrenocortical insufficiency is reported to have multiple possible etiologies, however ~80% of cases in the United States are caused by autoimmune adrenal destruction. The second most frequent cause is due to glandular infiltration by tuberculosis [2]. I would like to present a case of a young man who presented to the ED, with what I suspected to be this rare entity. 2. Case report A 26-year-old otherwise healthy male presented to our small community based ED with complaints of weakness, nausea, vomiting, and hiccups of 1.5-day duration. He also complained of lightheadedness, describing it as if he was going to pass out. He stated he had a similar presentation while backpacking with his sister in Europe during the spring, just a few weeks earlier. He said, while he was in France, he developed nausea, vomiting and while waiting to see a physician, passed out in
⁎ Emergency Medicine, Icahn School Of Medicine at Mount Sinai, One Gustave l. Levy Place, New York, NY 10128, USA. E-mail address: [email protected].
the triage area. He states he had severe electrolyte abnormalities and renal dysfunction (exact numbers are unknown) and they hydrated him with IV fluids. He said during his in-patient stay he had an ultrasound of his abdomen, which showed a mass on top of one of his kidneys. At this point, he wanted to return to the USA, and was discharged to the care of his PCP in Connecticut. Per the patient' father, his PCP ordered labs which were all within normal limits, and also ordered an MRI of his abdomen which as of the presentation to our ED tonight, had not yet been read. At tonight's presentation, patient denied any other constitutional symptoms such as fever, chills, sick contacts, hematemesis, hematochezia, diarrhea, dysuria, chest pain, sob, abdominal pain, headache, visual disturbances, or any other complaints. He did reiterate he felt very weak and felt like he was about to pass out. He denied taking any medications; he reported Acetaminophen gave him rashes and made him “sick”, and that he was lactose intolerant. He denied illicit drug use currently, but admitted to smoking marijuana a couple of times while in High School 10 years earlier. He denied cigarette use, and said he drank alcohol only occasionally. Of note, he went to Europe to chaperone his younger sister and as a result did not engage in any drug or alcohol use while in Europe, and has continued to remain a teetotaler. His initial vital signs were essentially normal except for a pulse of 100 (96.4, 22, 108/75, 98%). He appeared to be in no acute distress; Alert and oriented ×3, and other than looking somewhat more “tanned” than I would expect a Caucasian to be, the rest of his physical exam was completely unremarkable.
https://doi.org/10.1016/j.ajem.2017.10.043 0735-6757/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Giwa A, A case of primary adrenal failure in the emergency department, American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.10.043
2
A. Giwa / American Journal of Emergency Medicine xxx (2017) xxx–xxx
I ordered routine labs including lactate and urinalysis, as well as a CXR, CT Abdomen/Pelvis with IV contrast, and started him on a 2 liter NS bolus. He was also given IV Pepcid and Zofran, but within an hour, his father came out to the nurses' station and asked for more antinausea medicine due to his son's persistent symptoms. Upon reevaluation, I noticed the patient was pacing around his room and appeared very restless and somewhat agitated. He was very different from the person who just an hour earlier had calmly given me a very detailed history on his symptoms and recent travels to Europe and everything that since ensued. He continued to state he was feeling very nauseated, so I added Phenergan and Benadryl, in the hopes of giving him a little relaxation and somnolence. His CXR was read by me as No Acute Pulmonary Disease. Within a few minutes of leaving the patient's room, the lab called with a critical report. His Na+ was 111. His K + was 4.8, BUN/Cr was 25 and 0.89, CO2 was 21 and Cl- was 76. His lactate was 1.1. The lab called back again, this time stating they were having problems running his CBC, as it was “too thick”. His Unconjugated Bilirubin was 4.4 and conjugated was 0.3. The rest of his LFTs were essentially normal. The patient was sent for his CT Abdomen/Pelvis, but upon his return he started to complain of severe lower back pain of new onset. No other complaints, and no additional findings on reexamination. Due to the level of agony he appeared in, I gave him 50 ucg of Fentanyl IV and continued 0.9% NS. The CBC returned with a WBC of 7.2. Hct/Hgb of 18.2/51.2, and platelets of 269. A manual diff was performed and was all within normal limits. I reviewed the CT images of his abdomen, and saw nothing remarkable, but awaited the official read. The patient was reevaluated and gave me the thumbs up sign, stating his pain and nausea had all resolved. I told them about his hyponatremia and discussed the need to admit him and to start hypertonic saline. I discussed the case with the admitting team and awaited their evaluation. Approximately an hour later, his nurse observed that the patient was acting strange again, and called me back to the room. At this point, the hypertonic saline was infusing at 50 cm3/h. The admitting Family Medicine residents were at the bedside and were able to witness his changing mental status. They presented the case to their attending, but he asked for a urine toxicology, stating it sounded more like Ecstasy, Spice or K2, and discontinued the hypertonic saline. They said they would observe the patient in the ICU, and he was expeditiously moved out of the department. Initial Night Hawk Radiology read of his abdomen/pelvis CT was negative. A CT of his Head was ordered but patient was transferred out of the ED prior to it being performed. 3. Discussion According to Up-To-Date, “Adrenal insufficiency can be caused by diseases of the adrenal gland (primary), interference with corticotropin (ACTH) secretion by the pituitary gland (secondary), or interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus (tertiary)” [3]. For fear of losing my EM colleagues with an indepth analysis of the hypothalamic-pituitary axis, and the various components and regulatory mechanisms of the adrenocortical system, I will be providing only a cursory review of the role of the adrenals in primary adrenal insufficiency. In primary adrenocortical insufficiency, glucocorticoid and mineralocorticoid properties are lost. As you might recall, glucocorticoids are responsible for metabolism and immunologic function among many other postulated functions, whereas mineralocorticoids are primarily concerned with maintaining electrolyte and fluid balances [4]. Similarly, a discussion on the differential diagnosis of hyponatremia and altered mental status is beyond the scope of this paper, but the key causes of hyponatremia are as follows: • Pulmonary/Mediastinal Disease • Pseudo lowering due to a hyperosmolar agent
• • • •
CNS Disorders Water intoxication/SIADH Extreme activities causing profuse sweating Hormonal causes-Hypothyroid or Adrenal Insufficiency
Our patient had no pulmonary symptoms and had a completely unremarkable lung exam and chest X-ray. His neurological exam was completely normal, with an initial GCS of 15 and NIHSS of 0. He denied drug use and did not report excessive exercise or drinking large amounts of fluid (water or beer, as the latter has been reported to cause hyponatremia in a syndrome called Beer Potomania [5]). Lastly, his glucose and albumin were normal, and he was not spilling proteins in his urine to make me think of a pseudohyponatremia cause, which was traditionally defined as “a displacement of serum water by elevated concentrations of serum lipids or proteins” [6]. We have since, changed this definition to include all osmotically active substances, including but not limited to Glucose, proteins, lipids, etc. Hyponatremia is further characterized by the volume status of the patient in order to better elucidate a cause (and treatment). ACEP's online clinical management section discusses hyponatremia as follows: “Causes of hypovolemic hyponatremia may include excessive sodium losses from the kidneys, the skin, or the GI tract and also includes “third spacing” of fluids. Causes of euvolemic hyponatremia may include etiologies such as SIADH and psychogenic polydipsia. Many conditions stimulate ADH production including angiotensin release, hypovolemia, increased serum osmolality, hypotension, opiates, caffeine, and stress. ADH may be inappropriately secreted due to CNS or pulmonary infections and due to multiple medications including most diuretics. Causes of hypervolemic hyponatremia may include fluid overload states such as CHF, pregnancy, cirrhosis, and nephrotic syndrome. Serum sodium levels may also be artificially low with increased levels of plasma proteins or lipids and with increased serum concentration of osmotically active chemicals such as glucose and mannitol.” [7] I did not have an osmolality to determine the patient's volume status, but given his symptoms of vomiting and a prerenal azotemia on his labs, I presumed he was hypovolemic hyponatremia. Hence, given his hyponatremia, bronze-like skin, and the previously reported mass seen by the French, I suspected a primary Adrenal cause. He was not on any exogenous steroids (or any medications whatsoever) that could have caused a secondary or tertiary adrenal crisis. He denied any signs or symptoms of sepsis, with an initial qSOFA score of 0, and only 1 SIRS criterion (tachycardia), and hence an infectious etiology for adrenal failure was ruled out. According to the National Institute of Diabetes and Digestive and Kidney Diseases: “The most common symptoms of adrenal insufficiency are • • • • •
chronic, or long lasting, fatigue muscle weakness loss of appetite weight loss abdominal pain
Other symptoms of adrenal insufficiency can include • nausea • vomiting • diarrhea • low blood pressure that drops further when a person stands up, causing dizziness or fainting • irritability and depression • craving salty foods • hypoglycemia, or low blood sugar • headache
Please cite this article as: Giwa A, A case of primary adrenal failure in the emergency department, American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.10.043
A. Giwa / American Journal of Emergency Medicine xxx (2017) xxx–xxx
• sweating • irregular or absent menstrual periods • in women, loss of interest in sex Hyperpigmentation, or darkening of the skin, can occur in Addison's disease, although not in secondary adrenal insufficiency.” [8] Unfortunately, we see many of these symptoms in various disease processes, and as was in my case, many patients later found to have adrenal insufficiency may lack many of these symptoms or findings altogether. However, in the presence of some of these symptoms, with some electrolyte abnormalities and darkened skin, this should make the practitioner suspicious of a primary adrenal cause. In an attempt to determine the exact symptoms that cause Adrenal Crisis in patients with known Adrenal Insufficiency, Hahner et al. published the incidence of various presenting symptoms in their article “Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies” in 2010 [9], finding the following incidence of symptoms in their 444 datasets: • • • • • • • • •
Weakness (99%) Pigmentation of skin (98%) Weight loss (97%) Abdominal pain (34%) Salt craving (22%) Diarrhea (20%) Constipation (19%) Syncope (16%) Vitiligo (9%)
If there was a history of steroid use, and without skin changes, we would probably all recognize secondary adrenal insufficiency and treat accordingly. Of course, being told by a patient he had a history of a “mass above one of my kidneys” helps make one think of adrenal insufficiency as well. Presumably, his Acute Kidney Insufficiency (AKI) prompted the French to ultrasound his kidneys, otherwise this diagnosis might have never been entertained. I considered giving a stress dose of steroids, but was concerned about the affect on the cortisol stimulation test my admitting colleagues were sure to order. When I discussed this with the admitting attending, I was told to hold off on it, especially since he was convinced patient was just “high on something”, despite my insistence patient did not present with an illicit drug use prodrome. On follow-up, the patient's CT Abdomen/Pelvis was reread as showing a “suspicion of a subtle 2 cm mass in the lower pole of the L kidney. Further evaluation by ultrasound or MRI is recommended”. An ultrasound of his kidney failed to reveal a mass, with specific comments stating, “the suspicious mass found on CT scan in the medulla of the lower left kidney is most likely a prominent column of Bertin”. Further study shows the column of Bertin to be “the extension of renal cortical tissue which separates the pyramids, and as such are normal structures. They become of radiographic importance when they are unusually enlarged and may be mistaken for a renal mass” [10]. His Head CT was performed on his way to the ICU and showed possible areas of early infarction in the left parietal and temporal lobes, and MRI was recommended. The MRI showed no abnormalities and visualization of the pituitary was felt to be adequate and within normal limits. Interestingly, the radiologist felt the adrenals were well visualized on the CT Abdomen/Pelvis, and declined the admitting team's request to get an MRI of his abdomen to further look at his adrenals.
3
Patient had a cosyntropin test which was positive; levels were 6.57 to 6.73 at the 30-minute and 6.41 at the 1-hour mark. A diagnosis of primary adrenal insufficiency was made, and Endocrinology was consulted. Endocrine recommended special testing of ACTH plasma renin level activity and DHEA-S, but as of this writing the results are still pending. He was started on Solu-Cortef 100 mg TID and was eventually transitioned to hydrocortisone 20 mg po BID and Florinef 0.1 mg po QD. Nephrology was consulted later in the day, and they recommended that hypertonic saline be started, given the severe hyponatremia and altered mental status. His sodium eventually corrected to 133 on the day of his discharge. His bilirubin levels were also trended to normal without any intervention and further evaluation failed to reveal any obstructive process. It was thought patient might have Gilbert syndrome and he was referred for outpatient testing. Patient's Urine Toxicology was negative, including the send out for MDMA.
4. Why should an emergency physician be aware of this? As Emergency Medicine practitioners, we are all familiar with the need to aggressively identify and manage the patient presenting with hyponatremia, especially when associated with neurological symptoms. However, I think it would be fair to say that most EPs do not come across primary adrenal failure that often in their careers, and the knowledge of the intricacies of the adrenals production of glucocorticoid and mineralocorticoids may be lacking the further out we are from medical school. In the patient presenting with the aforementioned vague symptoms that is found to have severe electrolyte abnormalities, and darkening of their skin, one must consider primary adrenal failure, and admit the patient for urgent endocrine evaluation.
References [1] Klauer KM. Adrenal crisis in emergency medicine. Retrieved on August 23rd, 2017, from http://emedicine.medscape.com/article/765753-overview#a5; April 4th, 2017. (description of adrenal insufficiency). [2] Mayo Clinic Staff, et al. Retrieved on August 23rd, 2017, from http://www. mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/dxc20155757. (signs and sxs of primary adrenal insufficiency). [3] Nieman L. Causes of secondary and tertiary adrenal insufficiency in adults. Retrieved on August 23rd, 2017, from https://www.uptodate.com/contents/causes-ofsecondary-and-tertiary-adrenal-insufficiency-in-adults; September 2016. [4] Fuller PJ, et al. Specificity in mineralocorticoid versus glucocorticoid action. Retrieved on August 23rd, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/ 10760051; April 2000. (mineralocorticoids v glucocorticoids). [5] Craig S. Hyponatremia in emergency medicine clinical presentation. Retrieved on August 23rd, 2017, from http://emedicine.medscape.com/article/767624-clinical; February 17th, 2017. (beer potomania). [6] Awe TC, et al. Pseudohyponatremia. Am J Emerg Med May 1985;3(3):236–9 Retrieved on August 23rd, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/ 3994801. (pseudohyponatremia definition). [7] ACEP Case Reviews. Hyponatremia case review. Retrieved on August 23rd, 2017, from https://www.acep.org/Clinical—Practice-Management/Hyponatremia-CaseReview/#sm.0000hn7scjv3zcygsdu1pxpsxzprz. (ACEP Hyponatremia case). [8] National Institute of Diabetes and Digestive and Kidney Disease. Adrenal insufficiency and Addison's disease. Retrieved on August 23rd, 2017, from https://www.niddk. nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisonsdisease. (signs and sxs of adrenal failure). [9] Hahner S, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol Mar 2010;162(3):597–602 (Retrieved on August 23rd, 2017). [10] Gaillard F, et al. Hypertrophied column of Bertin. Retrieved on August 23rd, 2017, from https://radiopaedia.org/articles/hypertrophied-column-of-bertin. (column of Bertin).
Please cite this article as: Giwa A, A case of primary adrenal failure in the emergency department, American Journal of Emergency Medicine (2017), https://doi.org/10.1016/j.ajem.2017.10.043