Can I rule out primary adrenal insufficiency by obtaining a single morning serum cortisol level in my hospitalized patient with unexplained hyponatremia?

Primary adrenal insufficiency (PAI) can be confidently ruled out when the morning (eg, 6 AM) serum cortisol level is greater than 17 ug/dl. Lower cut-off values are associated with lower probability of excluding PAI: > 10 ug/dl, 62%-67% and ≥5 ug/dl, 36%. 1,2 Conversely, PAI is highly likely when the morning serum cortisol level is less than 3 ug/dl. 3

Since many patients may have serum cortisol levels between 3 ug/dl and 17 ug/dl (ie, in the “indeterminate” range), confirmatory testing commonly performed through cosyntropin stimulation test (CST) is often necessary.

Although the standard CST involves measuring serum cortisol levels at baseline, 30 min, and 60 min with peak cortisol level <18 ug/dl indicative of PAI, several studies have reported that a single post-CST cortisol level obtained at 60 min may also be diagnostic. 3

 

References

  1. Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 83;2350-54. https://www.ncbi.nlm.nih.gov/pubmed/9661607
  2. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016;101:364-89. https://academic.oup.com/jcem/article/101/2/364/2810222
  3. Odom DC, Gronowski AM, Odom E, et al. A single, post-ACTH cortisol measurement to screen for adrenal insufficiency in the hospitalized patient. J Hosp Med 2018;13: E1-E5. https://www.ncbi.nlm.nih.gov/pubmed/29444197
Can I rule out primary adrenal insufficiency by obtaining a single morning serum cortisol level in my hospitalized patient with unexplained hyponatremia?

My patient is admitted with diabetic ketoacidosis (DKA) and is testing positive for cocaine. Can cocaine cause DKA?

Cocaine use has been generally linked to DKA but whether it’s through its antagonizing effect on insulin action or more indirectly through its association with non-compliance with insulin, or both, is not totally clear.

A retrospective study found cocaine users to account for 14% of all DKA admissions.1 Cocaine users were also less likely than controls to have an intercurrent illness identified as a precipitant for DKA, and more likely to have missed taking insulin prior to admission. Another study also reported active cocaine use to be associated with DKA, but found its effect to be independent of non-compliance. 2

Yet another retrospective study limited to patients admitted with hyperglycemia, found no significant association between active cocaine use and development of hyperglycemic crisis.

There are reasons to believe that cocaine may contribute to DKA. Cocaine has been proposed as a possible precipitant of DKA due to its ability to potentially enhance counterregulatory mechanisms designed to antagonize the effect of insulin by increasing catecholamine and cortisol levels. 1,3

So next time you have a patient with DKA, consider cocaine as a possible precipitant, particularly when the cause of DKA is unclear.

 

References

  1. Warner EA, Greene GS, Buchsbaum MS et al. Diabetic ketoacidosis associated with cocaine use. Arch Intern Med 1998; 158:1799-802. https://www.ncbi.nlm.nih.gov/pubmed/9738609
  2. Nyenwe E, Loganathan R, Blum S, et al. Active use of cocaine: An independent risk factor for recurrent diabetic ketoacidosis in a city hospital. Endocr Pract 2007;13:22-29. https://www.ncbi.nlm.nih.gov/pubmed/17360297
  3. Modzelewski KL, Rybin DV, Weinberg JM, et al. Active cocaine use does not increase the likelihood of hyperglycemic crisis. J Clin Transl Endocrinol 2017;9:1-7 http://www.jctejournal.com/article/S2214-6237(16)30056-4/pdf

 

Contributed in part by Quin L Sievers, Medical Student, Harvard Medical School

My patient is admitted with diabetic ketoacidosis (DKA) and is testing positive for cocaine. Can cocaine cause DKA?

Is prolactin level useful in determining whether my patient with loss of consciousness suffered a seizure?

It depends on the timing of your patient’s presentation!

It is generally held that serum prolactin level peaks within 10-20 min after a generalized tonic-clonic or complex partial seizure and returns to baseline within 2-6 h. Even then, its sensitivity is no more than 50%-60% for these types of seizures.  Elevated PL is also seen in 60%-80% of patients with syncope.1

A report by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (2006) concluded that “elevated serum prolactin assay, when measured in the appropriate clinical setting at 10-20 min after a suspected event, is a useful adjunct for the differentiation of generalized tonic-clonic or complex partial seizure from psychogenic non-epileptic seizure among adults or older children (Level B).2 

In contrast, reports of PL increasing for up to 6 h after epileptic seizure or not reaching baseline for 12-18 h can also be found in the literature.3

Although the mechanism for elevation of PL in certain seizures is unknown,  one hypothesis proposes that prolactin is secreted due to the interference with the inhibitory control of hypothalamus by the electrical perturbation of this part of the brain.4  

References

  1. Nass RD, Sassen R, Elger CE. The role of postictal laboratory blood analyses in the diagnosis and prognosis of seizures. Seizure 2017;47:51-65. https://www.ncbi.nlm.nih.gov/pubmed/28288363
  2. Chen DK, So YT, Fisher RS. Is prolactin a clinically useful measure of epilepsy? Epilepsy Currents 2006;6:78-79. https://www.ncbi.nlm.nih.gov/pubmed/16157897
  3. Siniscalchi A, Gallelli L, Mercuri NB, et al. Serum prolactin levels in repetitive temporal epileptic seizures. Eur Rev Med Pharmacol Sci 2008;12:365-368. https://www.ncbi.nlm.nih.gov/pubmed/19146198
  4. Collins WCJ, Lanigan O, Callaghan N. Plasma prolactin concentrations following epileptic and pseudoseizures. J Neurol Neurosurg Psych 1983; 46:505-8. http://jnnp.bmj.com/content/jnnp/46/6/505.full.pdf

 

Is prolactin level useful in determining whether my patient with loss of consciousness suffered a seizure?

Should I consider octreotide in my patient with non-variceal upper GI bleed?

Octreotide is routinely used in the treatment of variceal bleeding due to its vasoconstrictive effects on the splanchnic vasculature.1 In non-variceal upper GI bleed (NVUGB), however, the evidence for routine use of octreotide is hard to come by with an international consensus panel recommending its use only on a case-by-case basis in patients with very active bleeding while awaiting endoscopy or surgery.2,3

These recommendations are based on the failure of several randomized controlled trials in demonstrating the superiority of octreotide in NVUGB over placebo, either alone or with ranitidine, except in a small subset of patients with actively oozing ulcers.4-6 Although a meta-analysis has suggested that octreotide may reduce the risk of continued bleeding in NVUGB,7 the validity of some of the included studies has been questioned.8

On the other hand, octreotide decreases gastric mucosal blood flow and inhibits acid and pepsin secretion, which may potentially benefit patients who are actively bleeding.9

Final fun fact: Did you know that octreotide may be effective in the treatment of chylothorax?

 

References

  1. Avgerinos A, Armonis A, Raptis S. Somatostatin and octreotide in the management of acute variceal hemorrhage. Hepatogastroenterology 1995;42:145-50. http://europepmc.org/abstract/med/7672763
  2. Barkun AN, Barrdou M, Kulpers EJ, et al. International concensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010;152:101-113. http://annals.org/aim/article/745521/international-consensus-recommendations-management-patients-nonvariceal-upper-gastrointestinal-bleeding
  3. Barkun A, Bardou M, Marshall JK, Nonvariceal Upper GIBCCG Consensus Conference Group. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2003;139:843–857. https://www.ncbi.nlm.nih.gov/pubmed/14623622
  4. Nikolopoulou VN, Thomopoulos KC, Katsakoulis EC, et al. The effect of octreotide as an adjunct treatment in active nonvariceal upper gastrointestinal bleeding. J Clin Gastroenterol 2004;38:243-7. http://journals.lww.com/jcge/Abstract/2004/03000/The_Effect_of_Octreotide_as_an_Adjunct_Treatment.9.aspx
  5. Archimandritis A, Tsirantonaki M, Tryphonos M, et al. Ranitidine versus ranitidine plus octreotide in the treatment of acute non-variceal upper gastrointestinal bleeding: a prospective randomized study. Curr Med Res Opin. 2000;16(3):178-83. http://www.tandfonline.com/doi/abs/10.1185/0300799009117023
  6. Okan A, Simsek I, Akpinar H, et al. Somatostatin and ranitidine in the treatment of non-variceal upper gastrointestinal bleeding: a prospective, randomized, double-blind, controlled study. Hepatogastroenterology 2000;47:1325-7. http://europepmc.org/abstract/med/11100343
  7. Imperiale TF, Birgisson S. Somatostatin or octreotide compared with H2 antagonists and placebo in the management of acute nonvariceal upper gastrointestinal hemorrhage: a meta-analysis. Ann Intern Med 1997;127:1062–1071. http://annals.org/aim/article/711021/somatostatin-octreotide-compared-h-2-antagonists-placebo-management-acute-nonvariceal
  8. Palmer KR. Non-variceal upper gastrointestinal haemorrhage: guidelines. Gut. 2002;51 (Suppl 4): iv1–iv6. http://gut.bmj.com/content/51/suppl_4/iv1.short
  9. Sgouros SN, Bergele C, Viazis N, et al. Somatostatin and its analogues in peptic ulcer bleeding: facts and pathophysiological aspects. Dig Liver Dis. 2006;38:143-8. http://www.sciencedirect.com/science/article/pii/S1590865805002434

 

Contributed byAlice Choi, Medical Student, Harvard Medical School

 

Should I consider octreotide in my patient with non-variceal upper GI bleed?

What is the utility of bedside skin-fold test in diagnosing Cushing’s syndrome?

Skin atrophy is a common feature of Cushing’s syndrome (CS), a hypercortisol state,  with multiple studies reporting radiographic evidence of reduced skin thickness in this condition1,2.

Measurement of skin thickness on the dorsal aspect of the 2nd or 3rd proximal phalanges on the non-dominant hand by using ECG calipers to pinch together a fold of skin has also been reported to assess skin atrophy in CS, with thickness less than 18 mm correlating strongly with CS3,4; the minimal subcutaneous fat at this location allows for a more accurate measurement of skin thickness.

However, caution should be exercised in interpreting the results of this study. Specifically, some overlap was observed between normal controls and patients with CS.  In addition, the study population was limited to women of reproductive age presenting with oligomenorrhea and hirsutism for at least 2 years, a subset of patients that may account for only 40% of cases with CS5,6.  Further studies are clearly needed to determine the clinical utility of the skin-fold test in patients suspected of CS.

References

  1. Sheppard RH, Meema HE. Skin thickness in endocrine disease. A roentgenographic study. Ann Intern Med 1967;66:531-9.
  2. Ferguson JK, Donald RA, Weston TS, et al. Skin thickness in patients with acromegaly and Cushing’s syndrome and response to treatment. Clin Endocrinol (Oxf) 1983;18:347-53.
  3. Corenblum B, Kwan T, Gee S, et al. Bedside assessment of skin-fold thickness: A useful measurement for distinguishing Cushing’s disease from other causes of hirsutism and oligomenorrhea. Arch Intern Med. 1994;154:777-781.
  4. Loriaux DL. Diagnosis and differential diagnosis of Cushing’s syndrome. N Engl J Med 2017;376:1451-9.
  5. Lindholm J, Juul S, Jorgensen JOL, et al: Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001;86:117–123.
  6. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, et al. Menstrual abnormalities in women with Cushing’s disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab. 1998;83:3083-8.

Contributed by Sagar Raju, Medical Student, Harvard Medical School

What is the utility of bedside skin-fold test in diagnosing Cushing’s syndrome?

My patient with hypercalcemia complains of polyuria. What is the mechanism of hypercalcemia-associated polyuria?

Polyuria is considered a classic symptom of hypercalcemia and was one of the symptoms described in the first published case of hyperparathyroidism (1). Several potential mechanisms may explain this phenomenon.

The calcium sensing receptors (CaSRs) found in the kidney play a major role in volume status due to their expression in the thick ascending loop (TAL) of Henle and the collecting duct. Interestingly, hypercalcemia activates the CaSR in the medullary portion of TAL, causing inhibition of the same cotransporter (Na-K-2Cl) inhibited by furosemide and other loop diuretics (2-4)! Hypercalcemia also inhibits vasopressin action ( therefore urine concentration) by activating CaSR in the collecting duct (5).  Lastly, inhibition of Na+-K+ ATPase in the proximal convoluted tubule may further contribute to natriuresis and subsequent polyuria.

Thus, hypercalcemia may lead to polyuria by interfering with the absorption of sodium as well as inhibiting the action of vasopressin.  One can’t help but compare its effect to that of a patient with diabetes insipidus taking a loop diuretic!  No wonder these patient may suffer from polyuria!

 

REFERENCES

  1. Goldfarb S, Agus ZS. Mechanism of the polyuria of hypercalcemia. Am J Nephrol. 1984;4:69-76.
  2. Quamme GA. Effect of hypercalcemia on renal tubular handling of calcium and magnesium. Can J Physiol Pharmacol. 1982;60:1275-80.
  3. Peterson LN. Vitamin D-induced chronic hypercalcemia inhibits thick ascending limb NaCl reabsorption in vivo. Am J Physiol. 1990;259:122-9.
  4. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010;298:485-99.
  5. Toka HR, Pollak MR, Houillier P. Calcium sensing in the renal tubule. Physiology (Bethesda). 2015;30:317-26.

 

Contributed by Michael Hughes, Medical Student, Harvard Medical School

 

My patient with hypercalcemia complains of polyuria. What is the mechanism of hypercalcemia-associated polyuria?

What is the connection between cirrhosis and adrenal insufficiency (AI)?

The reported prevalence of AI in patients with liver disease varies widely (30-60%)1. However, there is no consensus on how to define AI in such patients, nor is the methodology for its evaluation standardized.  A common criticism is the frequent reliance on total, not free, serum cortisol in cirrhosis which may overestimate the prevalence of AI because cortisol is bound to corticosteroid binding globulin and albumin, commonly found at lower concentrations in cirrhosis. However, even when based on measuring free cortisol, AI is found in 12%-29% of clinically stable cirrhotic patients1.

 Secondary AI due to hypothalamic-pituitary dysfunction has been reported in Child-Pugh class A, B, and C patients (42%, 69%, and 80%, respectively)2. The mechanism of AI in cirrhosis is unclear, but low serum cholesterol in cirrhosis leading to lack of substrate for steroidogenesis, and increased levels of circulating endotoxin and pro-inflammatory cytokines impairing the hypothalamic-pituitary-adrenal axis have been postulated1.

 

References

  1. Fede G, Spadaro L, Purrello F. Review: adrenal insufficiency in liver disease. J Liver 2014;3:1.
  2. Zietz, B, Lock, G, Plach, B, et al. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatology 2003;15:495-501.
What is the connection between cirrhosis and adrenal insufficiency (AI)?