Addison's disease differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

Addison's disease must be differentiated from other diseases that cause hypotension, skin pigmentation, and abdominal pain such as myopathies, celiac disease, Peutz-Jeghers syndrome, anorexia nervosa, syndrome of inappropriate antidiuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma.

Differentiating Addison's disease from other Diseases

Addison's disease (primary adrenal insufficiency) must be first differentiated from secondary and tertiary adrenal insufficiency as all the three of them present with similar symptoms due to cortisol and mineralocorticoid hormone deficiencies.

  • Serum ACTH level can help distinguish primary from secondary/tertiary adrenal insufficiency
Type of

Adrenal insufficiency

Skin Pigmentation ACTH  Normal ACTH
Addison disease + >60 ng/mL 5-30 ng/mL
Secondary /

tertiary adrenal insufficiency

- <5 ng/mL

Addison's disease must be differentiated from other diseases that cause hypotension, skin pigmentation, muscle weakness and abdominal pain which include myopathies, celiac disease, Peutz-Jeghers syndrome, anorexia nervosa, syndrome of inappropriate antidiuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma.[1][2][3][4][5]

Disease Differentiating symptoms Differentiating laboratory findings Gold standard test
Hypotension Abdominal pain Anorexia/

weight loss

Muscle weakness Hypoglycemia Skin pigmentation Other symptoms Hyponatremia Cortisol levels Other labs
Addison's disease + + + + + + + Low ACTH stimulation test
Myopathies

(polymyositis,

hereditary myopathies)

- - - + - Heliotrope rash and

Gottron's sign

- Normal - Muscle biopsy
Celiac disease - + + - - Dermatitis herpetiformis  - Normal - Abnormal small bowel biopsy
Syndrome of inappropriate anti-diuretic hormone

(SIADH)

- - - - - - - + Normal Water deprivation test
Neurofibromatosis - - + + - Axillary- and inguinal-area freckling - - - Biopsy of skin tissue
Peutz-Jeghers syndrome + + - Normal Colonic imaging showing the small intestinal polyps
Porphyria cutanea tarda - + - - - Blisters on sun-exposed sites - Normal or elevated High level of porphyrins in the urine
Salt-depletion nephritis + Flank pain - - - - + Elevated <15:1 BUN:CR
Bronchogenic carcinoma - - + - - + - Elevated Increased ACTH and

Hypokalemia

Cytological or histological evidence of lung cancer in sputum, pleural fluid, or tissue
Anorexia nervosa + - + + + - - Elevated - Psychiatric condition

Addison's disease should be differentiated from other diseases causing secondary adrenal insufficiency due to hypopituitarism.[6][7][8][9][10][11][12]

Diseases Onset Manifestations Diagnosis
History and Symptoms Physical examination Laboratory findings Gold standard Imaging Other investigation findings
Trumatic delivery Lactation failure Menstrual irregularities Other features
Sheehan's syndrome Acute ++ ++ Oligo/amenorrhea Symptoms of:
  • Clinical diagnosis
  • Most senitive test: Low baseline prolactin levels w/o response to TRH
CT/MRI:
  • Sequential changes of pituitary enlargement followed by:
  • Shrinkage and necrosis leading to decreased sellar volume or empty sella
Lymphocytic hypophysitis Acute +/- + Oligo/amenorrhea
  • Retro-orbital or Bitemporal pain
  • Diffuse and homogeneous contrast enhancement
Assays for:
  • Anti-TPO
  • Anti-Tg Ab
Pituitary apoplexy Acute +/- ++ Oligo/amenorrhea Severe headache
  • Decreased levels of anterior pituitary hormones in blood.
  • CT scan without contrast: Hemorrhage on CT presents as a hyperdense lesion

Blood tests may be done to check:

Empty sella syndrome Chronic - + Oligo/amenorrhea
  • Decreased levels of pituitary hormones in blood.
Simmonds' disease/Pituitary cachexia Chronic +/- + Oligo/amenorrhea
  • Loss of body hair
  • Decreased levels of anterior pituitary hormones in blood.
  • Done to rule out any pituitary cause
Hypothyroidism Chronic +/- - Oligomenorrhea/menorrhagia
  • Dry skin
  • Hair loss
  • Normal/ low TSH
  • Rest of pituitary hormone levels WNL
  • Done to rule out any pituitary cause
  • Assays for anti-TPO and anti-Tg Ab
  • FNA biopsy
Hypogonadotropic hypogonadism Chronic - - Oligo/amenorrhea
  • Energy and mood changes
  • Done to rule out any pituitary cause
Hypoprolactinemia Chronic - + -
  • Puerperal agalactogenesis
  • No workup is necessary
  • Decreased prolactin levels
  • Done to rule out any pituitary cause
Panhypopituitarism Chronic - + Oligo/amenorrhea
  • All pituitary hormones decreased
  • Done to rule out any pituitary cause
Primary adrenal insufficiency/Addison's disease Chronic - - -
  • Abdominal CT
  • Abdominal CT
  • Anti-adrenal Ab testing
Menopause Chronic - +/- Oligo/amenorrhea Normal

References

  1. Selva-O'Callaghan A, Labrador-Horrillo M, Gallardo E, Herruzo A, Grau-Junyent JM, Vilardell-Tarres M (2006). "Muscle inflammation, autoimmune Addison's disease and sarcoidosis in a patient with dysferlin deficiency". Neuromuscul. Disord. 16 (3): 208–9. doi:10.1016/j.nmd.2006.01.005. PMID 16483775.
  2. Kumar V, Rajadhyaksha M, Wortsman J (2001). "Celiac disease-associated autoimmune endocrinopathies". Clin. Diagn. Lab. Immunol. 8 (4): 678–85. doi:10.1128/CDLI.8.4.678-685.2001. PMC 96126. PMID 11427410.
  3. Adams R, Hinkebein MK, McQuillen M, Sutherland S, El Asyouty S, Lippmann S (1998). "Prompt differentiation of Addison's disease from anorexia nervosa during weight loss and vomiting". South. Med. J. 91 (2): 208–11. PMID 9496878.
  4. Lever EG, Stansfeld SA (1983). "Addison's disease, psychosis, and the syndrome of inappropriate secretion of antidiuretic hormone". Br J Psychiatry. 143: 406–10. PMID 6414566.
  5. BELL R, PATTEE CJ (1956). "Addison's disease associated with neurofibromatosis". Can Med Assoc J. 75 (5): 415–7. PMC 1823303. PMID 13356214.
  6. Sato N, Sze G, Endo K (1998). "Hypophysitis: endocrinologic and dynamic MR findings". AJNR Am J Neuroradiol. 19 (3): 439–44. PMID 9541295.
  7. Powrie JK, Powell M, Ayers AB, Lowy C, Sönksen PH (1995). "Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature". Clin. Endocrinol. (Oxf). 42 (3): 315–22. PMID 7758238.
  8. Honegger J, Schlaffer S, Menzel C, Droste M, Werner S, Elbelt U, Strasburger C, Störmann S, Küppers A, Streetz-van der Werf C, Deutschbein T, Stieg M, Rotermund R, Milian M, Petersenn S (2015). "Diagnosis of Primary Hypophysitis in Germany". J. Clin. Endocrinol. Metab. 100 (10): 3841–9. doi:10.1210/jc.2015-2152. PMID 26262437.
  9. Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S (1995). "Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings". J. Clin. Endocrinol. Metab. 80 (8): 2302–11. doi:10.1210/jcem.80.8.7629223. PMID 7629223.
  10. Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T, Fujisawa I, Yamabe H (1993). "Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus". N. Engl. J. Med. 329 (10): 683–9. doi:10.1056/NEJM199309023291002. PMID 8345854.
  11. Hsieh CY, Liu BY, Yang YN, Yin WH, Young MS (2011). "Massive pericardial effusion with diastolic right ventricular compression secondary to hypothyroidism in a 73-year-old woman". Emerg Med Australas. 23 (3): 372–5. doi:10.1111/j.1742-6723.2011.01425.x. PMID 21668725.
  12. Dejager S, Gerber S, Foubert L, Turpin G (1998). "Sheehan's syndrome: differential diagnosis in the acute phase". J. Intern. Med. 244 (3): 261–6. PMID 9747750.



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