Iron poisoning is often listed in the classic metabolic acidosis mnemonic MUDPILES, but how does it cause an anion gap metabolic acidosis?

HOW? The mechanism appears to be multi-factorial.

  1. Acute excessive ingestion of iron causes direct corrosive damage to the GI tract.
  2. Free iron penetrates numerous organs such as the liver. It enters hepatocytes, damaging the mitochondria (disrupts oxidative phosphorylation) and increases lipid peroxidation. It also damages microsomes, and other cellular organelles.
  3. Excessive iron can affect the heart: resulting in fatty necrosis of the myocardium, increased capillary permeability, and a reduction in cardiac output.
  4. Free iron also stimulates the release of pro-dilatory agents such as serotonin and histamine resulting in hypo perfusion, anaerobic metabolism and lactic acidosis.
  5. In addition ferrous iron is converted to ferric iron; hydrogen ions are released, adding to the metabolic acidosis.

The profound damage to the liver results in: hypoglycemia, hyperammonemia, coagulation defects,

and hepatic encephalopathy occurs in the context of fulminant liver failure.
REFERENCES
  1. Goyer RA. Toxic effects of metals. Klaassen CD, ed. Casarett & Doull’s toxicology:the basic science of poisons. 5th ed. New YorkCity, NY: McGraw-Hill, 1996;715-716.
  2. Williams RJ. Biomineralization: iron and the origins of life. Nature 1990;343:213-214.4.
  3. Osweiler GD, Carson TL, Buck WB, et al. Iron. Clinical and diagnostic veterinary toxicology. 3rd ed. Dubuque, Iowa: Kendall/Hunt Publishing Co, 1985;104-106.5.
  4. Hillman RS. Hematopoietic agents: growth factors, minerals, and vitamins. Hardman JG, Limbird LE, Molinoff PB, et al, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th ed. New York City, NY: McGraw-Hill,1995;1311-1340
  5. Proudfoot AT, Simpson D, Dyson EH. Management of acute iron poisoning. Med Toxicol. 1986 Mar-Apr;1(2):83-100.
  6. Greentree WF, Hall JO. Iron toxicosis. Bonagura JD, ed. Kirk’s current therapy XII small animal practice. Philadelphia, Pa: WB Saunders Co, 1995;240-242.3.

Hypothyroidism has been recognized as a cause of secondary hypertension.

Img Cred: http://circ.ahajournals.org/
Img Cred: http://circ.ahajournals.org/

Previous studies on the prevalence of hypertension in subjects with hypothyroidism have demonstrated elevated diastolic blood pressure values. (hypertension in ~30% of patients)

WHY???

In hypothyroidism, there is endothelial dysfunction and arterial smooth muscle compliance is reduced => leads to increased Systemic Vascular Resistance (SVR).

This appears to be a multi-factorial mechanism (increased adrenergic activity and reduction in endothelial-derived relaxation factor (EDRF) availability). 

REFERENCES

  1. Klein, I and Danzi, S. Thyroid Disease and the Heart. Circulation. 2007;116:1725-1735.
  2. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501.
  3. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Chiadoni L, Salvetti A, Ferrannini E, Monzani F. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003; 88: 3731–3737.

Primary: Elevated PTH that results in elevated Ca2+. Typically caused by parathyroid adenoma. 

Secondary: Elevated PTH due to Low Ca2+ (Hypocalcemia). Seen commonly in chronic kidney disease causing low Vitamin D synthesis and hyperphosphatemia. Also seen in several malabsorptive states (i.e chronic pancreatitis).

Tertiary: Elevated PTH due to hyperplasia/ hypersecretion from the paraythroid gland in the setting of long-standing secondary hyperparathyroidism (i.e CKD). This results in elevated PTH AND elevated Ca2+, even after correction of the secondary cause. 

REFERENCES

  1. Pitt SC, Sippel RS, Chen H. Secondary and Tertiary Hyperparathyroidism, State of the Art Surgical Management. The Surgical clinics of North America. 2009;89(5):1227-1239. doi:10.1016/j.suc.2009.06.011.
  2. Ahmad R., Hammond JM. Primary, secondary, and tertiary hyperparathyroidism. Otolaryngol Clin North Am. 2004 Aug;37(4):701-13, vii-viii.
  3. Russell RI. Hypoparathyroidism and malabsorption. British Medical Journal. 1967;3(5568):781-782.

Ionized Calcium (Ca2+) and Hydrogen ions (H+) compete for binding to Albumin (-) and other negatively charged protein molecules.

WHEN pH is low (acidosis)

  • Increase in Hydrogen (H+) molecules and therefore less protein binding of Ca2+, INCREASES serum Ca2+ levels.

WHEN pH is high (alkalosis)

  • Decrease in Hydrogen (H+) molecules and therefore more protein binding of Ca2+, DECREASES serum Ca2+ levels.

REFERENCES

  1. Nakamaru Y, Schwartz A. The Influence of Hydrogen Ion Concentration on Calcium Binding and Release by Skeletal Muscle Sarcoplasmic Reticulum. The Journal of General Physiology. 1972;59(1):22-32.
  2. Cooper MS, Gittoes NJL. Diagnosis and management of hypocalcaemia. BMJ : British Medical Journal. 2008;336(7656):1298-1302. doi:10.1136/bmj.39582.589433.BE.
  3. Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet 1998;352:306-11

During the first 20 weeks of pregnancy, serum TBG levels will increase by two fold. This causes more T3/T4 to be picked up by TBG → The body responds by producing more T3/T4.

NOTE: Though the total T3/T4 may increase, the total physiologically active T3/T4 is unchanged.

REFERENCES

  1. Ain KB, Mori Y, Refetoff S. Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: a mechanism for estrogen-induced elevation of serum TBG concentration. J Clin Endocrinol Metab. 1987;65(4):689.
  2. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev. 1997;18(3):404.

The serum osmolality is calculated by the concentrations of the different effective osmoles which compose it. The formula:

Calculated Sosm   =   (2  x  serum [Na])  +  [glucose]  + [urea] (SI)

Calculated Sosm   =   (2  x  serum [Na])  +  [glucose, in mg/dL]/18  + [blood urea nitrogen, in mg/dL] (US)

WHY SODIUM TIMES TWO? The serum sodium is multiplied by two in order to account for the negatively charged solutes that must accompany it in the serum to maintain net neutrality in the body (i.e chloride and bicarbonate).

REFERENCES

  1. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001.

Both will result in AM (morning) hyperglycemia.

DAWN: Think Dawn is Down” => Early morning hypergylcemia without preceding hypogylcemia. Secondary to Growth hormone surge at dawn (normal physiology), increasing insulin requirements and serum glucose levels. Treat: May need to increase dose of night time long acting insulin.

SOMOGYI:SoMo is So Much insulin” => Nocturnal hypoglycemia (from fasting or excess bedtime insulin) causing rebound hypergylcemia. Surge of counter-regulatory hormones (i.e epinephrine and glucagon) that results in hyperglycemia. Treat: Decreasing rather than increasing night time insulin.

NOTE: Evidence (1,2) exists that discredits the Somogyi hypothesis. In fact if a patient has high AM blood sugars, they likely had high blood sugars overnight.

REFERENCES

  1. Schernthaner, G. “Dawn phenomenon and Somogyi effect in IDDM.” Diabetes Care 1989 Apr; 12(4): 245-251.
  2. Rybicka M, Krysiak R, Okopień B. The dawn phenomenon and the Somogyi effect – two phenomena of morning hyperglycaemia. Endokrynol Pol. 2011;62(3):276-84.
Img Cred: Hinkle et al

Hyperprolactinemia is one of the most common endocrine disorders in the hypothalamic- pituitary axis. Although the most common etiologies of hyperprolactinemia are iatrogenic and prolactin producing adenoma (prolactinoma) — Another possible cause is primary hypothyroidism.

HOW? Secretion of Prolactin is primarily controlled by prolactin inhibitory hormone (dopamine) from the hypothalamus, however other factors [i.e VIP and Thyroid releasing hormone (TRH)] can influence its release. 

  • TRH is a hypothalamic tripeptide that sits atop the hypothalamic/pituitary/thyroid axis; its primary function is stimulating release of thyrotropin (TSH) from the anterior pituitary gland. However it can also cause an increase in prolactin (PRL) secretion!

REFERENCES

  1. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004 Jan 14; 291(2):228-38.
  2. Hinkle et al. Desensitization, trafficking, and resensitization of the pituitary thyrotropin-releasing hormone receptor. Front. Neurosci., 13 December 2012 | http://dx.doi.org/10.3389/fnins.2012.00180
  3. Bahar A, Akha O, Kashi Z, Vesgari Z. Hyperprolactinemia in association with subclinical hypothyroidism . Caspian Journal of Internal Medicine. 2011;2(2):229-233.
  4. Dragana J, Xiangbing W. Primary Hypothyroidism Associated with Hyperprolactinemia and Pituitary Macroadenoma. Thyroid Science 6 (10): CR1-4, 2011

Wolff-Chaikoff Effect: Iodine induced hypothyroidism. Can occur in normal or hyperthyroid state. Can be used as treatment against hyperthyroidism (i.e thyroid storm); Excess iodide transiently inhibits thyroid iodide organification. In individuals with normal thyroid function, they will undergo the escape phenomena (the gland escapes from this inhibitory effect and iodide organification resumes) after several days.

Jod-Basedow Phenomenon: Iodine induced hyperthyroidism. In individuals with iodine deficient hypothyroidism, thyroid hormone synthesis becomes excessive as a result of increased iodine exposure. NOTE: this does not occur in euthyroid individuals!

REFERENCES

  1. Woeber, KA. Iodine and thyroid disease. Med Clin North Am. 1991 Jan;75(1):169-78.
  2. El-Shirbiny AM, Stavrou SS, Dnistrian A, Sonenberg M, Larson SM, Divgi CR. Jod-Basedow syndrome following oral iodine and radioiodinated-antibody administration. 1997 Nov. J. Nucl. Med. 38 (11): 1816–7.
  3. Eng P, Cardona G, Fang S, Previti M, Alex S, Carrasco N, Chin W, Braverman L. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology. 1999 Aug;140(8):3404-10.

Pheochromocytoma= A rare catecholamine producing tumour that originate from chromaffin cells in the adrenal medulla. Patients classically present with: paroxysmal hypertension, palpitations, headache, and diaphoresis. The frequency varies from daily, weekly or monthly.  Patients generally have orthostatic hypotension on physical exam.

NOTE: Surgery is the definitive treatment. Pre-operatively the patient must be given both alpha- AND beta-blocking agents!

  • Alpha-blocker= opposes catecholamine-induced vasoconstriction
  • Beta-blocker= opposes the subsequent reflex tachycardia secondary to alpha-blockade

WARNING: Never give a patient with a pheochromocytoma a beta-blocker without first giving an alpha-blocker!!!

  • WHY? Epinephrine and Norepinephrine released by the adrenal medulla act on both alpha & beta receptors. In the absence of beta-2-mediated vasodilation, profound unopposed alpha-mediated vasoconstriction may lead to hypertensive crisis or pulmonary edema.
  • Use: phenoxybenzamine beforehand or consider Labetalol (mixed alpha/beta adrenergic antagonist)

REFERENCES

  1. Chapter 23: Hypertension. Symptom to Diagnosis: An Evidence-Based Guide, 3e
  2. Myklejord DJ. Undiagnosed Pheochromocytoma: The Anesthesiologist Nightmare. Clinical Medicine and Research. 2004;2(1):59-62.