A 52-year-old man presented to the emergency department with swelling in his legs and general weakness. Symmetric leg swelling had begun 4 weeks earlier. Two weeks before presentation, when it became difficult for him to wear shoes because of the swelling, he had presented to another emergency department, where he was found to have a thyrotropin level of 89mIU per liter (reference range: 0.5-5.7 mIU). He had been taking levothyroxine at a dose of 150 μg daily and the dose was increased to 175 μg daily. Furosemide was prescribed for swelling, with moderate benefit. Symmetric, progressive weakness and intermittent muscle aches subsequently developed, as well as generalized fatigue, nausea, diffuse abdominal pain, and one episode of nonbloody, nonbilious vomiting. He had no chest pain or shortness of breath.
This patient has severe edema accompanied by fatigue, pain and nausea. Notably, he does not have shortness of breath, which is a symptom of heart failure. Heart failure is a common cause of edema.
When he visited the emergency department two weeks earlier, it was determined that he had a very high level of thyrotropin.
What is another name for thyrotropin?
What condition causes increased thyrotropin secretion?
The patient had had papillary thyroid cancer 11 years earlier, which was treated with total thyroidectomy and radioiodine (iodine-131) ablation. He had a history of excellent adherence to levothyroxine, at doses of 125 to 175 μg per day...
Because of his thyroidectomy, the patient requires thyroid hormone replacement therapy with levothyroxine, which is a synthetic version of the thyroid hormone tetraiodothyronine, also known as thyroxine or T4. T4 is the principal thyroid hormone in the circulation. The other thyroid hormone is triiodothyronine or T3.
Of the two thyroid hormones, which is considered the active hormone?
How is the active hormone produced?
The thyrotropin level was 78.6mIU per liter (reference range, 0.5-5.7) and the free T4 level 0.8 ng per deciliter (10 pmol per liter) (reference range, 0.9 to 1.7 ng per deciliter [12 to 22 pmol per liter]).
Although the patient's dose of levothyroxine was increased after his first visit to an emergency room, this did not ease his symptoms, or bring his thyrotropin (TSH) level into the normal range.
What do you think is meant by "free T4"?
On examination, the temperature was 36.5°C (97.7°F), the pulse 56 beats per minute, the blood pressure 118/84 mm Hg, the respiratory rate 16 breaths per minute, and the oxygen saturation 99% while the patient was breathing ambient air. He appeared tired but in no distress...The cardiac and pulmonary examinations were normal.
Below are the doctor's comments:
In patients with severe hypothyroidism, myxedema coma is a concern. However, there is no report of mental-status changes, and this diagnosis is usually associated with other findings of severe hypothyroidism, such as hypothermia, marked bradycardia, hypoventilation and occasionally hypotension, none of which are present in this case...There is no evidence of heart failure.
What needs to be determined is what is causing edema in the patient. Edema can occur in myxedema coma, which is a manifestation of severe hypothyroidism that is precipitated by the stress of another illness. As described above, however, with myxedema coma one would expect to see hypothermia (low body temperature) or bradycardia (low heart rate). This patient's normal heart rate, blood pressure, and mental status argue against severe hypothyroidism as the cause for his edema.
Another cause of edema could be heart failure. Heart failure describes the situation that occurs when cardiac output is inadequate (the heart is unable to pump enough blood). Edema occurs in heart failure because decreased cardiac output leads to decreased blood flow to the kidney; the kidney responds by increasing regulatory molecules (renin-angiotenstin-aldosterone) that increase the extracellular fluid volume and peripheral resistance. However, this patient has no evidence of heart failure.
Electrolyte levels were normal, as were other
measurements. The blood level of albumin
was 2.6 g per deciliter (reference range 3.5 to 5.2), and the
total protein was 5.9 g per deciliter (reference range, 6.0 to
8.0). Urinalysis showed 3+ protein and no blood.
The above measurements indicate that he has a low level of blood
proteins. Blood proteins are mostly synthesized in the liver, and
include albumin, complement
factors, coagulation factors, and various binding proteins. Albumin is a generic blood protein
that helps to maintain the colloid osmotic pressure in the
capillaries. The colloid osmotic pressure due to the blood
proteins prevents fluid loss from the capillaries. Thus a
low level of blood proteins could be causing the edema.
The patient was admitted and treated with intravenous levothyroxine (75 μg in a single dose). On further questioning, he reported the onset of frothy urine at least 1 week before presentation. The spot urine protein level was 380.8 mg per deciliter (reference range, 0 to 15.0), and the urine creatinine level was 54.4 mg per deciliter, resulting in a spot urine protein-to-creatinine ratio of 7.
The doctors determined that the patient's edema was a
manifestation of nephrotic syndrome. Nephrotic
syndrome is a set of signs and symptoms that occur when kidney
disease leads to severe proteinuria
(loss of protein in the urine). The initial urinalysis ("3+
protein") is a non-quantitative test indicating proteinuria.
To establish the diagnosis of nephrotic syndrome, the doctors need
a quantitative test to show that proteinuria is at the high level
seen in nephrotic syndrome, which is 3.5 g of protein per
day. To avoid the need for a 24-hour urine collection, they
measure both protein and creatinine and determine the urine
protein-to-creatinine ratio. A normal protein-to-creatinine
ratio is less than 0.2; anything greater than 3.5 indicates
nephrotic syndrome.
Proteinuria does not usually cause symptoms, but the severe
proteinuria of nephrotic syndrome can cause the urine to appear
frothy, as reported by this patient. Various kidney
disorders that affect the glomerulus can cause the nephrotic
syndrome. In this patient, the severe proteinuria is causing low
levels of blood proteins. In turn, low levels of blood
proteins reduce the colloid osmotic pressure so that fluid leaves
the circulation and causes edema.
The patient presented with hypothyroidism (even while taking his normal dose of levothyroxine) along with edema (which is due to the severe proteinuria of nephrotic syndrome). How do you think the two are connected?
Normally nephrotic syndrome does not cause hypothyroidism because as thyroid hormone bound to protein is lost in the urine, TSH secretion would increase and then stimulate growth and increased hormone synthesis by the thyroid gland. However, because this patient had had a thyroidectomy, he could not compensate with increased thyroid hormone synthesis.
It was determined that the patient had a type of glomerulonephritis that responded to treatment with prednisone.
What type of drug is prednisone? (Hint: these drugs are often used to treat inflammatory and autoimmune disorders.)
Successful treatment of his kidney disorder caused a resolution of the nephrotic syndrome in the patient. The patient's hypothyroidism was treated with a slightly higher dose of levothyroxine.
OPTIONAL
The above case is adapted from this paper: Rabin, A.S.,
Ole-Petter, R., Hamnvik, M.B., Robinson, E.S., Miller, A.L., and
Loscalzo, J. (2015) "Springing a Leak" New England Journal
of Medicine 373: 1362-67. If you are interested,
you can look at the original paper.(link)