Hyponatremia and Isolated Free T4 Elevation in a Patient With Acute Intermittent Porphyria

Background: Porphyrias represent a spectrum of diseases that stem from dysfunction within the heme biosynthetic pathway. Acute intermittent porphyria (AIP) is the most common type of porphyria due to a genetic deficiency of porphobilinogen deaminase which results in a wide range of neurovisceral symptoms. Hyponatremia and abnormalities with thyroid function have been found in AIP but the mechanisms behind these processes are unclear. Clinical Case: A 26-year-old male with a history of chronic, recurrent abdominal pain presented with 10 days of progressively worsening periumbilical abdominal pain and constipation. He describes that preceding the onset of symptoms he had been binging 5-10 standard alcoholic drinks each day for a few days. Initial laboratory workup demonstrated hyponatremia with Na 114 mmol/L (n: 134 – 137 mmol/L), hypochloremia with Cl 76 mmol/L (n: 95 – 108 mmol/L), and hyperbilirubinemia with total bilirubin 2.5 mg/dL (n: 0.2 – 1.3 mg/dL). CT abdomen/pelvis was negative for any concerning pathology. Further studies showed low serum osmolality at 243 mOsm/kg (n: 275 – 295 mOsm/kg), urine Na 62 mmol/L (n > 20mmol/L), and urine osmolality at 394 mOsm/kg (n: 300 – 900 mOsm/kg) consistent with SIADH. The patient was treated with 3% NaCl and free water restriction to 1.2L/day with improvement in Na levels. Further laboratory workup demonstrated normal TSH, but persistently elevated free T4 with maximum free T4 of 2.77 ng/dL (n: 0.80 – 1.70 ng/dL) which downtrended to 1.99 ng/dL by discharge. Thyroid ultrasound was unremarkable. Pituitary evaluation via hormonal workup and MRI brain was negative for any abnormalities. Given the symptomatology and laboratory findings, the patient was evaluated for porphyria. Laboratory evaluation demonstrated severe elevations in urine porphyrins, urine delta aminolevulinic acid (56.8 mg/24h, n < 4.5 mg/24h), and urine porphobilinogen (82.5 mg/g, n < 2.3 mg/g) consistent with AIP. The patient was treated with four days of hematin infusions which resolved his abdominal pain and was discharged in an improved state. Conclusion: AIP is a rare entity brought out by a deficiency in porphobilinogen deaminase, a key enzyme in the heme biosynthesis pathway. Various metabolic disturbances have been described in AIP including hyponatremia and alterations in thyroid function tests suggestive of thyrotoxicosis. Hyponatremia in our patient was likely due to SIADH from neurovisceral pain. Our patient displayed isolated free T4 elevation as well. We hypothesize this developed due to his acute illness causing a greater decrease in D2 deiodinase activity compared to any concomitant increase in D3 deiodinase activity. This was supported by his free T4 level downtrending following treatment of his AIP attack. More research is needed to further elucidate the mechanism behind these derangements in biochemical markers and their impact on patient prognosis.

Inhibition of Type 1 Iodothyronine Deiodinase by Bisphenol A

Plastics are ubiquitously present in our daily life and some components of plastics are endocrine-disrupting chemicals, such as bisphenol A and phthalates. Herein, we aimed to evaluate the effect of plastic endocrine disruptors on type 1 and type 2 deiodinase activities, enzymes responsible for the conversion of the pro-hormone T4 into the biologically active thyroid hormone T3, both in vitro and in vivo. Initially, we incubated rat liver type 1 deiodinase and brown adipose tissue type 2 deiodinase samples with 0.5 mM of the plasticizers, and the deiodinase activity was measured. Among them, only BPA was capable to inhibit both type 1 and type 2 deiodinases. Then, adult male Wistar rats were treated orally with bisphenol A (40 mg/kg b.w.) for 15 days and hepatic type 1 deiodinase and brown adipose tissue type 2 deiodinase activities and serum thyroid hormone concentrations were measured. In vivo bisphenol A treatment significantly reduced hepatic type 1 deiodinase activity but did not affect brown adipose tissue type 2 deiodinase activity. Serum T4 levels were higher in bisphenol A group, while T3 remained unchanged. T3/T4 ratio was decreased in rats treated with bisphenol A, reinforcing the idea that peripheral metabolism of thyroid hormone was affected by bisphenol A exposure. Therefore, our results suggest that bisphenol A can affect the metabolism of thyroid hormone thus disrupting thyroid signaling.

Maternal BMI, Peripheral Deiodinase Activity, and Plasma Glucose: Relationships Between White Women in the HAPO Study

Objectives Explore the maternal body mass index (BMI) relationship with peripheral deiodinase activity further. Examine associations between deiodinase activity, glucose, and C-peptide. Consider findings in the historical context of related existing literature. Design Identify fasting plasma samples and selected demographic, biophysical, and biochemical data from a subset of 600 randomly selected non-Hispanic white women recruited in the Hyperglycemia Adverse Pregnancy Outcomes (HAPO) study, all with glucose tolerance testing [545 samples sufficient to measure TSH, free T4 (fT4), and T3]. Exclude highest and lowest 1% TSH values (535 available for analysis). Assess deiodinase activity by using T3/fT4 ratios. Among women with and without gestational diabetes mellitus (GDM), compare thyroid measurements, C-peptide, and other selected data. Examine relationships independent of GDM status between BMI and thyroid hormones and between thyroid hormones and glucose and C-peptide. Results Levels of BMI, T3/fT4 ratio, and T3 were significantly higher among women with GDM (P = 0.01, 0.005, and 0.001, respectively). Irrespective of GDM status, maternal BMI was associated directly with both T3/fT4 ratio (r = 0.40, P < 0.001) and T3 (r = 0.34, P < 0.001) but inversely with fT4 (r = −0.21, P < 0.001). In turn, fasting thyroid hormone levels (most notably T3/fT4 ratio) were directly associated with maternal glucose [z score sum (fasting, 1, 2 hours); r = 0.24, P < 0.001] and with C-peptide [z score sum (fasting, 1 hour); r = 0.27, P < 0.001]. Conclusions Higher BMI was associated with increased deiodinase activity, consistent with reports from elsewhere. Increased deiodinase activity, in turn, was associated with higher glucose. Deiodinase activity accounts for a small percentage of z score sum glucose.

Peripheral deiodinase activity: A potential explanation for the association between maternal weight and gestational hyperglycemia

Background High maternal weight is known to associate with both low free thyroxine and gestational diabetes mellitus. We explore a deiodinase-related mechanism that may help explain these associations. Methods Among 108 women receiving routine oral glucose tolerance testing for gestational diabetes mellitus, we collected biophysical data and measured free thyroxine and total triiodothyronine, using residual plasma samples. Results Fasting triiodothyronine/free thyroxine ratio and triiodothyronine were higher among women with gestational diabetes mellitus ( p = 0.02; p = 0.04). The triiodothyronine/free thyroxine ratio and triiodothyronine measurements at 2 h were associated with weight ( r = 0.20, p = 0.04; r = 0.22, p = 0.02); free thyroxine showed a non-significant inverse weight relationship ( r = −0.06, p = 0.55). Glucose at all four intervals was associated with triiodothyronine/free thyroxine ratios, and triiodothyronine at 2 h. In stepwise regression, triiodothyronine/free thyroxine ratio predicted glucose more strongly than did weight. Conclusion These relationships may be explained by higher maternal weight inducing peripheral deiodinase activity, resulting in higher plasma glucose (via triiodothyronine stimulation) and thereby increasing gestational diabetes mellitus risk.

Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients

Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion. Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships. Results: Under varying dose requirements (median 1.84 µg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH–FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3–TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (–0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels. Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH–FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control.