Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.

In 2018, Ataoglu and colleagues confirmed and expanded our knowledge of “Low T3 syndrome.” Despite a normalized TSH, a Low T3 is deadly not only in acute, critical illness, but in “chronic disease.”

To be specific, Low T3 is more deadly in some health conditions than others.

What should be really shocking to many is that high Free T4 couldn’t compensate for patients’ low Free T3, despite a normalized TSH.

The highest death rate was NOT in people with an isolated high FT4.

Surprisingly, the highest death rate was NOT in people with an isolated low FT3. This cohort, with Low Free T3 but with FT4 and TSH “normal” was the largest cohort in terms of its number of patients, and had the highest number of deaths (148 lived; 177 died), 45% survived and 55% died.

However, the highest death rate by far was in people with both a low T3 AND a high T4. In this category, only 27% survived and 73% died.

In Low T3 syndrome, a high T4 can be more deadly.

In other words, the people with the lowest T3:T4 ratio were at highest risk of death, especially in an elderly population.

Having extra T4 hormone does not compensate for T3 loss. It can make things worse.

How did their research demonstrate these risks?

METHODS

They performed a retrospective study of 1,164 hospitalized chronically ill patients over an average of 36 months (between 1 month and 41 months). 

They included patients with a variety of chronic diseases:

• Kidney disease (“Chronic renal disease: n= 267 patients),
• Cancer (“Malignancy” n = 170 patients),
• Cardiovascular disease (“Cardiac disease” n = 496 patients), and
• Brain / “Neurological disease” (n = 161 patients)

They excluded anyone who had been receiving treatment for any thyroid dysfunction.

They measured 16 factors: Gender, Age, C-reactive protein, Sedimentation rate, Ferritin, LDH, Albumin, Glucose, Creatinine, Hemoglobin, Leukocytes, Thrombocytes, FT3, FT4, TSH, and the FT3/FT4 ratio.

They divided the population into four groups by thyroid hormone values:

Group A = normal TSH, FT3, and FT4

Group B = High FT4 but normal TSH and FT3

Group C = Low FT3 but normal TSH and FT4

Group D = Low FT3 and High FT4, but normal TSH

They performed statistical analysis with distributions and analyzed the relationships between continuous variables.

The primary endpoint was all cause mortality.

BACKGROUND: WHAT IS LOW T3 SYNDROME?

Low T3 syndrome is the most honest, accurate name this syndrome has ever had, but it’s more commonly called “non-thyroidal illness” syndrome (NTIS) today.

Whether or not your thyroid gland is healthy, and whether or not you are being treated with thyroid hormones, your T3 hormone is at risk of depletion if or when you go through a critical illness.

NTIS occurs in several phases. First, your body will deplete its T3 supply to lower your metabolic rate. Your TSH will not elevate when this happens, but will stay normal. Next, your T4 level may slowly sap away as well, while your T3 goes even lower.

This loss of thyroid hormones might be protective at first, in the early stages of illness. But if you can’t restore T3 levels at the right time for your recovery, your health recovery is at risk. In fact, your life is at risk. 

This study measured thyroid hormones at the time of admission to hospital in patients presenting with a chronic, not critical illness. A patient in the study could have been in any of the phases of NTIS when blood was tested. Nevertheless, their biochemical profile at that time seems to be a strong prognostic indicator of health outcomes.

RESULTS: RISK RATIO FROM HIGHEST TO LOWEST

This was the ranking of the risk ratios per variable. The higher the number, the higher the risk of all cause mortality in their population. A risk ratio of 2.0 means a person in their study was twice as likely to die than people without that condition: 

1. Cancer = 2.515.

19.4% of people had cancer in Group D (the low FT3 + high FT4 group).

2. Age 65+ years  = 2.235

Group D (Low FT3 + High FT4) was the oldest cohort, averaging 77.3 years,

followed by Group B (high FT4) averaging 64.0 years,

followed by Group C (Low FT3) averaging 58.5,

followed by the youngest cohort Group A (euthyroid) averaging 40.6.

3. Low FT3 + High FT4 = 2.224.

The risk ratio is almost tied with #2, very close to the risk of age.

This risk ratio was based on Group D compared with Group A (euthyroid). In this Group D, only 27% survived (60 lived / 156 died). The second most deadly thyroid category was Group C, Low T3, in which 45% died (148 survived / 177 died).

The most common illness in this category was Cardiac disease (48.1%), followed by Kidney disease (24.1%).

Group D had the highest CRP (89.3 mg/L), the highest Ferritin (320.2 ng/mL), highest Leukocytes (9931 mm3/mcL).

Men and women were equally represented (107 F / 109 M).

4. Albumin <3.5 g/dL = 1.869

Notice that the risk ratio was significantly lower than #3. Low T3 + High T4 (2.224)

Groups C and D (the two Low T3 groups) had an equally low Albumin averaging 3.0 g/dL

5. Low Free T3 alone = 1.561.

Risk was based on this Group C (Low Free T3 alone) compared with Group A (euthyroid).

This was the largest category of patients (325 people). 

In this Group C, only 45% survived (148 lived / 177 died).

The average age in Group C was only 58.5 years old.

Kidney disease and Cardiac diseases were nearly tied as the most common disease in Group C (37.8%, 37.2%)

6. Neurological disease = 1.498

In Group D, 20.8% of people had neurological disease. It was only slightly less common in Group C, low T3 (18.2%).

Neurological disease was half as common in Group B, high T4 (9.3%) and Group A, euthyroid (8%).

7. Cardiac disease = 1.200.

In Group B, the smallest cohort (150 patients), high T4 Cardiac disease was the most common disease (54.7%), but more people survived than died (63%, 95 survived / 55 died).  In contrast, in Group D, low T3/T4 ratio, Cardiac disease was slightly less common (48.1%) but this group had the highest death rate (only 27% survived)

8. Creatinine = 1.114.

Group C, Low T3, had the highest Creatinine at 2.0 mg/dL, followed by Group D (1.5 mg/dL).

Groups A and B both had an average of 1.1 mg/dL.

9. High Free T4 alone = 1.072

The risk ratio was based on comparing this Group B and Group A (euthyroid).

In this Group B cohort, more people survived than died. (63% survived, 95 survived / 55 died). In Group A (euthyroid), 74% survived. There was only an 11% difference between these two groups.

The most common disease in this Group B was Cardiac disease (54.7%)

SOURCE

Ataoğlu, H. E., Ahbab, S., Serez, M. K., Yamak, M., Kayaş, D., Canbaz, E. T., … Yenigün, M. (2018). Prognostic significance of high free T4 and low free T3 levels in non-thyroidal illness syndrome. European Journal of Internal Medicine. https://doi.org/10.1016/j.ejim.2018.07.018