Total Thyroidectomy May Ease Persistent Hashimoto Symptoms

Total thyroidectomy may be a treatment option for patients with confirmed Hashimoto's disease who experience persistent symptoms despite adequate thyroid hormone replacement, novel research suggests.

Findings from the new randomized trial comparing total thyroidectomy with medical management alone in 147 such patients were published online March 11, 2019, in Annals of Internal Medicine by Ivar Guldvog, MD, PhD, head of the Department of Breast and Endocrine Surgery, Telemark Hospital Trust, Skien, Norway, and colleagues.

The approach is based on the hypothesis that persistent symptoms such as profound fatigue, poor sleep quality, muscle and joint tenderness, and dry mouth/eyes may relate to the underlying autoimmunity of Hashimoto's thyroiditis and therefore may only partially respond to thyroid hormone substitution with levothyroxine, even if euthyroid status is achieved.

In contrast, the authors say, complete removal of the antigenic tissue via total thyroidectomy may alleviate symptoms by normalizing levels of serum anti-thyroid peroxidase (anti-TPO) antibodies, thereby reducing inflammation.

In the study, thyroidectomy did normalize anti-TPO antibody levels, and only the surgical group reported significant improvement in self-reported symptoms.

"The take-home message should be that Hashimoto's disease is a surgical condition and should be referred as such," Guldvog told Medscape Medical News.

The new data, he said, "are sufficient to support a change in clinical practice guidelines due to the fact that our [data are] based on a randomized study, it showed highly significant differences, and for the patients there is no alternative treatment."

But endocrinologist Rhoda H. Cobin, MD, clinical professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, disagrees, noting that "their premise may be faulty since it is by no means certain that the symptoms evaluated are indeed related to generalized inflammation caused by thyroid-specific autoimmunity."

Cobin also pointed to the risks involved in the surgery, which included infections in three patients and nerve palsy (which later resolved) in four.

"I empathize with people who continue to suffer despite being euthyroid but I do not believe that the present paper convincingly shows causality between autoimmunity, inflammation, and symptoms. I do not believe that the results justify the risks," she cautioned.

Symptom Relief Reported Only by the Surgery Group

Hashimoto's disease is the most prevalent autoimmune disease worldwide: a T-cell–mediated disease of unknown cause, with elevated levels of serum anti-TPO antibody and proinflammatory cytokines. The disease process ultimately leads to hypothyroidism with attendant symptoms, which may respond only partly to adequate thyroid hormone substitution.

Hashimoto's disease has two types: one in which symptoms benefit from levothyroxine supplementation and another in which symptoms persist despite patients' euthyroid status while receiving hormone substitution.

Guldvog and colleagues noticed improvement in symptoms in the latter group of patients after total thyroidectomy for bilateral goiter in an earlier study that they reported as a conference poster in 2015.

The current study took place at a single Norwegian secondary care hospital.

The patients were aged 18-79 years and had persistent Hashimoto-related symptoms despite euthyroid status while receiving hormone replacement therapy and serum anti-TPO antibody titers greater than 1000 IU/mL.

At baseline, patients randomized to the surgery group (n = 73) received a median weekly levothyroxine dose of 618 μg while the controls (n = 74), who continued with medical therapy, received 550 μg.

A small number of patients in both groups (< 10%) received either a combination of levothyroxine (T4) and liothyronine (T3), the desiccated porcine product Armour Thyroid (Allergan) only, or Armour in combination with levothyroxine.

All achieved euthyroid status, defined as the absence of hyper- or hypothyroid symptoms and signs combined with serum thyroid stimulating hormone and serum free T4 or free T3 levels within the normal range.

For the primary outcome, general health score on the Short Form-36 Health Survey (SF-36) at 18 months, the surgery group increased from 38 to 64 points while the controls dropped from 38 to 35 points. The 29-point difference between the two groups was statistically significant beginning at 6 months after surgery, Guldvog and colleagues report.

Also at 18 months, the surgery group experienced a significant reduction in mean SF-36 total fatigue scores (from 23 to 14 points) versus virtually no change (23 to 24 points) in the controls. And the proportion of patients reporting chronic fatigue dropped from 82% to 35% in the surgery group, compared to a nonsignificant change from 84% to 74% among the controls.

Serum anti-TPO antibody titers at 18 months were normal in almost all patients in the surgery group and only modestly reduced in the controls. From median baseline values of 2232 IU/mL and 2052 IU/mL for the surgery and control groups, respectively, those values at 18 months were 152 IU/mL versus 1300 IU/mL, respectively.

In the surgery group, 4.1% (3/73) had post-surgical infections — one was initiated by a tracheal injury, while the other two were wound infections. Long-standing hypocalcemia was present in 4.1% (3/73), and 5.5% (4/73) had unilateral recurrent laryngeal nerve palsy at 4 and 12 months after surgery. All four were improved by 12 months. No major bleeding occurred.

"We believe that this is the first randomized controlled trial to demonstrate improvement in health-related quality of life and fatigue and normalization of serum anti-TPO antibody titer levels after complete removal of the diseased thyroid gland in patients with histologically verified Hashimoto disease," the authors write.

Just a Placebo Effect in Desperate Patients?

Cobin pointed out that the symptoms measured in the trial are "soft" endpoints, which are "extremely subjective and impossible to measure objectively or quantitatively.... To equate reduction in thyroid auto-antibodies with improvement in symptoms seems inappropriate."

In addition, both Cobin and the study authors note that the lack of a sham thyroidectomy group — impossible for ethical reasons — leaves open the possibility that the surgery is having a placebo effect.

"In desperate people treated with a dramatic procedure, one can only speculate on the extent and duration of a placebo effect," Cobin commented.

Indeed, Guldvog and colleagues acknowledge that: "The participants in our study were advised to consider surgery because of severe, unspecific symptoms ... therefore, they could be characterized as 'end of the road' in terms of available treatment options, and considered a highly select group ... with high motivation for surgery."

However, they point out that studies have found placebo effects in improved health-related quality of life scores tend to normalize within 6 months and would be unlikely to last 18 months.

Nonetheless, they say, "further studies, ideally with longer follow-up, should be encouraged."

Guldvog told Medscape Medical News, "Our next step in the research is the long-term results after 5 years and patients with low values of anti-TPO and increased need of thyroxine substitution. We are also in the middle of investigating patients with typical symptoms but no need of thyroxine and high levels of anti-TPO."

The study was funded by Inge Steenslands Stiftelse, Stavanger, Norway, and Telemark Hospital Trust. Guldvog and Cobin have disclosed no relevant financial relationships.

Ann Intern Med. Published online March 11, 2019. Abstract

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