COMMENTARY

Can Surgery Alleviate Persistent Symptoms in Hashimoto's Thyroiditis?

Benjamin J. Gigliotti, MD

Disclosures

July 17, 2019

Editorial Collaboration

Medscape &

"I feel like I've tried everything—why don't you just take the [expletive] thing out?"

This was my first encounter with a request to treat fatigue with a thyroidectomy.

The Patient Who 'Tried Everything'

A 34-year-old woman with Hashimoto's thyroiditis came to our endocrinology clinic with systemic symptoms that had lasted for several years. She felt "normal" until age 17, when she developed infectious mononucleosis. Despite resolution of most of her symptoms, her energy levels remained "low but functional."

For the past 4 years, she noticed a progressive worsening of her fatigue, depressed mood, "brain fog," cold intolerance, dry skin and hair, muscle and joint aches, menorrhagia, and abdominal bloating or cramping with alternating diarrhea and constipation. She also had a weight gain of 15 lb in 2 years.

She had no other medical or surgical history. Family history was significant for obesity, Hashimoto's thyroiditis in her mother, and hypertension in her father and grandparents. She is single, does not smoke or drink alcohol, and works as an administrator at a college.

Workup at symptom onset revealed a normal comprehensive metabolic profile, complete blood count, and vitamin B12 and iron studies. She had a 25-OH vitamin D level of 18 ng/mL, a TSH of 3.8 mIU/L, free T4 of 0.9 ng/dL, total T3 of 82 ng/dL, and an elevated anti-TPO antibody titer of 374 IU/mL.

She previously sought the care of a naturopath and has tried antibiotics, desiccated thyroid extract, supplements, low-dose naltrexone, and multiple diets, including gluten elimination and FODMAPs. Each intervention led to mild transient improvement or no change in symptoms.

Her exam revealed normal vital signs and she appeared well nourished but anxious. Her thyroid was symmetric, ~30 g (mildly enlarged), and firm/rubbery, with slight tenderness and no palpable nodules. She had mild diffuse abdominal and musculoskeletal tenderness, but the exam was otherwise normal.

At the end of her exam, the patient said, "I heard about a recent study that showed surgery improved quality of life in Hashimoto's. I feel like I've tried everything—why don't you just take the [expletive] thing out?"

Thyroidectomy for Symptom Improvement?

Referrals for constitutional symptoms can be as challenging as they are commonplace. Some patients come undifferentiated or with diagnoses such as "adrenal fatigue" or chronic fatigue syndrome. Many attribute their symptoms to Hashimoto's thyroiditis, despite being biochemically euthyroid. These visits typically involve fielding questions about whether symptoms will respond to levothyroxine initiation or titration to a lower TSH goal, changing to a brand-name formulation, or a trial of thyroid extract or liothyronine (T3).

In this case, my patient referenced the recent prospective interventional 1:1 randomized trial by Guldvog and colleagues[1] comparing thyroidectomy with standard-of-care thyroid hormone replacement (THR) for persistent Hashimoto-related symptoms. The study included 150 patients aged 18-79 years with a high anti-TPO titer (median, 2232; range, 1278-4263) who were followed for 18 months post-thyroidectomy or during THR titrated to a normal-range TSH.

The primary outcome was change in SF-36 general health survey scores. The thyroidectomy group improved from baseline after surgery, whereas the THR group exhibited no change. Secondary outcome analysis revealed a reduction in total and chronic fatigue scores and TPO antibody titer in the thyroidectomy group but not in the THR patients.

Of note, higher SF-36 scores were present despite surgical complications, which are typically associated with lower quality of life. The authors hypothesized that symptom improvement was due to removal of antigenic tissue and dampening of systemic inflammation and autoimmunity, citing the dramatic decline in anti-TPO titer after surgery.

The Data Fall Short

Although the study results are intriguing, the authors candidly admit to several limitations. The most significant criticisms include the lack of a true placebo group and blinding (cue debate on the ethics of sham surgery). The invasive nature of surgery and a decisive approach to treatment have both been associated with a strong and durable placebo effect.[2]

There are also issues of generalizability, given the selective nature of the cohort: Patients had a very high anti-TPO titer and persistent symptoms that were "severe enough" to warrant surgery, but symptoms were not otherwise articulated. The use of subjective endpoints is particularly problematic in this population, whom the authors characterized as at the "end of the road" for treatment options, with "high motivation for surgery."

Ultimately, the data fall short of proving a causal relationship between symptom burden and antigenic thyroid tissue, anti-TPO antibody titer, and/or circulating inflammatory markers. Additional studies and longer follow-up are clearly needed, ideally with more typical patients, harder endpoints, a focus on mechanism, and clarification of a clinical and biochemical phenotype that might predict a positive response to thyroidectomy. If an underlying systemic inflammatory response is found to be the true cause of symptoms, one hopes that a less invasive treatment might be found.

These symptoms are not a universal experience; we care for many patients with Hashimoto's who feel well despite their diagnosis.

At the heart of this study is the recognition that some patients with Hashimoto's thyroiditis don't feel well despite biochemical euthyroidism, whether on or off thyroid hormone. Euthyroid women with Hashimoto's have been demonstrated to have a high symptom burden (chronic fatigue, dry hair, anxiety, and lower quality-of-life scores) with anti-TPO > 121 IU/mL.[3] Additionally, anti-TPO positivity has been associated with low-grade systemic inflammation, higher rates of other autoimmune disorders, depression, fibromyalgia, small intestinal bacterial overgrowth, and obstructive sleep apnea, among other conditions.[4,5,6,7,8,9]

The underlying cause of these symptoms and associations remains unclear. Postulated mechanisms include systemic inflammation, comorbid autoimmune disease or functional disorders, deiodinase polymorphisms with reduced T4-to-T3 conversion, and/or an underlying proclivity for somatic and psychosocial distress.

However, these symptoms are not a universal experience; we care for many patients with Hashimoto's who feel well despite their diagnosis, and who only follow up for occasional TSH checks and renewal of their levothyroxine prescription. Therefore, it is plausible that there are distinct subgroups of THR "responders" and "nonresponders." It is equally plausible that selection bias is present. Patients with psychological distress are more likely to undergo thyroid function testing, even though they are no more likely to have hypothyroidism.[10] Perhaps it should not be surprising that levothyroxine is often used in an attempt to alleviate said distress, and that a higher proportion of patients on levothyroxine have distressed quality-of-life scores compared with matched peers, despite normalization of TSH.[11]

Weighing the Risks

While thyroidectomy is reasonable to consider for refractory pain or obstructive neck symptoms from a large or constrictive goiter, one must carefully weigh the risks, especially for a new indication where the benefit is unproven. Beyond the usual risks of surgery and anesthesia, thyroidectomy poses a risk for recurrent laryngeal nerve injury and hypoparathyroidism, both of which carry significant morbidity. And although complications are reduced in the hands of experienced surgeons, most thyroidectomies are performed by low-volume surgeons, with an overall complication rate of 6%.[12]

Furthermore, patients with Hashimoto's thyroiditis may have a several-fold higher risk for complications due to inflammatory changes and thyroidal adherence to surrounding tissues. These cases can be difficult, even for seasoned surgeons.[13] If one multiplies this complication rate by the number of patients with Hashimoto's thyroiditis who experience constitutional symptoms (many of whom do not fit the aforementioned inclusion criteria), thyroidectomy will likely harm many more patients than it will help.

Should I Refer My Patient?

The fundamental question remains: Should I refer my patient for thyroidectomy?

In short, I think not. Unlike the Guldvog et al study cohort, my patient has never had documented hypothyroidism, is euthyroid off hormonal therapy, and has an anti-TPO antibody titer that is nearly an order of magnitude lower than the average. Although she had an initial evaluation by an internist and tried multiple interventions with a naturopathic physician, nearly 4 years of progressive symptoms have passed without repeat medical evaluation. Given the commonly associated conditions stated above, the importance of conducting a careful and comprehensive investigation for alternative causes cannot be overstated.

I recommended treatment for her menorrhagia and vitamin D deficiency, and planned to retest her iron studies, inquire about quality/quantity of sleep, screen for depression, assess for evidence of other autoimmune diseases, and consider a referral to gastroenterology. Meanwhile, I did my best to actively listen, validate her frustrations, and set the expectation that there is rarely a single cause or simple treatment, but that multifaceted interventions can help. I often find that the simple act of acknowledging a patient's suffering can be therapeutic.

She was initially disappointed by my recommendation against surgery but was receptive to discussing risks and agreed to further testing, along with longitudinal monitoring for the development of hypothyroidism.

As the data from this study are disseminated, we may more frequently encounter questions about thyroidectomy for Hashimoto's thyroiditis. Patients with a high symptom burden should undergo a comprehensive medical evaluation, and their frustration should be met with compassion, persistence, and our most precious commodity—time. For those who insist on referral for thyroidectomy, it is prudent to steer them toward thoughtful endocrinologists and surgeons who can thoroughly review the risks and potential benefits on a case-by-case basis.

Meanwhile, we need dialogue at local and national levels to articulate a unified multidisciplinary approach to best care for these patients. A select subset may indeed benefit from thyroidectomy, but more research is necessary before Hashimoto's thyroiditis is considered to be a surgical disease.

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