This is a critical review that articulates a frustration many clinicians and patients have long experienced. It provide a strong physiological rationale for why the standard TSH-centric approach is insufficient for a significant portion of our patients.

The central takeaway is the biochemical evidence: LT4 monotherapy, even when it normalizes TSH, often fails to restore physiological serum T3 levels. The finding that up to 15% of these patients have T3 levels below the normal reference range is a direct explanation for persistent symptoms.

This underscores the absolute necessity of measuring T3 and free T3 levels in patients who remain symptomatic on levothyroxine, rather than dismissing their complaints of fatigue, cognitive fog, or weight gain which unfortunately happens far too often.

Furthermore, this review provides a much-needed validation for therapeutic options that contain T3. It explains why many patients report dramatic improvement when switched to desiccated thyroid extract (DTE) or a T4/T3 combination. These are not “unscientific” or “outdated” options; for the specific sub-population this paper highlights (perhaps those with DIO2 polymorphisms), they are in fact the more physiologically complete and logical treatment.

My clinical experience is that it likely far higher than the 15%, and any patient that shows imbalanced T4 vs T3 levels (high end T4, low end T3) will respond better to DTE.

Clinical Bottom Line

This article is a narrative review arguing that levothyroxine (LT4) monotherapy, while successful for most, is not a “one-size-fits-all” solution. The authors contend that up to 15% of patients remain symptomatic despite a normal TSH, and this is likely due to a failure to restore physiological serum T3 levels. For this specific subgroup of patients with persistent symptoms, the authors advocate for an individualized approach, including an open discussion and consideration of combination T4/T3 therapy or desiccated thyroid extract (DTE).

Results in Context: Summary of Arguments

This review synthesizes evidence to explain the physiological rationale for why LT4 monotherapy may be insufficient for some patients:

• Biochemical Imbalance: In most patients treated with LT4, normalizing the serum TSH results in a decreased serum T3/T4 ratio and relatively lower serum T3 levels compared to healthy controls. The authors highlight that in at least 15% of these cases, the serum T3 level falls below the normal reference range.

• Persistent Symptoms & Metabolic Issues: This state of relatively low T3, even with a normal TSH, is proposed to explain persistent hypothyroid symptoms like cognitive impairment and fatigue. It may also explain metabolic abnormalities, such as elevated serum cholesterol levels and a slower basal metabolic rate, seen in these patients.

• The “Second Hit” Hypothesis: The review proposes that most patients compensate for the lower T3, but a minority experience persistent symptoms because this low T3 state is compounded by a “second hit”. This second factor could be a specific genetic makeup (e.g., polymorphisms in the DIO2 gene that converts T4 to T3) or an underlying autoimmune component.

• Critique of Past Trials: The authors acknowledge that most randomized controlled trials (RCTs) and meta-analyses have not found combination therapy to be superior to monotherapy. However, they critically appraise these trials, arguing they lacked the statistical power and were not designed to detect a benefit, as they did not specifically enroll the subpopulation of patients who remain symptomatic on LT4.

Assertive Critical Appraisal

This document is a narrative review, not a systematic review or a primary research study.

• Strengths: The review clearly articulates a common and challenging clinical problem: the patient with persistent hypothyroid symptoms despite a “normal” TSH. It provides a strong and detailed physiological rationale (the “2-hit” hypothesis) for why this discrepancy may exist, moving the discussion beyond a simple TSH-centric approach.

• Limitations (As a Review Type): As a narrative review, this article does not follow the rigorous, systematic methods of a meta-analysis (like PRISMA). The evidence presented was gathered via PubMed and Google Scholar searches supplemented by the authors’ “prior knowledge”. This means the selection of studies is susceptible to selection bias, and the article functions primarily as an expert-driven position paper or an argument for a specific clinical viewpoint. It does not provide an unbiased, comprehensive summary of all available evidence.

• Call to Action: The authors conclude that new, robustly designed clinical trials are necessary. They specify these trials must be adequately powered and, crucially, must focus specifically on the target population of symptomatic patients, ideally screening them for genetic or other interfering variables.

Research Objective

The authors’ objective is to explore the evidence of abnormal thyroid hormone metabolism in LT4-treated patients and to offer a rationale for why some patients remain symptomatic and may benefit from individualized therapy that includes T3 (either as combination LT4/T3 or DTE).

Study Design

This is a narrative review. The authors state their evidence acquisition was based on a “collection of primary and review literature” from PubMed and Google Scholar, supplemented by their “prior knowledge of the subject”.

Bibliographic Data

• Title: Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?

• Authors: Matthew D. Ettleson, and Antonio C. Bianco

• Journal: The Journal of Clinical Endocrinology & Metabolism

• Year: 2020

• DOI: 10.1210/clinem/dgaa430

This AI-generated analysis is for informational and research purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified health prov⁶ider with any questions you may have regarding a medical condition.