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Dr. Gordon Skinner response to British Thyroid Association


Dr. D.G.H. Beastall
Guidelines Development Group
British Thyroid Foundation
Department of Clinical Biochemistry
Royal Infirmary
G4 0SF

Dear Dr. Beastall

I thank you for allowing comment on your consultation document.
General CommentsOne of the difficulties with Guidelines in modern day medicine is that there cannot be divorced from political and regulatory influences. I hope you will thus forgive a few comments on your hard work.

There is no doubt that in the present environment Guidelines tend to transmute into rules and caveats or reasonable argument against any aspect of such Guidelines becomes lost in time. In the unusual environment of modern day clinical practice, there is little doubt that to waver from Guidelines once they have become enshrined in publication becomes dangerous territory for a practitioner; Indeed colleagues involved in regulation of medical practice tend to reply more and more on Guidelines compounded by the difficulty that expert witnesses will often be lauded for quoting Guidelines rather than invoking their own (sometime) extensive experience in a subject which will not be considered evidence based medicine albeit culled over 40 years of hard won toil. It is thus crucial that the medical profession acknowledge and state in the public domain that Guidelines are there to assist practitioners but are not sticks to beast them if they fall out of line.

Guidelines usually proclaim the value of evidence based medicine wherein clinical evidence for example if the patient says he/she is not feeling well is somehow less weighty than evidence based on laboratory findings, albeit that this philosophy is selectively applied and there is little laboratory evidence for the extensive display of Prozac, Seroxat, etc. Endocrinology and particularly hypothyroidism have elevated laboratory-based medicine to a level which frequently gainsays unequivocal clinical evidence and the clinical features are then bizarrely ascribed to depression, peri-menopausal state (which used to be considered physiological) or over eating or a somatiform illness albeit the patient has classical features of hypothyroidism. THS situation is compounded by the political legal regulatory pressures, wherein a practitioner, who disclaims the diagnosis of hypothyroidism

if the thyroid chemistry is normal usually within a 95% reference range will receive no disapprobrium from peers or regulatory bodies, while practitioners, who diagnoses and treat patients with due cognisance of clinical evidence in the face of normal thyroid chemistry are in treacherous territory and is usually considered the province of marginal practioners (often private) who have not quite got their heads round the concept of evidence based medicine, albeit the patient returns to optimal health following thyroid replacement.

In summary, there is significant pressure on practitioners to use laboratory chemistry as a keep-safe to not make a diagnosis in the face of over whelming evidence of the condition.

It is pivotal that there is no confusion on this issue. Few practitioners will not agree that if a patient has high TSH level or a low FT4 level, that that patient is likely to be unwell and suffering from the clinical features of hypothyroidism. The mischief lies in assumption of the reciprocal and I am unaware of any evidence which teaches that if you have clinical features of hypothyroidism with reasonably normal thyroid chemistry, that the patient does not suffer from hypothyroidism and will not benefit from thyroid replacement. Two studies have tried to examine this issue.

Doctor McLarens group examined this matter in a left-handed way, although this was not the primary purpose of this study (1). The study identified patients who were deemed to have hypothyroid features but normal thyroid chemistry, which in itself, somewhat supports the notion. However, treatment in these patients did not reveal significant improvement. It is the easiest thing in this world to criticise a colleague or a colleagues work, but there were certain aspects of this trial which might explain the poor response to treatment and these points are engrossed in an enclosed note (3) where I have tried to argue these issues, and encourage investigation of this whole question of the diagnosis of hypothyroidism.

In our town centre, we conducted a temporal analysis of the results of treatment in patients who were diagnosed largely with depression or chronic fatigue like syndromes and who had normal thyroid chemistry, but clinical features of hypothyroidism and it did seem, that these patients improved significantly (2). This was not a placebo controlled trial, but the importance of the two studies rests in the original observation and selection of patients where it did seem that there were patients who had clinical features of hypothyroidism with normal thyroid chemistry and certainly, in one of these studies, there was improvement in the clinical status of most of the patients following thyroid replacement. It is crucial to institute formal clinical trial, but to date; we have been unable to obtain funding for this purpose.

The only other evidence (which one hesitate to include in these strange times) is clinical observation over many years, and in my own practice, I have seen many patients in this situation who returned to optimal health following thyroid replacement. While appreciating that statements of this nature will not only be discounted by (particular) younger colleagues and considered to be yet another example of the kind of thing that colleagues who do not understand evidence based medicine are inclined to say I feel I am a (relatively) sane citizen (and indeed lectured in statistics in the University of Birmingham in an earlier life) and am not embarrassed to make such a statement and request that it be entered into the portfolio of information on this matter.

I earnestly urge that this document makes an unequivocal statement that there is no evidence to suggest that normal thyroid chemistry excludes a diagnosis of hypothyroidism; this simple statement written in bold (I trust) may save literally thousands of patients during the next two decades from the unqualified misery of untreated hypothyroidism.
II. Thyroid Hormone LevelsReliance on thyroid chemistry is a backward, rather than a forward step and I have previously presented a number of arguments in support of this view (1,2,3 and 4). Two additional general points may be germane.

Critically, the tests measure the presence of thyroid hormones by immunological methods and it is well recognised that antigenicity and indeed, immunogenicity will survive deactivation for example, formalin or phenol treated vaccines and the immunological epitope can, and often does survive, in a chemical moiety, but there is no hormonal or enzymatic activity left in the molecule; this is well recognised in cellular biology. There is indeed, clinical evidence of this, in that I have come across a few patients whereby mischance, they had staggeringly high levels of thyroid hormones for example FT4 reading above 100.0 yet the patient seemed not in the slightest thyrotoxic and indeed, one of the patients was still clearly, hypothyroid; it is also true that many patients feel best when their FT4 readings are over 30.0 and have no clinical evidence of thyrotoxicity and until there are measures of the biological activity of these hormones, it is surely errant to equate biological activity with immunological presence; a graveyard has a high density of people with little activity.

Reference intervals which depend on the size and nature of the population selection often misleads. The distributions are skewed and a 95% reference interval indicates the 5% of the global population lie outwit this range which is cheerily ignored when a patient has their level of medication slashed, if their FT4 (for example) is a decimal point above the upper limit of a 95% reference interval; moreover, if a patient is within a 95#% reference interval, they are deemed, for some obscure reason to be in good health, thyroid wise. But if as obtains within 5% of the globe some 500,000,000 people are just above the upper limit of the reference interval, few practitioners would seek to proclaim that they are hyperthyroid! It should be emphasised that the statistical concept of a reference interval is a different issue from a health cut-off point, or some kind of regulatory meter in a machine where there is a safety zone and cut-off zone, and where to stray out of the zone is dangerous or instantly indicative of good or bad health. I hope you will not feel I am over labouring this point, but there is little doubt that this mode of thinking is operative for many practitioners when assessing the diagnosis of hypothyroidism and the notion that the patients personal computer which is their brain can incorporate, integrate, and distil a multitude of information is lost ion a legally driven misinterpretation of statistical scatter.
III. Miscellaneous comments on text3.1.1 Para.1. Patients who have no symptoms are surely not suffering hypothyroidism; I wonder if this would not be defined as subclinical hypothyroidism if there were coincident abnormal thyroid chemistry.

Para. 2. The first sentence is self-obvious, as everyone will agree that, for example, fatigue has a large number of diagnostic aetiologies. I really do not agree with the second sentence; I think that most colleagues would agree that Goitre with an enlarged tongue would point in the direction of hypothyroidism and over the years, I have found that patients with side vision hallucinations, or hallucination of objects on the floor relating to mucupolysaccharide opacities in the eyes tend to be associated with hypothyroidism. Most patients can be diagnosed by clinical features and this was once the only system of diagnosing hypothyroidism; I am unaware that results were worse prior to institution of thyroid chemistry, but I have no evidence that this is the case. The last sentence of para. 2 again, suffer from the assumption of reciprocal; are you really contending that a patient with a TSH of 9.9 should be considered to not have hypothyroidism? I think an unequivocal statement in this matter would be important.

Para.3. Is there a mix-up between sub-clinical, which means no symptoms and mild hypothyroidism, which would mean symptoms of hypothyroidism in small measure? I have seen many patients who have normal FT readings and are in fact very ill and I do think that this statement will confuse colleagues for years to come.

Para. 4. I do strongly disagree with this paragraph, in that it is at odds with clinical experience of many practitioners over many years. The first two bullet points I think are not true, and the second bullet point again suffers from the danger of assumption of the truth of the reciprocal which would leave many patients untreated.

3.1.2. I feel I am being tedious, but titrating dosage by laboratory tests may have become the mainstay with certain practitioners, but this should not be construed an optimal approach. It was shown, for example, some decades ago, that smaller doses of thyroid replacement would reduce TSH level, but many patients do not feel well until the TSH approaches zero. You are surely not advancing that a TSH level just below the upper limit of the reference interval indicates satisfactory replacement as in quoted references no. 18 and No, 19; The average for health patients lies around No. 1, a TSH of 4 times the average would be (usually) within a 95% reference interval, and surely not the objective of treatment.

I do earnestly urge that this concept is removed from the Guidelines and the mainstay of treatment should be when the patient has returned to feeling well with no residual hypothyroid features this principle will ensure that the present catastrophic situation where patients continue to be unwell, on account of TSH level, will not continue for future decades.

Para. 2. (Page 27) I did wonder if this was unnecessarily complicated, in that preventing over-replacement is an axiomatic schedule. However, if patients are replaced in small increments then this will not occur, and if clinical features of over treatment develop, then the dose can simply be reduced again. It would simplify matters if all patients short of hypothyroid emergencies, are started at 25 mcgs thyroxine for 1 week and then proceeding in 25 mcgs integers at sensible intervals. Cardiac complications have been seriously over emphasised and I think it would be useful, in the Guidelines, to mention that the main threat to cardiac status is continuing hypothyroidism with low physical activity, hypercholesterolaemia and deposition of atheroma; the latter has been significantly under noted in recent years, but featured highly in the earlier literature on the subject.

Para.3. Again, the assumed reciprocal; one asked the Development Group how secure they feel is the information that patients do not feel better if the TSH is below 2.0. In my own experience, and indeed in our published work, we found a rather poor relationship between TSH levels and clinical well-being.

Para.5. The most crucial aspect is how the patient feels, and not levels of these hormones. I would seriously contend that there are thousands of patients who are maintained in a state of sub health, because it is deemed that either TSH or FT4 are at satisfactory level, and indeed in some measure, the next paragraph (Para. 6.) does address the issue of the perfidy of using these levels as exclusive criteria.

Para. 6. I cannot agree with bullet points 1 and 2, particularly 2; surely a primary target of replacement is to restore clinical well-being.

I agree with the FT4 reading in patients taking triiodothyronine. I have come across a few patients who were taking T3 only and had a FT4 of zero, which rather confused certain laboratories.

Again, we are back to the reciprocal point, and to my knowledge, there is no evidence advocating that thyroxine alone is preferable to the combined therapy and, dare I say it, I have often noted patients to be considerably better using the combined therapy, but it is possible that the patient is merely having a higher level of replacement. On balance, I think that certain patients do benefit from combined therapy.

Again, I do not agree with the objective of therapy which should be return of well being and it happens in many patients who are still unwell and in fact, do not become well until the TSH is well below the lower end of the reference interval.

3.1.5. I do have some reservations about the excellent automated format which may be logistically efficient as a call-up system, but I have encountered, in a number of patients who are significantly disenchanted, in that they go for a blood test, and this is it, and nobody speaks to them or, in essence, attempts to discover how they do feel.
Summary Points on GuidelinesThe following are major points with which I am in disagreement vis-a-vis the Guidelines. I will preface these points by indicating that I appreciate, only too well, how much hard work and consultation has gone into the preparation of these Guidelines, although I do wonder if, perhaps, rather more consultation with patients or even thyroid self-help groups who might have perhaps, influenced major conclusions. I do formally thank Dr. Beastall and his colleagues for carrying out what is often a somewhat thankless task; it is only too easy these days, to put ones head below, rather than above the parapet.
Summary CommentsThe predication that criteria for diagnosis and dose level of thyroid replacement should be based on thyroid chemistry is doomed to failure; I have observed this over many years of practice.

Thyroid hormone levels, in particular thyroid and thyroid stimulating hormone, within 95% reference interval, does not equate with health or euthyroidism; there is no evidence to support this contention but a measure of evidence from 2 studies (1,2) and from clinical experience over many years, that this is not the case. I believe that this must be clearly stated in the Guidelines to avoid condemnation of many patients to continuing hypothyroidism based on this misassumption.

Laboratory tests for thyroid hormone levels do not measure biological activity and the adoption of reference ranges as action parameters is a significant problem in the diagnosis and treatment of hypothyroidism. This results in a serious shortfall in care with inadequate replacement based on the notion that TSHG levels should be returned to somewhere within the reference interval. TSH values have a left-sided skewed distribution and a value of, say, 2.5 is well within the average TSH level, which runs around 1.0 in most laboratories; thus, the contention that a patient is satisfactorily treated if they have a TSH which has declined to a level of (approximately twice the healthy average) is clearly in error. This mischief is compounded by anxiety over suppressed TSH. I believe that any perceived long-term detriment from suppressed TSH levels in a healthy patient is infinitesimal compared to the unequivocal detriment of inadequate replacement and continuing ill health.

Advise on FT4 higher levels seem overly cautious. Whilst some patients are returned to optimal health, with an FT4 reading toward the upper end of the 95% reference interval; I would have thought that a number of Endocrinologists would agree that in a patient with no clinical evidence of thyrotoxicity, there is little to be feared from a patient with FT4 readings, even approaching 35.0; It is difficult to believe that clinical euthyroidism is accompanied by unsuspected detriment from raised FT4 reading. Account must be taken of previous caveats concerning thyroid hormone estimation and pharmacological considerations where intracellular uptake rate or deactivation or neutralisation of thyroid hormones highlight the ill advisability of equating thyrotoxicity with a high level of a hormone which may not be de-iodinated effectively, or maybe inactivated, or may not be uptake by the cells in vivo; it has always been a mystery to me that my colleagues purport thyrotoxicity solely based on a hormone level in patients who are manifestly not thyrotoxic.

In summary, the major point of disagreement with these Guidelines rests on my earnest belief that exclusion of hypothyroidism through the criterion of normal thyroid chemistry will frequently miss the diagnosis and titration of dose levels through thyroid chemistry, will result in patients being chronically under treated with serious health risk. There is an overwhelming need for a properly controlled clinical trial to assess the results of thyroid replacement in patients who are clinically hypothyroid with normal thyroid chemistry and a prospective or even retrospective investigation of any detriment to health, in a patient who is clinically euthyroid but whose thyroid chemistry falls outwit 95% reference intervals. Both of these studies are ethical and should be undertaken with expedition.

Yours sincerely,

Gordon R.B.Skinner MD.DSc. FRCPath, FRCOG


Thyroxione treatment in Patients with Symptoms of Hypothyroidism but Thyroid Function Tests within the reference range: Randomised Placebo Controlled Crossover Trials: Pollack MA, Sturrock A, Marshall K, Davidson K M, Kelly C.J.G, McMahon A D, McLaren E H, BMJ 2001 323; 891-895 (20th October) Clinical Response Thyroxine Sodium in Clinically Hypothyroid but Biochemically Euthyroid Patients: GRB Skinner MD(hons) DSc, FRCPath, FRCOG. D Holmes, A. Ahmed PHD. GA Davies, BSc. Benitez MSc. Journal of Nutritional and Environmental Medicine (2000) 10, 115- 124 Letter to Sir Patrick McCormack FSA; MP. 02.12.2005 Diagnosis and Management of Hypothyroidism. GRB Skinner. Louise Lorne Publications. Birmingham UK 2003


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