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Scientific Highlights: Diabetes and thyroid diseases: clinical features and management

PART OF Manage Hypertension Online, Manage Diabetes Online, Manage Thyroid Online FEATURES
Scientific Highlights: Diabetes and thyroid diseases: clinical features and management
  • Cardiometabolic
    Endocrinology and metabolism
  • Diabetes
    Hypertension
    Thyroid disorder

Resource type

Publication

Usage

Practical

There is a large-scale effort to address the global burden of diabetes and thyroid disease. The obesity epidemic affects the developed and developing world, and has caused an inevitable upsurge in the incidence of prediabetes, type 2 diabetes and related multifactorial disorders such as the metabolic syndrome. The latest EXCEMED event to look at these conditions focused on research achievements and improvements in clinical practice that could have immediate impact on improving health.


Contents

 
Undiagnosed diabetes: an emergency waiting to happen

Delaying or preventing type 2 diabetes from developing is achievable and cost effective –  and may help to reduce the incidence of diabetes-related conditions. Professor John Kennedy Cruickshank emphasized that modest, sustained, lifestyle interventions are the most effective weapons in the global fight against obesity. And by reducing obesity, the risk of developing type 2 diabetes and its comorbidities also decreases.

Initiatives that start with weight loss and increased physical activity, then become lifelong behaviour changes, should be the first steps in attacking the global obesity and type 2 diabetes epidemics. Where required, metformin and statin therapy can be added to the lifestyle improvements in people with impaired glucose tolerance (prediabetes). In Table 1 the results of the most important prevention trials are summarized.

Redefining type 2 diabetes?

Professor Cruickshank advocated changing the definition of type 2 diabetes, as well as changing the focus of its management: both changes move away from the ‘glucocentric’ view of this condition. He said there are no benefits from over-focusing on glycaemia, therefore type 2 diabetes should not be defined solely by this parameter.

A growing body of metabolomics research indicates that multiple defects in metabolites and pathways of lipid regulation are observed in people with ‘prediabetes’, before hyperglycaemia occurs. Defects in adipocyte function (resulting from excess energy storage as relatively hypoxic visceral and hepatic fat, and impaired mitochondrial fatty acid oxidation) may initiate alterations in lipid metabolism. Together with evidence from the failure of glucose-directed treatments to improve cardiovascular outcomes (see Cardiovascular disease and diabetes: cause or consequence), these data suggest that the definition of type-2 diabetes should incorporate disturbed lipid metabolism and cardiovascular dysfunction prior to hyperglycaemia development.

The apparent disappearance of ‘irreversible’ type 2 diabetes following bariatric surgery provides further indication of the complex patterns of local and systemic cellular and cardiovascular disruption with this disease.

Anderson SG, et al. PLoS One. 2014 Sep 3;9(9). e103217.

Table 1: Summary of the risk reductions reported in trials of lifestyle and pharmacologic interventions for people with impaired glucose tolerance (IGT), a precursor of diabetes

Cardiac benefits of thyroid hormone therapy

Experimental and proof-of-concept study findings suggest that thyroid hormone therapy may help to alleviate some cardiac conditions, including ischaemic heart disease, explained Dr Salman Razvi (UK).

Early data suggest that treating subclinical hypothyroidism leads to modest but significant health improvements, including a reduction in atherogenic lipid profiles. Treatment may be particularly beneficial for younger people with subclinical hypothyroidism.

The cardiovascular system is very sensitive to changes in circulating thyroid hormone levels. Subclinical hypothyroidism is observed in up to 15% of the adult population, globally; it has long been associated with adverse outcomes, particularly in relation to cardiovascular disease.

Fluctuating thyroid hormone levels are observed in people with cardiac disease, and low thyroid hormone levels are associated with worse outcomes. Whether such changes are adaptive (to conserve metabolism) or maladaptive is unclear. However, observational studies and small-scale trials suggest that a low T3 state may be maladaptive, and that corrective thyroid hormone treatment may be beneficial. Dr Razvi added that favourable survival rates were observed when L-thyroxine was given to relatively young people with ischaemic heart disease (Figure 1).

Using thyroid hormone therapy in small-scale cardiac studies of acute myocardial infarction, heart failure or coronary artery bypass led to marginal improvements in surrogate markers. However, results from high quality safety and efficacy studies are required before thyroid hormone therapy is routinely incorporated into clinical practice.

Figure 1: L-thyroxine treatment and ischaemic heart disease events in people aged 40-70 years, with subclinical hypothyroidism; HR=0.56 (0.39 – 0.81); p=0.002 (Razvi S et al, Arch Intern Med 2012)

 

Subclinical hypothyroidism: myths, presumptions and facts

Clinical recommendations to treat, or not to treat, subclinical hypothyroidism remain controversial. Professor Peter Andreas Kopp (USA) said that it remains unclear whether subclinical hypothyroidism is a minor biochemical abnormality or has a hidden impact on health-related quality of life and survival.

Subclinical hypothyroidism may warrant treatment if TSH levels are >10 mIU/l, or the patient is at heightened risk of overt hypothyroidism (Table 2). However, robust evidence is needed before definitive conclusions can be drawn: current advice is largely based on epidemiological associations and expert opinion.

A diagnosis of subclinical hypothyroidism does not always justify treatment, added Professor Kopp. Treatment is not widely recommended for moderately elevated TSH levels (4.5–10 mIU/l) in the absence of other conditions such as antibody positivity; in such patients, TSH levels should be monitored every 6–12 months. Treatment is unnecessary if elevations are transient (i.e. persist for < 3-6 months) or if the patient is at low risk of overt hypothyroidism.

However, pathophysiological alterations in association with subclinical hypothyroidism have been widely reported. In addition, many studies report an increased risk of progression to overt hypothyroidism in patients with elevated TSH and antithyroid antibodies. Moreover, prospective data show an increased risk of coronary heart disease events, heart failure, and cardiovascular mortality in people with subclinical hypothyroidism.

Conversely, there is no proven association between subclinical hypothyroidism and cognitive impairment, depression or fracture risk. Likewise, some – but not all – studies indicate that subclinical hypothyroidism negatively affects pregnancy outcomes and fecundity. In addition, recent research concluded that treating women in whom subclinical hypothyroidism or hypothyroxinaemia was identified during the first half of pregnancy does not result in improved cognitive outcomes in offspring through 5 years of age.

Clinical condition

Strength of association

Benefits of treatment

TSH 4.5-9.9 mU/l

TSH ≥10 mU/l

Progression to overt hypothyroidism

Good

Stronger

Insufficient

Elevation in cholesterol and LDL-C

Fair

Stronger

Insufficient

Risk of coronary heart disease

Insufficient

Stronger

No evidence

Risk of congestive heart failure

Insufficient

Stronger

No evidence

Systemic symptoms of clinical hypothyroidism

Insufficient

Insufficient

Insufficient

Neuropsychiatric dysfunction: depression, cognitive dysfunction

Insufficient

Insufficient

Insufficient

Muscle strength

Insufficient

Insufficient

Insufficient

Fatigue

Insufficient

Insufficient

Insufficient

 

 

 

 

Risks of treatment

Development of subclinical hyperthyroidism

 

 

14–21%

Table 2. Levels of evidence on possible associations and benefits of treatment for subclinical hypothyroidism

Managing diabetes during Ramadan

During the holy month of Ramadan, when Muslims practice dawn-to-dusk fasting, the interval between meals can be a major challenge, especially for people with type 1 diabetes, said Dr Nader Lessan (UAE). People with diet-controlled type 2 diabetes do not face serious health risks if they fast, provided they have good diabetic management, he added. However, those on insulin or sulphonylureas should consult their doctor/diabetes educator before Ramadan begins, so that changes in the treatment regimen are made in preparation for fasting.

Dr Lessan led an interactive workshop that featured common scenarios facing patients with diabetes who wish to fast. The workshop helped delegates to make informed treatment decisions, thereby facilitating safer Ramadan fasting for different patient groups.

Physiologically, the Ramadan fast is characterized by gradual glycogen depletion and a shift to gluconeogenesis: body fat stores become the main fuel. Glycogen stores are replenished soon after the fast is broken (iftar time). Hypoglycaemia during the fasting period, hyperglycaemia at iftar time, diabetic ketoacidosis, dehydration and thrombosis are the key risks facing fasting people with diabetes.

Ramadan-related guidelines from the American Diabetes Association (www.diabetes.org) and the DAR (Diabetes and Ramadan group; www.daralliance.org) provide helpful tips on different risk categories and treatment decisions.

Although illness is a legitimate exemption from fasting during Ramadan, many people with health issues (including diabetes) choose to fast, for social, cultural and personal reasons. It is therefore important that clinicians are aware of the risks and challenges that these people face, to ensure that they fast during Ramadan in the safest possible way.

The fasting in Ramadan involves full abstinence from eating and drinking between dawn and dusk. Length of the fasting period varies each year, and also depends on latitude.

Algorithms for personalized therapies in diabetes

Ernesto Maddaloni (Italy) led a workshop that discussed patient-centred and guideline-based algorithms proposed for personalized therapy in type 2 diabetes mellitus.

Type 2 diabetes is a complex condition that affects each patient differently in terms of pathophysiology and organ involvement. Consequently, the development of unequivocal guidelines for this multifaceted disease is a difficult task: one that is further complicated when the 10 pharmacological classes of oral or injectable agent, and the many molecular combinations of agents, are added to the mix.

Therapeutic decisions should take into account the patient’s age, phenotype, disease duration, presence/severity of diabetes complications, frailty, personal preferences and costs. Given the complexities, the value of algorithms for facilitating therapeutic decisions is likely to increase.

Thyroid cancer: pre- and postoperative management according to the new guidelines

Peter Andreas Kopp (USA) presented interactive clinical case studies, applying diagnostic and management recommendations as reported in the 2015 American Thyroid Association Guidelines for the Management of Thyroid nodules and Thyroid Cancer. These guidelines emphasize the following:

  • Fine-needle aspiration is recommended, based on ultrasound risk stratification models
  • Cytological results should be reported according to the Bethesda cytology system

                         -Molecular markers are beginning to complement cytology in the diagnosis of indeterminate results

  • Low-volume lymph nodal metastases are considered low risk
  • Radioiodine remnant ablation and therapy should follow a risk-based indication

                         -Low risk patients do not benefit from radioiodine therapy (Table 3)

  • Systemic therapies for advanced thyroid cancer (e.g. tyrosine-kinase inhibitors) have increased the progression-free survival time, although impact on long-term survival remains unclear
  • Emerging redifferentiation therapies may reinduce radioiodine uptake in selected patients

The new ATA risk stratification (Table 4) builds on the 2009 guidelines (primary tumour size, resection margin, lymph node involvement, distant metastasis), adding histologic variants, vascular invasion/number of invaded vessels, multifocality, number of lymph nodes examined/involved, site of the largest metastatic lymph node focus, and extranodal extensions.

ATA low risk

ATA intermediate risk

ATA high risk

RAI not typically recommended (if all are present)

RAI selectively recommended

RAI recommended

●Classic papillary thyroid carcinoma

●Intrathyroidal lesion

●Unifocal/multifocal

●Postoperative Tg<1 ng/ml

●No Tg-antibodies

●Primary tumour 1 –4 cm

●High risk histology

●Lymphovascular invasion

●Cervical lymph node metastases

●Macroscopic multifocality (one focus > 1 cm)

●Postoperative Tg<5-10 ng/ml

●Presence of Tg-Abs

●Gross extrathyroidal extension

●Primary tumour > 4 cm

●Postoperative Tg>5-10 ng/ml

●Known or suspected distant metastases

Table 3. Differentiated use of radioactive iodine

ATA low risk

ATA intermediate risk

ATA high risk

●Papillary Thyroid Cancer (with all of the following in italics):

No local or distant metastases • all macroscopic tumour resected • no tumour invasion of loco-regional tissues/structures • tumour has no aggressive histology • if 131I is given, no RAI avid metastatic foci outside thyroid bed on first post-treatment whole-body RAI scan

 

●No vascular invasion

Clinical N0 or ≤ 5 pathologic N1 micrometastases (<0.2 cm in largest dimension)

●Intrathyroidal, encapsulated follicular variant of papillary thyroid cancer

●Intrathyroidal, well differentiated follicular thyroid cancer with capsular invasion and no or minimal (<4 foci) vascular invasion

Intrathyroidal, papillary microcarcinoma, unifocalor multifocal, including BRAF V600E mutated (if known)

●Microscopic invasion of tumour into the perithyroidal soft tissues

●RAI avid metastatic foci in the neck on the first post-treatment whole-body RAI scan ●Aggressive histology

●Papillary thyroid cancer with vascular invasion

●Clinical N1 or >5 pathologic N1 with all involved lymph nodes < 3 cm in largest dimension

●Multifocal papillary microcarcinomawith extrathyroidal extension and V600E BRAF mutated (if known)

●Macroscopic invasion of tumour into perithyroidal soft tissues (gross extrathyroidal extension)

●Incomplete tumour resection

●Distant metastases

●Postoperative serum thyroglobulin suggestive of distant metastases

 

Table 4. 2015 ATA initial risk stratification

Diabetes in pregnancy

Leilo Morviducci (Italy) said that adopting the International Association of Diabetes and Pregnancy Study Group (IADPSG) recommendations for diagnosing GDM remains a controversial approach: one that will substantially increase (possibly double) of the incidence of the condition. The decision to adopt the IADPSG recommendations should take into consideration costs and the local infrastructure, given that the benefits for perinatal outcome for this approach remain unclear.

The IADPSG advocates a one-step strategy for GDM diagnosis (based on a 75g oral glucose tolerance test); Carpenter and Coustain advocate a two-step approach (50 g glucose challenge test followed by 75 g OGTT in women who test positive to the challenge).

Although the IADPSG approach is justified on clinical evidence from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, the additional women identified by the new criteria could be at lower risk of perinatal complications than women identified using the traditional guidance.

There is consensus that overt diabetes during pregnancy, whether symptomatic or not, is associated with significant risk of adverse perinatal outcomes. However, the risk of adverse perinatal outcome associated with degrees of hyperglycemia less severe than overt diabetes is controversial. Therefore, globally agreed diagnostic criteria for GDM remain elusive.

HAPO aimed to clarify risks of adverse outcome associated with degrees of maternal glucose intolerance less severe than those with overt diabetes during pregnancy. Questions have been raised regarding cost-effectiveness and benefit of detecting and treating GDM based on lower glucose levels alone.

Subclinical hypo- and hyperthyroidism in pregnancy

Bernadette Biondi (Italy) said that the goal of L-thyroxine treatment for subclinical hypothyroidism is to normalise serum thyroid stimulating hormone within the trimester-specific range. Guidelines suggest reference ranges for serum thyroid stimulating hormone such as 0.1 to 2.5 mU/l in the first trimester, 0.2 to 3.0 mU/l in the second trimester, and 0.3 to 3.0mU/l in the third trimester.

Subclinical Hypothyroidism in pregnancy is defined as a serum thyroid stimulating hormone level of 2.5 to 10 mU/l with normal free thyroxine. Risk of progression to hypothyroidism is increased in pregnant women with positive thyroid autoantibodies during the first trimester.

Higher rates of obstetric complications (e.g. miscarriage, gestational hypertension or diabetes, and pre-eclampsia) are observed in women with untreated subclinical hypopthyroidism. However, conflicting data are reported for any association between subclinical hypothyroidism in pregnancy and impaired neuropsychological development of the offspring.

The 2011 American Association of Clinical Endocrinologists- American Thyroid Association guidelines recommended subclinical hypothyroidism treatment for all women positive for TPOAb; the 2012 Endocrine Society recommends L-thyroxine in women with subclinical hypothyroidism who are TPOAb+ or TPOAb-. These guidelines do not advocate L-thyroxine for euthyroid women with positive thyroid antibodies because of lack of robust evidence for any benefit.

Cardiovascular disease and diabetes: cause or consequence?

John Kennedy Cruickshank (UK) called for type 2 diabetes to be redefined as a cardiovascular, not a glucocentric, disease. People with diabetes are twice as likely as people without diabetes to have a heart attack, stroke or heart failure.

He argued for the redefinition because arterial dysfunction is detectable during the pre-diabetes or very early diabetes phases, before classic identifiers (such as hyperglycaemia) emerge.

As type 2 diabetes is associated with both generalized and perivascular fat deposits, Professor Cruickshank called for high-quality research to clarify the inflammatory processes involving fat deposition and blood vessel pathophysiology, and identify potential treatment mechanisms.

He outlined the metabolic changes observed during the progression from pre-diabetes to type 2 diabetes. Following oxidative stress or membrane damage in lipoproteins, alterations in lysophosphocholines result in fatty acid oxidation in mitochondria, then proinflammatory stress. Such changes result in tissue damage.

With the exception of metformin, randomized controlled trials of treatments that focus on glycaemic correction fail to reduce the rate of cardiovascular events, and often lead to weight gain. Hypoglycaemic treatments show no benefits for macrovascular endpoints and any impact on microvascular events is slow and contentious (UKPDS, no impact at 10 years, other than for retinopathy; Accord and VA trials, excess mortality; ADVANCE, renal changes only; Gliptin trials, no impact on vascular parameters).

Insulin resistance almost certainly does not cause vascular disease, he added. Instead, it is a consequence of bad fat (i.e. visceral fat, or ‘prehepatic fat’ that is secondary to liver triglyceride build up).

Professor Cruickshank said that 21st Century therapeutic targets should focus on fat and blood-vessel involvement in cardiovascular disease pathogenesis, and emphasize healthy lifestyles, involving appropriate diet and physical activity.

Terms of use

This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.

Regional conference
Lisbon, Portugal
May 14, 2016
Target audience
Endocrinologists and specialists involved in the diagnosis and management of patients with diabetes and thyroid disorders.
EACCME®
by Excemed
Cardiometabolic, Endocrinology and metabolism

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