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A model of thyroid cancer initiation and growth in autoimmune thyroiditis Stephen J. Merrill Program in Computational Sciences Department of MSCS Marquette University Milwaukee, Wisconsin USA 12/9/2010 NAMIAM 2010 1 Thyroid Gland • One of the largest endocrine gland, controlling metabolism in the body • Also controls how the body should react to other hormones (such as products of the adrenal gland) • Produces two hormones, T3, which has 3 atoms of iodine and T4, which has 4. • T3 is the active form, produced from T4 by one of two deiodination enzymes. • Hypothyroidism (low T4) is most commonly caused by an autoimmune condition. Incidence is increasing world-wide • Hypothyroidism is usually treated by hormone replacement with synthetic T4, Levothyroxine. 12/9/2010 NAMIAM 2010 2 Basic Idea • Basic feedback control -- the HPT axis. • This control is disrupted in autoimmune (Hashimoto’s) thyroiditis • As the thyroid is slowly destroyed, the thyroid is unable to respond to the TSH signal • As T4 falls -- TSH increases. 12/9/2010 NAMIAM 2010 3 Consequences of increasing TSH • Areas of the thyroid are stimulated to grow, forming “nodules” of follicular cells (the T4producing cells). • The overall size of the thyroid can grow dramatically, forming a temporary thyroid goiter. • In the face of autoimmune thyroiditis, there is a large inflammatory response and sometimes a large short-term release of T4, Hashitoxicosis. • For any cancers that form in a nodule, TSH acts as a hormonal growth factor. 12/9/2010 NAMIAM 2010 4 Thyroid Nodules • Found in 20-70% of the population • About 5% (and to up to 15% in thyroiditis) are malignant • Main type of thyroid cancer is carcinoma, papillary (75%), follicular (10%), other types (15%). • Treatment options: thyroidectomy sometimes followed by radioactive iodine or TSH suppression by levothyroxin (T4) 12/9/2010 NAMIAM 2010 5 Outline of the model 1. Due to the nature of the process, a stochastic model (with a continuous input) is chosen. 2. In any Dt of time, a region in the thyroid may be stimulated to begin a nodule. This rate is determined by TSH. 3. Growth of an existing nodule is determined by TSH. 4. Cancer development rate is determined by the nodule growth rate. Once started, growth rate of cancer is higher than the growth rate of other nodules. 12/9/2010 NAMIAM 2010 6 How many areas get a nodule initiation signal? • Assuming N potential growth sites, consider the distribution of M TSH molecules distributed to the N sites (assuming a large signal would mean a nodule initiation). • Number of molecules per site follows a binomial distribution. Counting the number of sites that exceed a threshold given M molecules in this case can be 4 TSH approximated by K TSH 4 12/9/2010 NAMIAM 2010 7 Number of Nodules As TSH changes, the number of nodules increases (100 paths at each TSH level) 35 mean number of nodules 30 25 20 15 10 5 0 0 0.5 1 1.5 2 2.5 TSH 3 3.5 4 4.5 5 Over 30 years, effect of elevated TSH. 12/9/2010 NAMIAM 2010 8 Largest Nodule increases with TSH 100 simulations -- TSH=1 100 simulations -- TSH=5 100 60 90 50 80 40 60 frequency frequency 70 50 30 40 20 30 20 10 10 0 0 0.2 0.4 0.6 0.8 largest nodule size (in cm) 1 1.2 1.4 0 3.2 3.4 3.6 3.8 4 4.2 4.4 4.6 largest nodule size (in cm) 4.8 5 5.2 Frequency of large, 4 cm nodules increases if TSH increases. Half of these may be cancerous in autoimmune thyroiditis. 12/9/2010 NAMIAM 2010 9 The connection to autoimmune thyroiditis • There can be a long period of asymptomatic hypothyroidism (T4 normal or low, TSH increasing). • Treatment (with levothyroxin) is often started when TSH is beyond normal reference (4-5 mU/mL) . • This can result in a long (several year) period where TSH is high and nodule formation is encouraged. • In undiagnosed conditions, TSH can reach very high levels, raising the risk of cancer. 12/9/2010 NAMIAM 2010 10 Question of Interest • What is the cost (in terms of increased thyroid cancer) for late treatment of hypothyroidism? Approach is to compare the untreated and treated simulated populations and to compare cancer incidence. Need to find a way to mimic the natural changes in TSH in this disease. 12/9/2010 NAMIAM 2010 11 Model of Autoimmune Thyroiditis • The work of a doctoral student, Bala Pandiyan, along with Dr. Salvatore Benvenga, University of Messina in Sicily and an undergraduate McNair Fellow, Mike Castillo (Marian University) • Based on data from Benvenga’s clinic of hundreds of thyroiditis patients. • Describes the disruption of the feedback system as a result of the disease. • Takes the form of a nonlinear system of differential equations. 12/9/2010 NAMIAM 2010 12 Pandiyan’s Model • T is the functional (active) size of the thyroid • Ab is the level of antithyroid antibodies (TPOAb) and TgAb 12/9/2010 k1T 4 d (TSH ) k1 k2TSH dt ka T 4 d (T 4) k3T (TSH ) k4T 4 dt kd T TSH dT TSH k5 N k6 ( Ab)T dt T d ( Ab) k7 ( Ab)T k8 Ab dt NAMIAM 2010 13 Parameters Free T4 • Determined by the literature, data, and equilibrium arguments, and simulation. • For this talk, using a simplified model, 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 0 T 4(t ) 1.8e .12t 12/9/2010 NAMIAM 2010 5 10 15 time(years) 20 25 30 14 TSH increases over time 16 14 12 TSH 10 8 6 4 2 0 12/9/2010 0 5 10 15 time (years) NAMIAM 2010 20 25 30 15 Disease Progression 16 14 12 TSH 10 8 6 4 2 0 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 T4 12/9/2010 NAMIAM 2010 16 Untreated 40 35 30 frequency 25 20 15 10 5 0 12/9/2010 0 10 20 30 40 50 60 largest nodule size (cm) NAMIAM 2010 70 80 90 17 With Treatment TSH returns To normal levels Treatment beginning at t=15 4.5 4 TSH with treatment 3.5 3 2.5 2 1.5 1 0.5 0 12/9/2010 0 5 NAMIAM 2010 10 15 time (years) 20 25 30 18 Nodule sizes – with Treatment With Treatment 80 70 60 frequency 50 40 30 20 10 0 12/9/2010 0 0.1 0.2 0.3 0.4 0.5 0.6 largest nodule size (cm) NAMIAM 2010 0.7 0.8 0.9 19 Summary • A dynamic model of autoimmune thyroiditis enables one to study consequences of the disease, such as initiation and growth of thyroid cancer. • Similar studies could be done to study other treatment effects, such as side effects or even patient satisfaction. • Patient-specific parameters can be identified. 12/9/2010 NAMIAM 2010 20 Thank You! Much of this presented work was joint with Mike Castillo (no picture available) 12/9/2010 NAMIAM 2010 21