Endocrine PBL PDF - Wayne State University School of Medicine

# WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE __Problem-Based Learning__ __M1 Fundamentals of a Healthy Patient: Human Body Foundations III Course__ __Case: Mrs. Potter's Fatigue__ __Authors: Rod D. Braun, Ph.D., Robert Lasley, Ph.D., and Mary Meinke, M.D.__ ## RESOLUTION AND REVIEW ### GOAL To use...

# WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE __Problem-Based Learning__ __M1 Fundamentals of a Healthy Patient: Human Body Foundations III Course__ __Case: Mrs. Potter's Fatigue__ __Authors: Rod D. Braun, Ph.D., Robert Lasley, Ph.D., and Mary Meinke, M.D.__ ## RESOLUTION AND REVIEW ### GOAL To use your knowledge and understanding of normal body structure and function to investigate a case of a middle-aged woman presenting with fatigue and general weakness. ### CASE RESOLUTION AND REVIEW The diagnosis for this patient is Hashimoto's thyroiditis, a chronic autoimmune disease in which the induced thyroid autoimmunity results in a progressive destruction of thyroid epithelial cells (follicular cells) by apoptosis. Destruction of the follicular cells results in decreased production of the thyroid hormones triiodothyronine (T3) and thyroxine (T4), and patients present with the symptoms of hypothyroidism. #### Case On her initial visit, Mrs. Potter reports that she has experienced fatigue, general weakness, and frequent muscle cramping over the past several months. She also reports frequent constipation, weight gain, and a perception of feeling cold. These symptoms are all consistent with hypothyroidism. Thyroid hormone (TH) enhances muscle contractility, muscle regeneration, and muscle metabolism. In patients with hypothyroidism, muscle contraction and relaxation times are delayed, which can be a source of pain and cramps. Constipation is one of the most common symptoms associated with hypothyroidism, since TH plays a role in increasing peristalsis in the Gl tract. In addition, TH enhances the secretion of digestive enzymes. Hypothyroidism can also lead to chronic fatigue and weight gain, since low levels of thyroid hormone slow the body's metabolism and lower the basal metabolic rate (BMR). The decreased thermogenesis associated with low BMR can lead to a feeling of being cold. Although the patient's medical history is minimal, it is revealed that she has a history of rheumatoid arthritis, and her husband discloses that she is recently more forgetful and seems depressed. The presence of rheumatoid arthritis highly suggests that the hypothyroidism is due to Hashimoto's thyroiditis. Rheumatoid arthritis is an autoimmune disease, a condition in which an individual develops antibodies against their own cells, tissues, and/or organ systems. Rheumatoid arthritis, which attacks the joints of the body, and other autoimmune diseases are risk factors for Hashimoto's thyroiditis, an autoimmune disease that attacks the thyroid gland. Although iodine deficiency can also lead to hypothyroidism, the fact that she "eats a well-balanced diet" means that diet is most likely not a factor in this patient's condition. Inability to concentrate, memory loss, and depression are reported frequently (> 25% of cases) in Hashimoto's thyroiditis. There is evidence that deficiency of TH reduces synaptic transmission and plasticity in the CA1 region of the hippocampus, which may lead to memory impairment. The physical examination reveals that she has areas of dry, coarse skin on her arms, a significant bald spot, thinning of her eyebrows, and a delayed deep tendon reflex. The skin of hypothyroid patients is typically dry, cold, yellowish, and thickened. These changes are sustained by dermal accumulation of hydrophilic mucoproteins (such as hyaluronic acid), which bind water. This accumulation of mucoproteins results in a condition referred to as myxedema. It is not clear whether these effects are due to direct effects of TH or the autoimmune response. Human hair follicles are direct targets of TH, which induces epithelial cell proliferation and keratin expression. Therefore, hypothyroidism can result in hair loss and hair thinning. The delayed deep tendon reflex is related to the effects of thyroid hormone on muscle function. Examination of her neck reveals fullness, and palpation of the thyroid gland indicates the presence of a nodule. Although over 90% of thyroid nodules are benign (non-cancerous), it is recommended that thyroid nodules be evaluated to rule out cancer. A malignant (cancerous) nodule is usually indicative of papillary thyroid carcinoma, the most common type of thyroid cancer. The cause of most benign nodule formation in the thyroid is unknown. However, Hashimoto's thyroiditis, the most common cause of hypothyroidism, is associated with an increased risk of developing thyroid nodules. Mrs. Potter's vital signs reveal low heart rate (bradycardia) and high diastolic blood pressure. The expression of the slow inward $Na^+$ channel in sinoatrial (SA) nodal cells, the site of the heart's primary pacemaker, is dependent on TH. The expression of $ẞ1$ adrenergic receptors, the receptors initiating sympathetic nervous system signaling in the heart, is also upregulated by TH. Both of these contribute to decreased heart rate in hypothyroidism. In hypothyroidism, it is thought that endothelial dysfunction and impaired vascular smooth muscle relaxation lead to increased systemic vascular resistance; these effects lead to diastolic hypertension in~25% of patients. Blood tests reveal low erythrocyte count, high total cholesterol level, high triglyceride level, and high LDL cholesterol level. Since TH enhances erythropoiesis, hypothyroidism can result in decreased RBC count, erythrocyte size (MCV), and hemoglobin concentration. Large decreases in these could result in anemia and, if present, could have explained the patient's weakness and tiredness. There are multiple effects of TH on lipid metabolism, but the primary effect of TH is the stimulation of transcription of the LDL receptor (LDL-R) to increase uptake of cholesterol. So, hypothyroidism can result in high total cholesterol and high LDL cholesterol levels. TH also increases lipoprotein lipase activity; elevated triglycerides in hypothyroidism are due to reduced lipoprotein lipase activity. The thyroid panel shows abnormally low levels of TH, i.e., thyroxine (T4) and triiodothyronine (T3), which is consistent with hypothyroidism. In an effort to increase the low T3 and T4 levels, the hypothalamus releases thyroid releasing hormone (TRH). TRH acts on the anterior pituitary gland to release thyroid stimulating hormone (TSH) (Figure A). Thus, the patient's serum TSH/thyrotropin level is greatly elevated. TSH acts on the thyroid gland to produce T3 and T4. The elevated level of anti-thyroperoxidase (TPO) antibody confirms that the patient's hypothyroidism is due to Hashimoto's thyroiditis, a chronic autoimmune inflammation of the thyroid gland. TPO catalyzes the iodination of tyrosine residues and the oxidative coupling of two iodotyrosine residues on the thyroglobulin (TG) molecule (Figure B). While antibodies against other molecular targets are possible in Hashimoto's thyroiditis, anti-TPO antibody is reported in over 90% of patients. Antibodies against TPO target the follicular cells of the thyroid for destruction. Large numbers of white blood cells, including B lymphocytes, accumulate in the thyroid, and their progeny, plasma cells, make the antibodies that start the autoimmune process. The core biopsy of Mrs. Potter's thyroid reveals that the nodule is clearly benign, but it also shows that the thyroid is abnormal. In all three panels of Figure 3 in the case, it is obvious that there is a loss of thyroid follicles, a large amount of lymphocytic infiltration, and the presence of secondary lymphatic nodules. All of these components are typical of Hashimoto's thyroiditis, in which there is extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and secondary lymphatic nodules with well-developed germinal centers. Mrs. Potter is treated with levothyroxine, a synthetic form of thyroxine (T4) that exerts the same effects as naturally produced T4. A repeat of the thyroid blood test after 8 weeks shows that all values have moved closer to the normal ranges, but that T3 and T4 levels are still slightly lower than normal. Titration of the levothyroxine dose brings her values within the normal range on a subsequent visit. Mrs. Potter's hypothyroidism is under control, and she feels like her old self again. Levels should then be monitored annually. ### Figure Descriptions * **Figure A:** Diagram showing regulation of thyroid hormone production. T3: triiodothyronine, T4: thyroxine, TRH: thyroid regulating hormone, TSH: thyroid stimulating hormone. * **Figure B:** Diagram showing the steps in the synthesis of thyroid hormone, T3 and T4, by a follicular cell in the thyroid gland. T3: triiodothyronine or T3, T4: thyroxine or T4, MIT: monoiodotyrosine, DIT: diiodotyrosine, TYR: tyrosine, and TPO: thyroid peroxidase. The images are diagrams illustrating the regulation of thyroid hormone production and the steps in the synthesis of thyroid hormone by a follicular cell in the thyroid gland. They include labels and annotations to describe the different hormones, enzymes, and processes involved.