Hashimoto Thyroiditis

A 35-year-old woman presents with progressive fatigue, weight gain, cold intolerance, constipation, dry skin, and menstrual irregularities. She reports gradually increasing neck fullness. On examination, she has a diffuse, firm, non-tender goiter, dry skin, bradycardia, and delayed relaxation of deep tendon reflexes. Laboratory investigations show elevated TSH, low free T4, and positive anti-thyroid peroxidase (anti-TPO) antibodies. Diagnosis?

Diagnosis is Hashimoto Thyroiditis (Chronic Autoimmune Thyroiditis).

1. Definition

1. Hashimoto thyroiditis is a chronic autoimmune inflammatory disease of the thyroid gland.
2. It is characterized by immune-mediated destruction of thyroid tissue, eventually leading to hypothyroidism.
3. It is a leading cause of primary hypothyroidism and the most common cause in many iodine-sufficient populations.
4. It is more common in women.

2. Etiology / Risk Factors

1. Autoimmune destruction of the thyroid gland
2. Genetic predisposition:
1. Family history of autoimmune thyroid disease
2. Certain HLA and immune-regulatory gene associations
3. Environmental and clinical associations:
1. Female sex
2. Increasing age
3. Excess iodine exposure
4. Certain medications
5. Previous radiation exposure
4. Associated autoimmune diseases:
1. Type 1 diabetes mellitus
2. Celiac disease
3. Pernicious anemia
4. Addison disease
5. Vitiligo
6. Rheumatoid arthritis

3. Pathophysiology

1. Loss of immune tolerance to thyroid antigens
2. Activation of autoreactive T lymphocytes
3. Immune-mediated destruction of thyroid follicular cells
4. Formation of thyroid autoantibodies:
1. Anti-thyroid peroxidase (anti-TPO) antibodies
2. Anti-thyroglobulin (anti-Tg) antibodies
5. Progressive thyroid destruction → decreased T4/T3 production
6. Reduced thyroid hormone → loss of negative feedback
7. Increased pituitary TSH secretion
8. Result → primary hypothyroidism
9. Histology classically shows:
1. Dense lymphocytic infiltration
2. Germinal center formation
3. Destruction and atrophy of thyroid follicles
4. Hürthle cell change

4. Clinical Features

4.1 General Features

1. Fatigue
2. Weight gain
3. Cold intolerance
4. Lethargy
5. Reduced exercise tolerance

4.2 Gastrointestinal Features

1. Constipation
2. Reduced appetite

4.3 Skin and Hair Features

1. Dry, coarse skin
2. Hair loss
3. Brittle hair
4. Reduced sweating

4.4 Cardiovascular Features

1. Bradycardia
2. Reduced cardiac output
3. Diastolic hypertension may occur

4.5 Neurological / Musculoskeletal Features

1. Slowed mentation
2. Depression
3. Muscle weakness
4. Muscle cramps
5. Delayed relaxation of deep tendon reflexes
6. Carpal tunnel syndrome

4.6 Reproductive Features

1. Menstrual irregularities
2. Menorrhagia
3. Infertility
4. Reduced libido

4.7 Thyroid Findings

1. Diffuse, firm, non-tender goiter is typical
2. A goiter is not always present
3. The thyroid may become atrophic later in the disease

5. Diagnosis

5.1 Thyroid Function Tests

1. Overt primary hypothyroidism
1. ↑ TSH
2. ↓ Free T4
2. Subclinical hypothyroidism
1. ↑ TSH
2. Normal free T4
3. Early disease may be euthyroid.

5.2 Thyroid Antibodies

1. Anti-TPO antibodies
1. Most useful antibody marker
2. Present in most patients with Hashimoto thyroiditis
2. Anti-thyroglobulin antibodies
1. May also be present
2. Less sensitive than anti-TPO antibodies
3. Positive antibodies support an autoimmune etiology, but antibody positivity alone does not necessarily indicate hypothyroidism.
4. Anti-TPO antibody levels should not be serially monitored.
5. Once the diagnosis is established, follow thyroid function, particularly TSH, rather than antibody titers.

5.3 Imaging

1. Thyroid ultrasound is not routinely required when the diagnosis is clear clinically and biochemically.
2. Ultrasound is useful when:
1. Thyroid nodules are present
2. The gland is asymmetric
3. Structural thyroid disease is suspected
3. Typical ultrasound findings:
1. Heterogeneous echotexture
2. Reduced echogenicity

5.4 Fine-Needle Aspiration

1. Not routinely required for Hashimoto thyroiditis.
2. Indicated when a suspicious thyroid nodule or other concerning structural abnormality requires evaluation.

6. Differential Diagnosis

1. Other causes of primary hypothyroidism
2. Iodine deficiency or excess
3. Drug-induced hypothyroidism
4. Post-radioiodine hypothyroidism
5. Post-thyroidectomy hypothyroidism
6. Subacute thyroiditis
7. Postpartum thyroiditis
8. Graves disease
9. Infiltrative thyroid disease
10. Thyroid malignancy when a suspicious nodule or asymmetric enlargement is present

7. Management

7.1 Core Principle

1. Replace deficient thyroid hormone → normalize TSH → monitor clinically and biochemically

7.2 Levothyroxine Therapy

1. Levothyroxine (T4) is the treatment of choice for hypothyroidism.
2. In otherwise healthy younger adults requiring full replacement:
1. Approximate dose = 1.6 µg/kg/day
3. Patients with residual thyroid function may require lower doses.
4. Dose should be individualized according to:
1. Age
2. Body weight
3. Severity and duration of hypothyroidism
4. Cardiovascular disease
5. Pregnancy
5. In older patients or patients with coronary artery disease:
1. Start with a lower dose
2. Titrate gradually

7.3 How to Take Levothyroxine

1. Take consistently on an empty stomach.
2. Common approaches:
1. 30 to 60 minutes before breakfast
2. At bedtime, several hours after the last meal
3. Separate from substances that impair absorption, particularly:
1. Iron
2. Calcium
3. Certain antacids and interacting medications

7.4 Subclinical Hypothyroidism

1. Treatment is individualized.
2. In nonpregnant adults, consider treatment when TSH ≥10 mIU/L and persistently elevated, for example on two measurements approximately 3 months apart.
3. When TSH is below 10 mIU/L, consider:
1. Age
2. Hypothyroid symptoms
3. Anti-TPO positivity
4. Progressive TSH elevation
5. Cardiovascular risk
4. Pregnancy and preconception require separate pregnancy-specific treatment thresholds and targets.

7.5 Euthyroid Hashimoto Thyroiditis

1. Patients with positive antibodies but normal TSH and free T4 generally do not require levothyroxine.
2. Periodic thyroid function monitoring is appropriate.
3. Repeated measurement of thyroid antibody titers is not required.

8. Hashitoxicosis

1. Some patients develop a transient hyperthyroid phase called hashitoxicosis.
2. It results from release of preformed thyroid hormone from damaged thyroid follicles, not increased hormone synthesis.
3. Features may include:
1. Palpitations
2. Tremor
3. Heat intolerance
4. Weight loss
4. Usually self-limited.
5. Symptomatic treatment with a beta-blocker may be used when appropriate.
6. Antithyroid drugs are generally not useful because hormone synthesis is not increased.
7. If differentiation from Graves disease is uncertain:
1. Measure TSH receptor antibodies (TRAb/TSI)
2. Consider thyroid radionuclide uptake/scanning when appropriate
8. Graves disease shows increased hormone synthesis, whereas destructive thyroiditis typically has low thyroid uptake.

9. Monitoring

1. Measure TSH approximately 6 to 8 weeks after starting or changing the levothyroxine dose.
2. Adjust the dose according to TSH and clinical response.
3. Once stable:
1. Monitor TSH periodically, commonly every 6 to 12 months
4. Reassess earlier when:
1. Symptoms change
2. Pregnancy occurs
3. Major weight change occurs
4. Interacting medications are started or stopped
5. Avoid excessive levothyroxine replacement.
6. Do not routinely monitor anti-TPO titers.

10. Pregnancy

1. Thyroid hormone requirements commonly increase during pregnancy.
2. Pregnancy requires pregnancy-specific TSH targets and treatment thresholds.
3. Women already taking levothyroxine commonly require an early dose increase after pregnancy is confirmed.
4. Thyroid function should be monitored closely, typically about every 4 weeks during the first half of pregnancy.
5. Adequate maternal thyroid hormone is important for maternal and fetal health.

11. Complications

1. Overt hypothyroidism
2. Dyslipidemia
3. Cardiovascular disease
4. Infertility
5. Pregnancy complications
6. Neuropsychiatric manifestations
7. Myxedema coma in severe untreated hypothyroidism
8. Increased risk of primary thyroid lymphoma, although the absolute risk remains low
9. Red flags for thyroid lymphoma:
1. Rapidly enlarging thyroid or neck mass
2. Dysphagia
3. Dyspnea
4. Hoarseness
5. New cervical lymphadenopathy

12. Associated Conditions

1. Type 1 diabetes mellitus
2. Celiac disease
3. Pernicious anemia
4. Addison disease
5. Vitiligo
6. Other autoimmune disorders

13. Key Clinical Insight

1. Fatigue + weight gain + cold intolerance + constipation + firm non-tender goiter + ↑ TSH + ↓ free T4 + anti-TPO antibodies = Hashimoto thyroiditis

14. Key Exam Points

1. Hashimoto thyroiditis = chronic autoimmune thyroiditis
2. Leading cause of primary hypothyroidism
3. Most useful antibody = anti-TPO
4. Do not serially monitor anti-TPO titers
5. Anti-thyroglobulin antibodies may also be present
6. Overt hypothyroidism = ↑ TSH + ↓ free T4
7. Subclinical hypothyroidism = ↑ TSH + normal free T4
8. Histology = lymphocytic infiltration + germinal centers + Hürthle cells
9. Typical thyroid = firm, diffuse, non-tender goiter, but goiter is not obligatory
10. Treatment of hypothyroidism = levothyroxine
11. Full replacement in healthy younger adults = approximately 1.6 µg/kg/day, but individual requirements vary
12. Check TSH approximately 6 to 8 weeks after dose adjustment
13. Persistent TSH ≥10 mIU/L is an important threshold for considering treatment of subclinical hypothyroidism in nonpregnant adults
14. Pregnancy requires separate treatment thresholds and closer monitoring
15. Hashitoxicosis results from release of stored thyroid hormone
16. Antithyroid drugs are generally not indicated for hashitoxicosis
17. TRAb/TSI and thyroid uptake testing can help distinguish Graves disease from destructive thyroiditis when necessary
18. Positive antibodies with normal thyroid function generally require monitoring rather than treatment
19. Hashimoto thyroiditis is associated with primary thyroid lymphoma, but lymphoma remains rare
20. Rapid thyroid enlargement or compressive symptoms are red flags for lymphoma

Peptic Ulcer Disease (PUD)

A 45-year-old man presents with recurrent burning epigastric pain for 3 months. The pain is related to meals and is occasionally associated with nausea and bloating. He frequently uses NSAIDs for chronic back pain. On examination, there is mild epigastric tenderness without guarding or rigidity. Upper gastrointestinal endoscopy reveals a gastric ulcer. Biopsy testing is positive for Helicobacter pylori. Diagnosis?

Diagnosis is Peptic Ulcer Disease (PUD).

1. Definition

1. Peptic ulcer disease is a break in the gastric or duodenal mucosa extending through the muscularis mucosae into the submucosa or deeper.
2. It occurs when mucosal defensive mechanisms are overwhelmed by acid-peptic injury.
3. Major types:
1. Gastric ulcer
2. Duodenal ulcer

2. Etiology / Risk Factors

1. Two major causes:
1. Helicobacter pylori infection
2. NSAID use
2. Other risk factors and associations:
1. Aspirin
2. Smoking
3. Older age
4. Previous peptic ulcer or GI bleeding
5. Severe physiological stress in critically ill patients
6. Concomitant anticoagulants, antiplatelets, corticosteroids, or SSRIs may increase bleeding risk, particularly with NSAIDs
3. Rare causes:
1. Zollinger-Ellison syndrome
2. Crohn disease
3. CMV infection in immunocompromised patients

3. Pathophysiology

1. PUD results from an imbalance between aggressive factors and mucosal defenses.
2. Aggressive factors:
1. Gastric acid
2. Pepsin
3. H. pylori
4. NSAIDs
3. Protective factors:
1. Mucus-bicarbonate barrier
2. Prostaglandins
3. Adequate mucosal blood flow
4. Epithelial repair
4. H. pylori:
1. Colonizes gastric mucosa
2. Produces urease
3. Causes chronic gastritis
4. Disrupts mucosal defenses
5. Can alter gastrin and acid secretion
6. Predisposes to gastric and duodenal ulcers
5. NSAIDs:
1. Inhibit cyclooxygenase
2. Reduce prostaglandin synthesis
3. Decrease mucus and bicarbonate secretion
4. Impair mucosal blood flow and repair
5. Increase ulceration and bleeding risk

4. Clinical Features

4.1 Typical Features

1. Burning or gnawing epigastric pain
2. Dyspepsia
3. Nausea
4. Bloating
5. Early satiety
6. Symptoms may be related to meals

4.2 Gastric vs Duodenal Ulcer

1. Gastric ulcer
1. Pain may worsen with meals
2. May cause reduced food intake and weight loss
2. Duodenal ulcer
1. Pain may improve after eating
2. May recur several hours after meals or at night
3. These classical patterns are not sufficiently reliable for diagnosis or ulcer localization.

4.3 Features of Complications

1. Hematemesis or melena → upper GI bleeding
2. Sudden severe abdominal pain → perforation
3. Persistent vomiting and early satiety → gastric outlet obstruction
4. Dizziness, syncope, or hypotension → significant blood loss

5. Diagnosis

5.1 Diagnostic Approach

1. Evaluate:
1. Symptoms
2. NSAID/aspirin use
3. Previous ulcer disease
4. H. pylori status
5. Alarm features
2. Upper GI endoscopy (EGD) directly visualizes ulcers.
3. EGD allows:
1. Identification of ulcer location
2. Biopsy
3. Evaluation for malignancy
4. Endoscopic treatment of bleeding

5.2 H. pylori Testing

1. Noninvasive tests:
1. Urea breath test
2. Stool antigen test
2. Endoscopic tests:
1. Rapid urease test
2. Histology
3. Urea breath and stool antigen tests detect active infection.
4. Serology may remain positive after eradication and cannot reliably confirm active infection or cure.

5.3 Gastric Ulcer Biopsy

1. Gastric ulcers should be appropriately evaluated for malignancy.
2. The need for biopsy and follow-up endoscopy depends on:
1. Endoscopic appearance
2. Clinical context
3. Histopathology
4. Local guidelines
3. Duodenal ulcers are very rarely malignant and generally do not require routine biopsy for malignancy.

6. Alarm Features

1. GI bleeding
2. Iron-deficiency anemia
3. Unintentional weight loss
4. Persistent vomiting
5. Dysphagia or odynophagia
6. Palpable abdominal mass or lymphadenopathy
7. Features suggesting malignancy
8. Older age at new onset of dyspepsia

Age and alarm features guide the need for endoscopy. In younger patients, alarm features should be assessed individually rather than automatically mandating EGD.

7. Differential Diagnosis

1. Gastritis
2. Gastroesophageal reflux disease
3. Functional dyspepsia
4. Gastric malignancy
5. Pancreatitis
6. Biliary disease
7. Esophagitis
8. Mesenteric ischemia
9. Acute coronary syndrome

8. Management

8.1 Core Principle

1. Acid suppression → eradicate H. pylori → stop/reduce ulcerogenic drugs → treat complications

8.2 Acid Suppression

1. Proton pump inhibitors (PPIs) are the mainstay of ulcer healing.
2. Examples:
1. Omeprazole
2. Pantoprazole
3. Esomeprazole
3. Treatment duration depends on ulcer location, size, cause, complications, and continued NSAID exposure.

8.3 H. pylori Eradication

1. All patients with confirmed H. pylori infection should receive eradication therapy.
2. When antibiotic susceptibility is unknown, optimized bismuth quadruple therapy for 14 days is the preferred empiric regimen.
3. Optimized bismuth quadruple therapy:
1. PPI twice daily
2. Bismuth four times daily
3. Tetracycline 500 mg four times daily
4. Metronidazole 500 mg three or four times daily
5. Duration: 14 days
4. Alternative regimens in appropriate patients include:
1. Rifabutin-based triple therapy
2. Vonoprazan-amoxicillin dual therapy
5. Avoid empiric clarithromycin-containing or levofloxacin-containing regimens unless susceptibility is demonstrated.

8.4 Confirm Eradication

1. Test of cure is required in all treated patients.
2. Preferred methods:
1. Urea breath test
2. Stool antigen test
3. Biopsy-based testing when indicated
3. Perform testing at least 4 weeks after completion of therapy.
4. Before testing:
1. Hold PPI/PCAB for 2 weeks
2. Hold antibiotics and bismuth for 4 weeks
5. These measures reduce the risk of false-negative results.

8.5 NSAID-Associated Ulcer

1. Stop NSAIDs if possible
2. Treat with a PPI
3. Test for and eradicate H. pylori if present
4. If NSAIDs must continue:
1. Use the lowest effective dose
2. Consider a COX-2 selective NSAID when appropriate
3. Provide PPI gastroprotection in high-risk patients

9. Management of Complications

9.1 Upper GI Bleeding

1. Initial management:
1. Airway, breathing, circulation
2. IV access
3. Hemodynamic resuscitation
4. CBC, coagulation studies, renal function, and blood grouping/crossmatch as appropriate
2. After appropriate resuscitation and stabilization, hospitalized patients with UGIB generally undergo upper endoscopy within 24 hours.
3. High-risk bleeding ulcers require:
1. Endoscopic hemostasis
2. PPI therapy

9.2 Perforation

1. Presents with sudden severe abdominal pain
2. May cause:
1. Peritonitis
2. Free intraperitoneal air
3. Requires:
1. Resuscitation
2. IV antibiotics
3. Acid suppression
4. Urgent surgical evaluation

9.3 Gastric Outlet Obstruction

1. Presents with:
1. Persistent vomiting
2. Early satiety
3. Abdominal distension
2. Management may include:
1. Gastric decompression
2. IV fluids and electrolyte correction
3. PPI therapy
4. Endoscopic or surgical treatment depending on the cause

10. Monitoring

1. Assess symptom improvement
2. Monitor for GI bleeding
3. Confirm H. pylori eradication
4. Review NSAID/aspirin requirement
5. Monitor hemoglobin if bleeding or anemia is present
6. Follow-up endoscopy may be required for gastric ulcers, depending on clinical and endoscopic findings

11. Complications

1. Upper GI bleeding, most common major complication
2. Perforation
3. Penetration into adjacent organs
4. Gastric outlet obstruction
5. Recurrent ulceration
6. Iron-deficiency anemia

12. Prevention

1. Diagnose and eradicate H. pylori
2. Avoid unnecessary NSAIDs
3. Use the lowest effective NSAID dose
4. Use PPI gastroprotection in high-risk NSAID users
5. Avoid smoking
6. Review medications that increase GI bleeding risk

13. Key Clinical Insight

1. Epigastric pain + NSAID use or H. pylori infection = suspect PUD
2. Hematemesis/melena, sudden severe abdominal pain, or persistent vomiting = evaluate for complicated PUD

14. Key Exam Points

1. Two major causes = H. pylori + NSAIDs
2. PUD extends through the muscularis mucosae into the submucosa or deeper
3. H. pylori produces urease
4. NSAIDs → ↓ prostaglandins → ↓ mucus/bicarbonate + impaired mucosal protection
5. EGD = direct visualization and allows biopsy/treatment
6. Gastric ulcers require appropriate evaluation for malignancy
7. Urea breath test or stool antigen = preferred noninvasive tests for active H. pylori
8. Preferred empiric H. pylori regimen when susceptibility is unknown = optimized bismuth quadruple therapy for 14 days
9. Avoid empiric clarithromycin or levofloxacin regimens unless susceptibility is demonstrated
10. Always confirm H. pylori eradication
11. Test of cure → ≥4 weeks after therapy, off PPI/PCAB for 2 weeks and antibiotics/bismuth for 4 weeks
12. PPI = mainstay of ulcer healing
13. Most common major complication = upper GI bleeding
14. UGIB → stabilize first, then generally EGD within 24 hours
15. Sudden severe abdominal pain → suspect perforation
16. Persistent vomiting → consider gastric outlet obstruction
17. Gastric vs duodenal meal-related pain patterns are classical but not diagnostically reliable