Laboratory Investigations of Myocardial Infarction

Diagnostic Framework

• Symptoms of myocardial ischemia
• New ischemic ECG changes
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
• Identification of a coronary thrombus by angiography or autopsy (Type 1 MI)

Symptom to Diagnosis: An Evidence-Based Guide, 4th Ed. | Harrison's Principles of Internal Medicine, 22nd Ed.

1. Cardiac Troponins (Primary Biomarker)

Biochemistry

• Troponin C - calcium-binding subunit (not cardiac-specific - same isoform as slow-twitch skeletal muscle)
• Troponin I (cTnI) - inhibitory subunit; cardiac-specific due to a unique 31-amino-acid N-terminal extension not present in skeletal muscle isoforms
• Troponin T (cTnT) - tropomyosin-binding subunit; cardiac-specific due to an 11-amino-acid amino-terminal residue

Tietz Textbook of Laboratory Medicine, 7th Ed.

Release Mechanism

Kinetics

• cTnI and cTnT are normally undetectable in serum
• Persist elevated for 7-10 days, allowing diagnosis even when presentation is delayed
• Serial measurements over 3-6 hours improve sensitivity for early presentations

Robbins & Kumar Basic Pathology | Robbins, Cotran & Kumar Pathologic Basis of Disease

Threshold

• Diagnosis requires at least one value above the 99th percentile URL of a healthy reference population
• Modern high-sensitivity cTn (hs-cTn) assays allow detection at much lower concentrations, enabling 0h/1h or 0h/2h rapid rule-out protocols
• Sex-specific URL values are recommended (women have lower 99th percentile thresholds)

Tietz Textbook of Laboratory Medicine, 7th Ed. | Harrison's Principles, 22nd Ed.

Causes of Troponin Elevation Other Than MI

• Myocarditis, myocardial trauma
• Heart failure, pulmonary embolism
• Renal failure (reduced clearance), sepsis
• These causes do not follow the characteristic rise-and-fall pattern of acute MI

2. Creatine Kinase - MB Isoform (CK-MB)

• No longer recommended as the primary marker for initial diagnosis of NSTEMI (Washington Manual of Medical Therapeutics)
• May still be used to detect reinfarction (since troponin remains elevated for 7-10 days, CK-MB's shorter window makes a second rise detectable)
• Occasionally used in perioperative settings (e.g., post-cardiac surgery)

Washington Manual of Medical Therapeutics | Robbins & Kumar Basic Pathology

3. Myoglobin

• A heme-containing oxygen-binding protein found in both cardiac and skeletal muscle
• Earliest to rise after MI onset (detectable within 1-3 hours)
• Returns to normal within 24 hours - shortest window
• Very low specificity - released by any muscle injury (skeletal, cardiac)
• Not recommended as a standalone diagnostic test but historically used as an early sensitive marker
• Useful as a negative predictor if levels are normal very early after symptom onset

4. Other Routine Lab Investigations

Washington Manual of Medical Therapeutics

5. BNP / NT-proBNP (Natriuretic Peptides)

• BNP (B-type natriuretic peptide) is a biomarker of myocardial wall stress and ventricular dysfunction
• Elevated BNP in the setting of ACS indicates:
  • Larger infarction size
  • Worse outcomes / higher mortality
  • Possible large infarction requiring urgent angiography (if severely elevated in a patient without known HF)
• Aids in distinguishing cardiac vs. pulmonary cause of dyspnea

Washington Manual of Medical Therapeutics | Tietz Textbook of Laboratory Medicine, 7th Ed.

6. Universal MI Classification and Biomarker Thresholds

Harrison's Principles of Internal Medicine, 22nd Ed. | Sabiston Textbook of Surgery

Summary Table: Biomarker Kinetics

Robbins, Cotran & Kumar Pathologic Basis of Disease | Tietz Textbook of Laboratory Medicine, 7th Ed. | Symptom to Diagnosis: An Evidence-Based Guide, 4th Ed. | Washington Manual of Medical Therapeutics

Functional Tumors of the Ovary

Classification

Berek & Novak's Gynecology, Table 39-8

1. Granulosa Cell Tumors (GCT)

Overview

• Most common type of malignant sex cord-stromal tumor
• Account for 2-5% of all ovarian malignancies
• Considered low-grade malignancies
• Almost always unilateral (bilateral in only 2%)
• Tumors that are hormonally active show yellow coloration on cut surface (due to intracellular lipids)

Subtypes

Histology - Call-Exner Bodies (Pathognomonic)

Hormone Secretion & Clinical Effects

• Prepubertal girls: isosexual precocious puberty (breast development, premature menarche)
• Reproductive age women: menstrual irregularities, secondary amenorrhea, infertility
• Postmenopausal women: abnormal uterine bleeding (most common presenting symptom)
• Endometrial effects: cystic hyperplasia → endometrial hyperplasia → endometrial carcinoma in 10-15%; low-grade endometrial cancer co-exists in at least 5% of adult GCTs; endometrial hyperplasia in 25-50%
• Proliferative breast disease

Tumor Markers

• Inhibin A and B - secreted by granulosa cells; inhibin B more frequently elevated. Useful for:
  • Diagnosis (elevated inhibin in premenopausal woman with amenorrhea/infertility)
  • Monitoring treatment response
  • Detecting recurrence - lead time of ~12 months before clinical recurrence
• Anti-Müllerian Hormone (AMH) - elevated in 75% of adult GCTs preoperatively; >90% sensitivity for detecting recurrence

Molecular Genetics

• FOXL2 mutation (C134W) in 97% of adult GCTs - encodes a transcription factor important in granulosa cell development; nearly pathognomonic
• Molecular FOXL2 testing improves diagnostic accuracy (almost 30% of adult GCTs were misdiagnosed historically)
• FOXL2 mutation is absent in juvenile GCTs

Malignant Potential & Prognosis

• All GCTs are potentially malignant - impossible to predict biologic behavior from histology alone
• Malignant behavior (recurrence, extension): 5-25%
• Characteristically indolent course - recurrences may appear 10-20 years after original tumor removal
• 10-year survival: ~90-95% for Stage I

Robbins, Cotran & Kumar Pathologic Basis of Disease | Berek & Novak's Gynecology

2. Thecomas and Fibromas

Thecoma

• Composed of plump spindle cells with lipid droplets
• Represents theca cell differentiation
• Almost always benign (tumors composed predominantly of theca cells are almost never malignant)
• Hormonally active - typically estrogenic; produce endometrial hyperplasia, abnormal bleeding
• Usually unilateral, postmenopausal women

Fibroma

• Composed of well-differentiated fibroblasts with scant collagenous stroma
• Not usually hormonally active, but may occasionally be
• Unilateral in ~90% of cases; solid, hard, gray-white mass
• Account for ~4% of all ovarian tumors
• Meigs Syndrome - classic triad of:
  • Ovarian fibroma (or thecoma)
  • Ascites
  • Right-sided pleural effusion
  • (Resolves after tumor removal)
• Associated with Basal Cell Nevus Syndrome (Gorlin syndrome)

Robbins, Cotran & Kumar Pathologic Basis of Disease

3. Sertoli-Leydig Cell Tumors (Androblastoma)

Overview

• Recapitulate testicular architecture (Sertoli cells and Leydig cells)
• Extremely rare - <0.2% of ovarian cancers
• Peak incidence: 2nd and 3rd decades (75% under age 40)
• Unilateral; low-grade malignancies
• Associated with DICER1 gene somatic mutations (encodes endonuclease for micro-RNA processing)

Histology

Differentiation Grades

Hormone Secretion & Clinical Effects

• Predominantly androgenic (testosterone and androstenedione elevated)
• Virilization/defeminization in 70-85% of patients:
  • Oligomenorrhea → amenorrhea
  • Breast atrophy
  • Acne, hirsutism
  • Clitoromegaly
  • Voice deepening
  • Receding hairline
• Rarely - estrogenic effects (isosexual precocity or postmenopausal bleeding)
• Plasma DHEAS normal or only slightly elevated (helps distinguish from adrenal source)

Prognosis

• Recurrence or metastasis: <5% (most are stage I, low grade)
• 5-year survival: 70-90%
• Most fatalities occur with poorly differentiated tumors

Berek & Novak's Gynecology | Robbins, Cotran & Kumar Pathologic Basis of Disease

4. Leydig Cell (Hilus Cell) Tumors

• Rare, unilateral tumors located in the ovarian hilus
• Composed of large lipid-laden Leydig cells with characteristic Reinke crystalloids (cytoplasmic crystalline inclusions - pathognomonic)
• Androgen-secreting → predominantly testosterone → mild-to-moderate virilization (hirsutism, voice changes, clitoromegaly)
• Milder virilization than Sertoli-Leydig cell tumors
• Almost always benign
• Treatment: surgical excision

5. Steroid Cell Tumors

• Account for <1% of ovarian neoplasms
• Most associated with virilization (most common)
• Some produce corticosteroids → obesity, hypertension, glucose intolerance (Cushing-like features)
• Rare cases of estrogen secretion and isosexual precocity
• ~20% may metastasize (especially if >8 cm)
• Treatment: surgical removal; no established role for radiation or chemotherapy

6. Gynandroblastoma and Sex Cord Tumor with Annular Tubules

• Gynandroblastoma: rare; contains both well-differentiated male (Sertoli/Leydig) and female (granulosa/theca) elements; may produce mixed hormonal effects
• Sex cord tumor with annular tubules (SCTAT): distinctive tumor with ring-shaped tubules; strongly associated with Peutz-Jeghers syndrome; may produce progesterone; occasionally malignant

Summary Table

Robbins, Cotran & Kumar Pathologic Basis of Disease | Berek & Novak's Gynecology | Robbins & Kumar Basic Pathology | Guyton & Hall Textbook of Medical Physiology