HESI RN ADVANCED PATHOPHYSIOLOGY
Actual EXAM 2026 – Comprehensive Review &
Verified Guide
SECTION 1: CELLULAR & MOLECULAR FOUNDATIONS (Questions 1-30)
Q1: A 38-year-old female with BRCA1 mutation develops invasive ductal carcinoma.
Genetic testing shows loss of heterozygosity at the BRCA1 locus in tumor cells. Which
molecular mechanism primarily explains the transition from hereditary predisposition to
active carcinogenesis?
A. Proto-oncogene amplification leading to uncontrolled cell proliferation
B. Loss of tumor suppressor function through "second hit" somatic mutation
C. DNA mismatch repair deficiency causing microsatellite instability
D. Chromosomal translocation creating novel fusion oncogenes
Correct Answer: B
MOLECULAR/CELLULAR MECHANISM:
• Primary Disruption: BRCA1 is a tumor suppressor gene involved in DNA double-strand
break repair via homologous recombination. The first hit is the germline mutation; the
second hit is somatic loss of the remaining wild-type allele.
• Pathway Affected: Knudson's "two-hit hypothesis" - complete loss of tumor suppressor
function requires both alleles to be inactivated.
• Cascade Initiated: Unrepaired DNA damage accumulates → genomic instability →
activation of oncogenes and loss of additional tumor suppressors → malignant
transformation.
,SYSTEMIC INTEGRATION:
• Breast Tissue: Loss of DNA repair in mammary epithelial cells leads to uncontrolled
proliferation and invasion.
• Endocrine System: BRCA1 interacts with estrogen receptor signaling; loss disrupts
hormone-regulated growth control.
• Compensatory Mechanisms: p53 may attempt to induce apoptosis in damaged cells,
but selective pressure favors p53 mutations in tumor progression.
CLINICAL CORRELATION:
• Presentation: Early-onset breast cancer (often <50), bilateral disease, triple-negative
phenotype common.
• Complications: Ovarian cancer risk, prostate/pancreatic cancer in families.
• Treatment: PARP inhibitors exploit synthetic lethality in cells deficient in homologous
recombination.
• Nursing Surveillance: Monitor for secondary malignancies, genetic counseling for
family members.
COMMON ERRORS:
• Error 1: Confusing BRCA1 with oncogenes (choice A) rather than tumor suppressor.
• Error 2: Confusing with Lynch syndrome (mismatch repair - choice C).
• Error 3: Thinking of hematologic translocations (choice D) rather than solid tumor
suppressor loss.
Q2 (SATA): A 65-year-old male with long-standing hypertension develops heart failure
with preserved ejection fraction (HFpEF). Which cellular and molecular alterations
contribute to HFpEF pathophysiology? Select all that apply.
A. Increased myocardial fibroblast activity and collagen deposition
B. Downregulation of β-adrenergic receptors with reduced cyclic AMP
C. Abnormal cardiomyocyte calcium handling with prolonged relaxation
D. Shift from α-myosin heavy chain to β-myosin heavy chain isoform
,E. Reduced nitric oxide bioavailability and endothelial dysfunction
Correct Answer: A, C, E
MOLECULAR/CELLULAR MECHANISM:
• A: Mechanical stress from hypertension activates TGF-β → fibroblast proliferation →
type I/III collagen deposition → myocardial stiffness.
• C: Impaired SERCA2a function and increased phospholamban activity reduce calcium
reuptake into sarcoplasmic reticulum → prolonged relaxation → diastolic dysfunction.
• E: eNOS uncoupling and oxidative stress reduce NO → impaired vasodilation and
myocardial perfusion.
SYSTEMIC INTEGRATION:
• Cardiovascular: Stiff ventricle requires higher filling pressures → pulmonary
congestion.
• Renal: Elevated filling pressures cause renal venous congestion → RAAS activation.
• Pulmonary: Left atrial pressure transmission causes pulmonary hypertension.
CLINICAL CORRELATION:
• Presentation: Exertional dyspnea, preserved EF >50%, elevated BNP.
• Treatment: Limited disease-modifying therapies; focus on comorbidity management.
• Nursing: Monitor volume status, renal function, exercise tolerance.
INCORRECT OPTIONS:
• B: Characteristic of HFrEF (systolic failure), not HFpEF primary mechanism.
• D: Occurs in chronic pressure overload but more associated with systolic dysfunction;
primary issue in HFpEF is relaxation, not contraction velocity.
Q3: Which cellular adaptation allows a 45-year-old with chronic obstructive pulmonary
disease (COPD) to maintain oxygen delivery despite chronic hypoxemia?
A. Metaplasia of bronchial epithelium to stratified squamous epithelium
B. Hypertrophy of type II pneumocytes to increase surfactant production
, C. Hyperplasia of carotid body glomus cells enhancing ventilatory drive
D. Increased 2,3-diphosphoglycerate (2,3-DPG) in erythrocytes shifting the
oxyhemoglobin curve rightward
Correct Answer: D
MOLECULAR/CELLULAR MECHANISM:
• Primary Disruption: Chronic hypoxemia stimulates glycolytic pathway in RBCs.
• Pathway Affected: 2,3-DPG binds to hemoglobin tetramer → reduces affinity for
oxygen → shifts dissociation curve rightward.
• Cascade Initiated: Enhanced oxygen unloading at tissue level despite lower arterial
PO2.
SYSTEMIC INTEGRATION:
• Hematological: Increased erythropoietin production also causes secondary
polycythemia (increased Hgb).
• Cardiovascular: Pulmonary hypertension develops from hypoxic vasoconstriction
(different adaptation).
• Respiratory: Increased minute ventilation via peripheral chemoreceptor stimulation.
CLINICAL CORRELATION:
• Presentation: "Blue bloater" phenotype with compensated hypoxemia.
• Complications: Cor pulmonale from pulmonary hypertension.
• Nursing: Monitor oxygen saturation targets (88-92% to avoid CO2 retention).
COMMON ERRORS:
• Error 1: Selecting C (carotid body) - this increases ventilation rate but doesn't improve
oxygen delivery at cellular level.
• Error 2: Selecting A - metaplasia protects against irritation but doesn't improve gas
exchange.
• Error 3: Selecting B - surfactant prevents collapse but doesn't solve
oxygen-hemoglobin binding.
Actual EXAM 2026 – Comprehensive Review &
Verified Guide
SECTION 1: CELLULAR & MOLECULAR FOUNDATIONS (Questions 1-30)
Q1: A 38-year-old female with BRCA1 mutation develops invasive ductal carcinoma.
Genetic testing shows loss of heterozygosity at the BRCA1 locus in tumor cells. Which
molecular mechanism primarily explains the transition from hereditary predisposition to
active carcinogenesis?
A. Proto-oncogene amplification leading to uncontrolled cell proliferation
B. Loss of tumor suppressor function through "second hit" somatic mutation
C. DNA mismatch repair deficiency causing microsatellite instability
D. Chromosomal translocation creating novel fusion oncogenes
Correct Answer: B
MOLECULAR/CELLULAR MECHANISM:
• Primary Disruption: BRCA1 is a tumor suppressor gene involved in DNA double-strand
break repair via homologous recombination. The first hit is the germline mutation; the
second hit is somatic loss of the remaining wild-type allele.
• Pathway Affected: Knudson's "two-hit hypothesis" - complete loss of tumor suppressor
function requires both alleles to be inactivated.
• Cascade Initiated: Unrepaired DNA damage accumulates → genomic instability →
activation of oncogenes and loss of additional tumor suppressors → malignant
transformation.
,SYSTEMIC INTEGRATION:
• Breast Tissue: Loss of DNA repair in mammary epithelial cells leads to uncontrolled
proliferation and invasion.
• Endocrine System: BRCA1 interacts with estrogen receptor signaling; loss disrupts
hormone-regulated growth control.
• Compensatory Mechanisms: p53 may attempt to induce apoptosis in damaged cells,
but selective pressure favors p53 mutations in tumor progression.
CLINICAL CORRELATION:
• Presentation: Early-onset breast cancer (often <50), bilateral disease, triple-negative
phenotype common.
• Complications: Ovarian cancer risk, prostate/pancreatic cancer in families.
• Treatment: PARP inhibitors exploit synthetic lethality in cells deficient in homologous
recombination.
• Nursing Surveillance: Monitor for secondary malignancies, genetic counseling for
family members.
COMMON ERRORS:
• Error 1: Confusing BRCA1 with oncogenes (choice A) rather than tumor suppressor.
• Error 2: Confusing with Lynch syndrome (mismatch repair - choice C).
• Error 3: Thinking of hematologic translocations (choice D) rather than solid tumor
suppressor loss.
Q2 (SATA): A 65-year-old male with long-standing hypertension develops heart failure
with preserved ejection fraction (HFpEF). Which cellular and molecular alterations
contribute to HFpEF pathophysiology? Select all that apply.
A. Increased myocardial fibroblast activity and collagen deposition
B. Downregulation of β-adrenergic receptors with reduced cyclic AMP
C. Abnormal cardiomyocyte calcium handling with prolonged relaxation
D. Shift from α-myosin heavy chain to β-myosin heavy chain isoform
,E. Reduced nitric oxide bioavailability and endothelial dysfunction
Correct Answer: A, C, E
MOLECULAR/CELLULAR MECHANISM:
• A: Mechanical stress from hypertension activates TGF-β → fibroblast proliferation →
type I/III collagen deposition → myocardial stiffness.
• C: Impaired SERCA2a function and increased phospholamban activity reduce calcium
reuptake into sarcoplasmic reticulum → prolonged relaxation → diastolic dysfunction.
• E: eNOS uncoupling and oxidative stress reduce NO → impaired vasodilation and
myocardial perfusion.
SYSTEMIC INTEGRATION:
• Cardiovascular: Stiff ventricle requires higher filling pressures → pulmonary
congestion.
• Renal: Elevated filling pressures cause renal venous congestion → RAAS activation.
• Pulmonary: Left atrial pressure transmission causes pulmonary hypertension.
CLINICAL CORRELATION:
• Presentation: Exertional dyspnea, preserved EF >50%, elevated BNP.
• Treatment: Limited disease-modifying therapies; focus on comorbidity management.
• Nursing: Monitor volume status, renal function, exercise tolerance.
INCORRECT OPTIONS:
• B: Characteristic of HFrEF (systolic failure), not HFpEF primary mechanism.
• D: Occurs in chronic pressure overload but more associated with systolic dysfunction;
primary issue in HFpEF is relaxation, not contraction velocity.
Q3: Which cellular adaptation allows a 45-year-old with chronic obstructive pulmonary
disease (COPD) to maintain oxygen delivery despite chronic hypoxemia?
A. Metaplasia of bronchial epithelium to stratified squamous epithelium
B. Hypertrophy of type II pneumocytes to increase surfactant production
, C. Hyperplasia of carotid body glomus cells enhancing ventilatory drive
D. Increased 2,3-diphosphoglycerate (2,3-DPG) in erythrocytes shifting the
oxyhemoglobin curve rightward
Correct Answer: D
MOLECULAR/CELLULAR MECHANISM:
• Primary Disruption: Chronic hypoxemia stimulates glycolytic pathway in RBCs.
• Pathway Affected: 2,3-DPG binds to hemoglobin tetramer → reduces affinity for
oxygen → shifts dissociation curve rightward.
• Cascade Initiated: Enhanced oxygen unloading at tissue level despite lower arterial
PO2.
SYSTEMIC INTEGRATION:
• Hematological: Increased erythropoietin production also causes secondary
polycythemia (increased Hgb).
• Cardiovascular: Pulmonary hypertension develops from hypoxic vasoconstriction
(different adaptation).
• Respiratory: Increased minute ventilation via peripheral chemoreceptor stimulation.
CLINICAL CORRELATION:
• Presentation: "Blue bloater" phenotype with compensated hypoxemia.
• Complications: Cor pulmonale from pulmonary hypertension.
• Nursing: Monitor oxygen saturation targets (88-92% to avoid CO2 retention).
COMMON ERRORS:
• Error 1: Selecting C (carotid body) - this increases ventilation rate but doesn't improve
oxygen delivery at cellular level.
• Error 2: Selecting A - metaplasia protects against irritation but doesn't improve gas
exchange.
• Error 3: Selecting B - surfactant prevents collapse but doesn't solve
oxygen-hemoglobin binding.
