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2nd MBBS Pathology - MUHS Exam Notes

Endocrine Pathology: Diabetes, Thyroid & MEN Syndromes

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1. DIABETES MELLITUS ★★★

Classification (WHO / ADA)

DIABETES MELLITUS
├── Type 1 DM (5-10%) - Absolute insulin deficiency
│   ├── 1A: Immune-mediated (HLA-DR3, HLA-DR4)
│   └── 1B: Idiopathic
├── Type 2 DM (90-95%) - Insulin resistance + relative deficiency
├── Gestational DM
└── Other Specific Types
    ├── MODY (Maturity Onset DM of Young) - Autosomal dominant
    │   ├── MODY1: HNF4A mutation
    │   ├── MODY2: Glucokinase (GCK) mutation
    │   └── MODY3: HNF1A mutation (most common)
    ├── Diseases of exocrine pancreas
    │   (Pancreatitis, CF, Hemochromatosis, Neoplasia)
    ├── Endocrinopathies
    │   (Acromegaly, Cushing's, Glucagonoma, Pheochromocytoma)
    ├── Drug/Chemical-induced (Steroids, Thiazides, Pentamidine)
    ├── Infections (Congenital Rubella, CMV, Coxsackievirus)
    └── Genetic syndromes (Down, Klinefelter, Turner syndromes)

Type 1 vs Type 2 - Key Comparison

Etiology/Pathogenesis

• Genetic: HLA-DR3 and HLA-DR4 (95% of Type 1 patients carry one or both)
• Environmental trigger (viral infection, dietary factors) in genetically susceptible individual
• Autoimmune destruction of beta cells by:
  • CD8+ cytotoxic T cells (direct killing)
  • CD4+ Th1 cells releasing IFN-gamma → macrophage activation
  • Autoantibodies (GAD65, IA-2, ZnT8, insulin autoantibodies)
• Progressive "insulitis" - lymphocytic infiltration of islets
• Loss of >90% of beta cell mass → absolute insulin deficiency

• Insulin resistance (muscle, liver, adipose tissue) - primary defect
• Progressive beta cell dysfunction (exhaustion, glucotoxicity, lipotoxicity)
• Genetic predisposition (polygenic) + environmental factors (obesity, sedentary lifestyle)
• Glucotoxicity and lipotoxicity cause beta cell apoptosis over time

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Diagnostic Criteria (ADA) ★★★

┌─────────────────────────────────────────────────────────────┐
│              DIAGNOSTIC CRITERIA FOR DM                      │
│                                                              │
│  1. FPG ≥ 126 mg/dL (7.0 mmol/L) — fasting ≥8 hrs          │
│  2. 2-hr PG ≥ 200 mg/dL during OGTT (75g glucose)          │
│  3. HbA1c ≥ 6.5% (48 mmol/mol)                             │
│  4. Random PG ≥ 200 mg/dL + classic symptoms               │
│     (polyuria, polydipsia, unexplained weight loss)         │
│                                                              │
│  NOTE: Criteria 1-3 require confirmation on repeat          │
│        testing on a different day (unless unequivocal)      │
└─────────────────────────────────────────────────────────────┘

• Impaired Fasting Glucose (IFG): FPG 100-125 mg/dL
• Impaired Glucose Tolerance (IGT): 2-hr OGTT 140-199 mg/dL
• HbA1c 5.7-6.4%

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Laboratory Investigations with Significance ★★

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2. ORAL GLUCOSE TOLERANCE TEST (OGTT) ★★

Indications

INDICATIONS FOR OGTT
├── Diagnosis of GDM (Gestational Diabetes Mellitus) - PRIMARY use
├── Borderline fasting glucose (IFG: 100-125 mg/dL)
├── Suspected DM when FPG is normal but symptoms present
├── Reactive hypoglycemia evaluation
├── Diagnosis of IGT (Impaired Glucose Tolerance)
├── Follow-up of women with previous GDM
└── Screening in high-risk individuals (PCO, obesity, family history)

Method (Standard 75g OGTT)

PREPARATION (3 days before):
• Unrestricted diet (≥150g carbohydrate/day)
• Normal physical activity
• No drugs affecting glucose metabolism

PROCEDURE:
Day of test → 8-12 hours overnight fast
↓
Fasting blood sample drawn (baseline)
↓
75g anhydrous glucose dissolved in 250-300 mL water
(For GDM: 100g glucose used in some protocols)
↓
Patient rests (no smoking, eating, vigorous activity)
↓
Blood sample at 1 hour (optional)
↓
Blood sample at 2 hours

NOTE: In pregnancy, samples taken at 0, 1, 2, 3 hours (Carpenter & Coustan criteria)

Interpretation

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3. GLYCOSYLATED HEMOGLOBIN (HbA1c) ★★

Definition

Key Points

┌──────────────────────────────────────────────────────────┐
│                    HbA1c FACTS                           │
│                                                          │
│  • Reflects AVERAGE blood glucose over 2-3 months       │
│    (reflects lifespan of RBCs ~120 days)                 │
│  • Measured as % of total hemoglobin                     │
│  • Formula: Average Glucose (mg/dL) = (28.7 × HbA1c) - 46.7 │
│                                                          │
│  NORMAL: <5.7%                                           │
│  PRE-DIABETES: 5.7-6.4%                                  │
│  DIAGNOSTIC OF DM: ≥6.5%                                │
│  TARGET IN TREATED DM: <7%                               │
└──────────────────────────────────────────────────────────┘

Methods of Measurement

1. High-Performance Liquid Chromatography (HPLC) - gold standard
2. Immunoassay
3. Affinity chromatography
4. Ion-exchange chromatography

Factors Causing False Results

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4. DIABETIC NEPHROPATHY / GLOMERULOSCLEROSIS ★★★

Pathogenesis

HYPERGLYCEMIA
     │
     ├── ↑ Advanced Glycation End Products (AGEs)
     │       → Cross-links collagen → GBM thickening
     │       → Binds RAGE receptor → TGF-β, VEGF upregulation
     │
     ├── Activation of Protein Kinase C (PKC)
     │       → ↑ VEGF, TGF-β → mesangial expansion
     │
     ├── Polyol pathway activation
     │       (Glucose → Sorbitol via aldose reductase)
     │       → Osmotic damage to cells
     │
     ├── Hemodynamic changes
     │       → Afferent arteriole dilation > efferent
     │       → ↑ Intraglomerular pressure (hyperfiltration)
     │       → GFR initially ↑ (hyperfiltration phase)
     │
     └── TGF-β overproduction
             → Mesangial matrix expansion
             → Basement membrane thickening
             → Fibrosis

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Morphology (Glomerular Lesions) ★★★

A. Diffuse Glomerulosclerosis (More Common)

• Diffuse increase in mesangial matrix and basement membrane thickening
• All glomeruli affected
• Early lesion; associated with microalbuminuria

B. Nodular Glomerulosclerosis (PATHOGNOMONIC) ★★★

• Kimmelstiel-Wilson lesion - ovoid/spherical deposits of laminated matrix in the periphery of the glomerulus
• PAS-positive, acellular nodules in the mesangium
• Nodule pushes capillaries to periphery
• Present in ~25% of patients
• Pathognomonic of diabetic nephropathy (but similar pattern in amyloidosis, light-chain deposition disease)

Other Morphologic Features:

• Exudative lesions: "Capsular drop" (accumulation between parietal epithelium and Bowman's capsule) and "fibrin cap" (hyaline deposits overlying peripheral capillaries)
• Glomerular basement membrane (GBM) thickening
• Afferent AND efferent arteriolar hyalinosis (hyalinosis of efferent arteriole is virtually DIAGNOSTIC of DM)
• Tubular lesions: Armanni-Ebstein lesion (glycogen accumulation in tubular epithelium, especially in renal medulla)
• Interstitial fibrosis and tubular atrophy (IFTA) in advanced disease

Stages of Diabetic Nephropathy (Mogensen Stages):

Stage I:   Hyperfiltration - ↑GFR, kidney enlargement, no albuminuria
Stage II:  Silent - GBM thickening, mesangial expansion; normal urine
Stage III: Incipient nephropathy - MICROALBUMINURIA (30-300 mg/day); BP rises
Stage IV:  Overt nephropathy - MACROALBUMINURIA (>300 mg/day); declining GFR
Stage V:   End-stage renal disease (ESRD) - GFR <15 mL/min; dialysis needed

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5. MEN SYNDROMES (Multiple Endocrine Neoplasia) ★★

Overview

┌──────────────────┬────────────────────────────────────────────────────┐
│    SYNDROME      │         KEY FEATURES                               │
├──────────────────┼────────────────────────────────────────────────────┤
│ MEN 1            │ "3 P's" - Parathyroid + Pancreas + Pituitary      │
│ (Wermer's)       │ Gene: MEN1 (Chromosome 11q13) - MENIN protein      │
│                  │ Tumor suppressor - Autosomal Dominant              │
│                  │ Parathyroid: ~100% (most common, first to appear)  │
│                  │ Pancreatic NETs: Gastrinoma > Insulinoma            │
│                  │ Pituitary: Prolactinoma > GH-oma > ACTH-oma        │
│                  │ Also: Carcinoid, Lipomas, Angiofibromas             │
├──────────────────┼────────────────────────────────────────────────────┤
│ MEN 2A           │ MTC + Pheochromocytoma + Hyperparathyroidism       │
│ (Sipple's)       │ Gene: RET proto-oncogene (Chr 10) - gain of function│
│                  │ MTC: 95-100% (often first manifestation)           │
│                  │ Pheo: 50%                                           │
│                  │ PHPT: 20-30%                                        │
├──────────────────┼────────────────────────────────────────────────────┤
│ MEN 2B           │ MTC + Pheochromocytoma + Mucosal Neuromas          │
│                  │ Gene: RET (specific codon 918 mutation)             │
│                  │ + Marfanoid habitus + Ganglioneuromatosis of GIT    │
│                  │ Most aggressive MTC (NO hyperparathyroidism)        │
├──────────────────┼────────────────────────────────────────────────────┤
│ MEN 4            │ MEN1-like phenotype                                 │
│                  │ Gene: CDKN1B (p27 cyclin-dependent kinase inhibitor)│
│                  │ Parathyroid + Pituitary + PNET (like MEN1)         │
└──────────────────┴────────────────────────────────────────────────────┘

Genetics Summary:

• MEN1: MEN1 gene (11q13) - encodes menin (tumor suppressor) - "2-hit hypothesis" (Knudson)
• MEN2A/2B: RET proto-oncogene (10q11.2) - gain-of-function mutation
• MEN4: CDKN1B gene

Zollinger-Ellison Syndrome (in MEN1):

• Gastrinoma of pancreas/duodenum → hypergastrinemia → peptic ulcers
• Treated with PPIs + surgical resection

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6. THYROID TUMORS - CLASSIFICATION ★★

Classification of Thyroid Tumors (WHO)

THYROID TUMORS
│
├── A. BENIGN
│   └── Follicular Adenoma (most common benign thyroid tumor)
│       ├── Simple/Normofollicular adenoma
│       ├── Macrofollicular (colloid) adenoma
│       ├── Microfollicular (fetal) adenoma
│       ├── Embryonal (trabecular) adenoma
│       └── Hurthle cell (oxyphilic/oncocytic) adenoma
│
└── B. MALIGNANT (Thyroid Carcinomas)
    │
    ├── EPITHELIAL (from follicular cells)
    │   ├── Differentiated
    │   │   ├── Papillary Carcinoma (most common ~85%)
    │   │   └── Follicular Carcinoma (~10%)
    │   ├── Poorly Differentiated Carcinoma
    │   └── Undifferentiated/Anaplastic Carcinoma (~1-2%, worst prognosis)
    │
    ├── C-CELL ORIGIN
    │   └── Medullary Carcinoma (~5%) - secretes Calcitonin + Amyloid
    │
    └── OTHERS
        ├── Primary Thyroid Lymphoma (B-cell, associated with Hashimoto's)
        └── Metastatic (from breast, lung, renal cell carcinoma)

Papillary Carcinoma (Most Common)

• Genetics: BRAF V600E mutation (most common), RET/PTC rearrangement
• Gross: Irregular, white, firm, non-encapsulated; may be cystic; "ground glass" or stippled calcification (psammoma bodies)
• Histology:
  • Papillary architecture (finger-like projections with fibrovascular core)
  • Orphan Annie eye nuclei - ground-glass, "Optically clear" nuclei with nuclear grooves and inclusions (PATHOGNOMONIC)
  • Psammoma bodies (concentrically laminated calcifications) - in 40-50%
  • Lymphatic invasion and cervical lymph node metastasis (common)
• Prognosis: Excellent (>98% 10-year survival); spreads to lymph nodes but rarely blood

Follicular Carcinoma

• Genetics: RAS mutations, PAX8-PPARG fusion (translocation)
• Gross: Encapsulated with capsular and/or vascular invasion (differentiates from adenoma)
• Histology: Follicles of varying size; capsular invasion and/or vascular invasion required for diagnosis
• Spread: Hematogenous (to lung, bone, liver) - NOT lymphatic
• Hurthle cell carcinoma - variant with oxyphilic cells

Medullary Carcinoma (MTC)

• Origin: Parafollicular C cells (neuroendocrine)
• Genetics: RET mutation (sporadic and familial/MEN2)
• Gross: Solitary nodule (sporadic); Bilateral/multicentric (syndromic/MEN2)
• Histology:
  • Polygonal/spindle cells in nests and trabeculae
  • Amyloid stroma (derived from calcitonin polypeptides) - Congo red positive
  • Neurosecretory granules on EM
• Markers: Calcitonin (serum marker), CEA, Chromogranin A
• Prognosis: Intermediate (better than anaplastic, worse than papillary)

Anaplastic Carcinoma

• Most aggressive thyroid malignancy; rare but deadly
• Undifferentiated cells, spindle cells, giant cells
• No radioiodine uptake; no effective treatment
• Median survival: 3-6 months

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COLLOID GOITRE (Multinodular Goitre / Follicular Nodular Disease) ★★

Iodine deficiency / ↑TSH → Follicular hyperplasia
        ↓
Colloid accumulation when TSH falls → Involution
        ↓
Repeated cycles of hyperplasia and involution
        ↓
Nodule formation (some cells more responsive than others - polyclonal)
        ↓
Multinodular Goitre (Colloid Goitre)

1. Diffuse Non-toxic Goitre - uniform enlargement, often in endemic iodine-deficient areas (endemic goitre)
2. Multinodular Goitre (MNG) - multiple nodules; most common cause of thyroid enlargement in adults

• Markedly enlarged thyroid (can reach enormous size - >100g; normal ~25g)
• Multiple nodules of varying size
• Cut section: colloid-filled distended follicles (glistening, brown/tan)
• Areas of hemorrhage, fibrosis, cystic change, and calcification
• Nodules compressed by fibrous septae

• Markedly enlarged follicles distended with colloid ("colloid" goitre)
• Follicular epithelium: flattened (involuted) to hyperplastic (cuboidal/columnar)
• Areas of "resorption vacuoles" (Sanderson's polsters) - scalloped colloid at edges of follicles
• Fibrous septae separating nodules
• Focal hemorrhage, hemosiderin deposits, dystrophic calcification
• Papillary projections may mimic papillary carcinoma (but no nuclear features of malignancy)

• Usually euthyroid
• Pressure effects: dysphagia, stridor, dyspnea, Pemberton's sign
• Rarely: hyperthyroidism (toxic MNG = Plummer's disease)
• Risk of malignancy: low but present (particularly papillary carcinoma)

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7. HASHIMOTO'S THYROIDITIS ★★★

Introduction

• Most common cause of hypothyroidism in iodine-sufficient areas
• Autoimmune destruction of the thyroid gland
• Female:Male = 10:1 to 20:1
• Age: 45-65 years (most common), but also affects children
• Originally described by Hashimoto in 1912 as "struma lymphomatosa"

Pathogenesis

• Anti-thyroglobulin antibodies
• Anti-thyroid peroxidase (TPO) antibodies (microsomal antibodies) - most sensitive marker

1. CD8+ cytotoxic T cells → direct cell-mediated killing of thyrocytes
2. CD4+ Th1 cells → IFN-γ release → macrophage activation → thyroid damage
3. Anti-TPO and anti-thyroglobulin antibodies → complement-dependent 
   cytotoxicity + ADCC (antibody-dependent cell-mediated cytotoxicity)
4. Genetic susceptibility: CTLA-4, PTPN22, IL2RA polymorphisms

Gross Morphology

• Thyroid: diffusely enlarged (symmetric)
• Well demarcated from adjacent structures (no invasion - differentiates from Reidel's thyroiditis)
• Cut surface: pale, yellow-tan, firm, somewhat nodular

Microscopic / Histological Features ★★★

1. Diffuse lymphocytic infiltration - small lymphocytes, plasma cells
2. Lymphoid follicles with well-developed germinal centers (hallmark)
3. Atrophic thyroid follicles - small, reduced colloid
4. Hurthle cell (oncocytic/oxyphilic) metaplasia - follicular epithelium replaced by cells with abundant eosinophilic granular cytoplasm (mitochondria-rich) - represents metaplastic response to chronic injury
5. Interstitial fibrosis - increased connective tissue (does NOT extend beyond gland capsule - unlike Reidel's)

• Hurthle cells + heterogeneous population of lymphocytes = characteristic of Hashimoto's

Clinical Features

• Painless enlargement of thyroid (may be asymmetric initially)
• Gradual development of hypothyroidism (T3, T4 ↓; TSH ↑ compensatory)
• "Hashitoxicosis" - transient thyrotoxicosis initially (due to follicle disruption and hormone release)
• Lab: Anti-TPO antibodies (positive in >95%); Anti-thyroglobulin antibodies

Complications ★★

┌─────────────────────────────────────────────────────────┐
│            COMPLICATIONS OF HASHIMOTO'S                  │
│                                                          │
│  1. HYPOTHYROIDISM (most common outcome)                 │
│  2. Increased risk of PRIMARY THYROID LYMPHOMA           │
│     (Extranodal marginal zone B-cell lymphoma - MALT)   │
│  3. Other autoimmune diseases:                           │
│     - Endocrine: Type 1 DM, Autoimmune adrenalitis      │
│     - Non-endocrine: SLE, Myasthenia gravis, Sjögren's  │
│  4. Possible increased risk of PAPILLARY CARCINOMA       │
│     (controversial but some evidence supports this)     │
│  5. Hashitoxicosis (transient, early)                   │
└─────────────────────────────────────────────────────────┘

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QUICK REVISION DIAGRAM SUMMARIES

DM Complications (for context with nephropathy)

DIABETES MELLITUS
       │
   Chronic Hyperglycemia
       │
   ┌───┴────────────────────────────────────────┐
   │                                            │
Microvascular                            Macrovascular
(small vessel disease)                   (large vessel disease)
   │                                            │
   ├── Diabetic Nephropathy                     ├── Coronary artery disease
   │   (Kimmelstiel-Wilson lesions)             ├── Peripheral arterial disease
   ├── Diabetic Retinopathy                     └── Cerebrovascular disease
   │   (dot-blot hemorrhages, microaneurysms)
   └── Diabetic Neuropathy
       (Peripheral > Autonomic)

MEN Syndromes Quick Diagram

MEN1 (Wermer's)          MEN2A (Sipple's)         MEN2B
MEN1 gene (11q13)        RET gene (10q11)          RET gene (codon 918)
Menin protein            Proto-oncogene            Proto-oncogene
(Tumor suppressor)       (Gain of function)        (Gain of function)
        │                        │                        │
  Parathyroid (100%)      Medullary Thyroid Ca     Medullary Thyroid Ca
  Pancreatic NETs         Pheochromocytoma         Pheochromocytoma
  Pituitary adenoma       Hyperparathyroidism      Mucosal Neuromas
  (Gastrinoma=ZES)                                 Marfanoid habitus
  (Insulinoma)                                     No PHPT

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EXAM HIGH-YIELD POINTS (MUHS Focus)

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Histopathology & Gross Diagrams - MUHS Pathology Notes

(Additions to previous notes - All images from Robbins Pathology)

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COLLOID GOITRE (Multinodular / Follicular Nodular Disease) - Gross & Histo

Gross Morphology

• (A) GROSS: Cut surface shows tan, glistening, gelatinous (colloid-rich) nodules of varying sizes. Note areas of dark hemorrhage and brown/orange coloration due to hemosiderin.
• (B) HISTO: Markedly enlarged follicles filled with abundant pale pink colloid. Follicular lining epithelium is flattened and inactive (low cuboidal). Large follicles with scalloped edges (resorption vacuoles - Sanderson's polsters) are visible.

- Follicles greatly distended with colloid (pale pink, PAS+)
- Lining epithelium: FLAT / LOW CUBOIDAL (inactive)
- Scalloped/vacuolated colloid margins (resorption vacuoles)
- Fibrous septae separating nodules
- No capsule between nodules (unlike follicular adenoma)
- Areas of old hemorrhage, hemosiderin, calcification

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HASHIMOTO'S THYROIDITIS - Gross & Histo

Pathogenesis Diagram

Histology

LEFT SIDE of image:
- Residual thyroid follicles (atrophic, small)
- Hurthle cells (oncocytes): follicular epithelium replaced by 
  cells with abundant BRIGHT PINK GRANULAR cytoplasm 
  (due to mitochondrial accumulation - metaplastic response)
- Colloid: reduced or absent

RIGHT SIDE of image:
- Dense LYMPHOCYTIC INFILTRATE replacing parenchyma
- GERMINAL CENTERS (secondary lymphoid follicles) - 
  HALLMARK of Hashimoto's, distinguishes from normal
- Plasma cells
- Increased interstitial fibrosis (pale areas between follicles)

1. Dense lymphocytic infiltration with germinal center formation
2. Hurthle cell (oxyphilic/oncocytic) metaplasia of follicular epithelium
3. Atrophic follicles + interstitial fibrosis

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PAPILLARY CARCINOMA OF THYROID - Gross & Histo ★★★

1. PAPILLAE: Branching finger-like projections with fibrovascular stalks
2. ORPHAN ANNIE EYE NUCLEI: Ground-glass, optically clear, pale nuclei
3. NUCLEAR GROOVES: "Coffee bean" shaped nuclei
4. INTRANUCLEAR PSEUDOINCLUSIONS: cytoplasm pushed into nucleus
5. PSAMMOMA BODIES: Concentric laminated calcifications (40-50% cases)
6. LYMPHATIC INVASION (not blood vessel invasion)

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FOLLICULAR CARCINOMA - Gross & Histo

Gross

• Large, light-tan/grey mass substantially replacing the thyroid lobe
• Small foci of hemorrhage visible
• Sharply demarcated but WITHOUT a well-formed capsule (unlike adenoma)
• Note: Gross appearance alone CANNOT reliably distinguish follicular adenoma from carcinoma

Histology - Capsular Invasion (Key Diagnostic Feature)

(A) FOLLICULAR ADENOMA:
    - Complete, intact fibrous capsule (circumferential)
    - No capsular breach
    - Compressed normal thyroid outside capsule
    - Follicular cells uniform; colloid-filled follicles

(B) FOLLICULAR CARCINOMA:
    - CAPSULAR INVASION - tumor mushrooming through capsule
    - And/or VASCULAR INVASION (tumor in venous vessels)
    - These two features = DIAGNOSTIC of malignancy
    - FNAC CANNOT distinguish adenoma from carcinoma
      (requires histology of capsule)

Capsular invasion + Vascular invasion = Follicular CARCINOMA Absence of both = Follicular ADENOMA (regardless of nuclear atypia)

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MEDULLARY CARCINOMA - Gross & Histo

Gross

• Firm, pale grey-tan to cream-colored SOLITARY nodule (in sporadic)
• Bilateral and multicentric in MEN2 syndrome
• Infiltrative, no true capsule
• May contain areas of necrosis/hemorrhage in large lesions

Histology (Amyloid stroma)

Key histological features:
1. POLYGONAL to SPINDLE-SHAPED cells
2. Arranged in NESTS, TRABECULAE (neuroendocrine pattern)
3. Round nuclei with STIPPLED/SALT-AND-PEPPER CHROMATIN
   (typical of all neuroendocrine tumors)
4. AMYLOID STROMA (pink, acellular, intercellular material)
   - Derived from calcitonin polypeptides
   - Congo red POSITIVE (apple-green birefringence under polarized light)
5. C-cell hyperplasia in surrounding parenchyma (in MEN2 cases)

EM of Medullary Carcinoma

• Dense, membrane-bound neurosecretory granules (dark oval bodies)
• Granules are the storage sites of calcitonin and other peptides
• Confirms neuroendocrine (parafollicular C cell) origin

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DIABETIC NEPHROPATHY - Pathophysiology Diagram

NORMAL:              Balanced afferent/efferent tone
                     ↓
DIABETES:            Dilated AFFERENT + Constricted EFFERENT (Ang II)
                     → Glomerular HYPERTENSION (↑ intraglomerular pressure)
                     → Protein leaks across GBM
                     → Proteins endocytosed by proximal tubular cells
                     → Inflammation → Interstitial fibrosis
                     ↓
ACE-I / ARBs:        Dilate efferent arteriole
                     → ↓ Intraglomerular pressure → ↓ Proteinuria
                     → Slow progression of nephropathy

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SUMMARY TABLE - Gross & Histo Features for Exam

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