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Endocrine Complications (Implications) of Tuberculosis

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Overview

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1. Hypothalamo-Pituitary TB

Epidemiology

• TB accounts for 20% of intracranial space-occupying lesions in India
• Sellar/suprasellar tuberculomas = 1% of all intracranial tuberculomas
• Western countries: sellar tuberculomas in 0.25–4% of cases
• Female predominance (F:M = 2:1), mostly <45 years

Pathogenesis

• Can be a localised sellar/suprasellar lesion or part of widespread CNS disease
• Route of spread: haematogenous or direct spread from paranasal sinus
• Intra-sellar tuberculomas may present as pituitary apoplexy

Clinical Presentation

Diagnosis

• MRI: Pituitary tuberculomas are isointense on T1, exhibit intense post-contrast enhancement; stalk thickening (though non-specific — also seen in sarcoidosis, lymphocytic hypophysitis, neoplasms, syphilis)
• Features on MRI: peripheral ring enhancement, basal enhancing exudates, isolated stalk thickening, sellar/suprasellar calcification, apoplexy, erosion of sellar floor
• Definitive diagnosis: Transsphenoidal surgery + histopathology (caseating granuloma with epithelioid cells, Langhans giant cells, AFB identification)
• Molecular testing (CSF PCR) can help

Treatment

• Standard anti-TB treatment (as for other EPTB forms) — good response
• Some patients require lifelong hormone replacement therapy

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2. TB and Altered Water & Electrolyte Metabolism (SIADH)

Mechanism

• SIADH (Schwartz et al, 1957): Incomplete suppression of peripheral arginine vasopressin (AVP) despite subnormal plasma osmolarity and no volume depletion
• Postulated mechanisms:
  1. Increased adsorption of AVP in lung tissue
  2. Disturbed/down-set osmoregulatory mechanisms in active TB
  3. Inflammatory cytokines (TNF, IL-1) acting on posterior pituitary → ↑ AVP secretion

Associations

• Pulmonary TB — unexplained hyponatraemia
• TB meningitis (most common EPTB cause), miliary TB, TB epididymo-orchitis

Clinical Features

• Usually mild, asymptomatic, and self-limiting
• Lab: hyponatraemia + elevated urine sodium + elevated urine osmolarity

Management

• Water restriction for serum Na <125 mEq/L
• SIADH in TB meningitis = poor prognosis — prompt recognition mandatory

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3. Adrenal TB (Addison's Disease)

Epidemiology & Context

• Thomas Addison described chronic adrenocortical insufficiency in 1855
• TB is the most common cause of primary hypoadrenalism in developing countries
• 92% of Caucasians: autoimmune cause; TB causes 63% in Polynesians
• Up to 6% of active pulmonary TB patients have adrenal involvement
• Adrenal glands are a "good nidus" for mycobacteria: rich vascularity + high local corticosteroids suppress CMI

Pathogenesis

• Immune-mediated adrenal damage
• ↑ Cortisol secretion (activation of HPA axis) → shifts Th1/Th2 balance toward Th2 → T-cell dysfunction
• Rifampicin (potent hepatic microsomal enzyme inducer) reduces cortisol half-life → can unmask subclinical adrenal insufficiency → Addisonian crisis
• Overt insufficiency when >80–90% of both adrenal glands are destroyed

Clinical Presentation

⚠️ If these symptoms appear after starting anti-TB therapy, suspect hypocortisolism.

Investigations

• Paired 8 AM cortisol + ACTH (differentiates primary vs secondary)
• ACTH stimulation test: 250 µg cosyntropin IM → serum cortisol at 0, 30, 60 min (gold standard)
• Basal cortisol: normal or elevated in active TB (hyperfunctioning in response to stress); inversely proportional to duration of symptoms
• Direct correlation between: AFB smear positivity, extent of disease, pyrexia, ESR and adrenal reserve

Adrenal Imaging

Key Studies (Indian Data — Table 34.2)

• Zargar et al (2001): 35% sub-optimal cortisol reserve; radiological severity inversely related to adrenal reserve
• Sharma et al (2005): 49.5% had compromised adrenal reserve at baseline; reversed in majority — 71% at 6 months, 97% at 24 months of anti-TB treatment

Treatment

• Patients on corticosteroids: increase dose before starting anti-TB therapy (especially rifampicin)
• Reversal of adrenal function with anti-TB therapy possible (can occur as early as 2 weeks)
• Adrenal insufficiency compromised in ~50% of HIV co-infected patients with TB too

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4. Thyroid TB

Epidemiology

• Extremely rare — first case: Lebret, 1862; primary thyroid TB: Burns, 1893
• Prevalence: ~0.2% in chronic thyroiditis specimens; up to 14% in miliary TB
• F:M = 2:1 (female preponderance)
• Prevalence by FNAC (Das et al): 0.6% of 1283 thyroid lesions
• Reasons for rarity: rich blood flow, lymphatic drainage pattern, excess stored iodine (anti-mycobacterial), stored thyroid hormone's possible anti-tubercular nature, protective fibrous capsule

Clinical Presentation

• Usually presents as painless thyromegaly ± lymphadenopathy
• May present on pre-existing multinodular goitre, solitary nodule, or abscess
• Hyperthyroidism (from thyroiditis) and hypothyroidism (from total glandular destruction) both reported

Diagnosis

• Most diagnoses are retrospective (histopathological)
• FNAC — cost-effective first-line; if AFB negative → molecular methods
• Association with papillary carcinoma thyroid reported

Effect of Anti-TB Drugs on Thyroid

• PAS and ethionamide → goitre (resolves on discontinuation)
• Anti-TB treatment → ↑ thyroid binding globulin levels

Sick Euthyroid Syndrome in TB

• Pattern: Low/normal T4, low T3, ↑ reverse T3, normal TSH
• Prevalence in TB patients: 63% (Chow et al)
• Low serum T3 predicts higher mortality

Treatment

• Full course standard anti-TB treatment (as other EPTB)
• Surgery (lobectomy/partial thyroidectomy) if FNAC inconclusive or abscess drainage needed
• Lifelong thyroid replacement therapy if widespread glandular destruction

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5. Diabetes Mellitus and TB

Epidemiology

• Risk of TB in DM: 4.8% vs 0.8% in general population
• Relative risk of pulmonary TB: 3.5× higher in DM; in type 1 DM <40 years: 24%
• India TB-DM Study: of 7218 DM patients screened, 254 (3.5%) had TB; 46% were sputum smear-positive
• DM patients requiring >40 units insulin/day are 2× more likely to develop TB
• MDR-TB more common in DM (36% vs 10%)

Pathogenesis

• Hyperglycaemia + cellular insulinopenia → ↑ susceptibility to Mtb
• Impaired: macrophage/lymphocyte function, chemotaxis, phagocytosis, antigen presentation
• ↓ IFN-α production, T-cell growth/proliferation
• ↓ IL-1β and TNF-β (poor glycaemic control)
• Thickened alveolar epithelium, altered diffusion capacity, reduced elastic recoil
• Non-enzymatic glycosylation of tissue proteins
• Autonomic neuropathy → reduced bronchial activity → dilated bronchus → ↑ susceptibility
• Genetic: *DRB[1]09 allele increases TB susceptibility; *DQB[1]05 is protective

Radiological Features (important exam point)

• DM-TB: Lower lung field involvement (vs upper lobe in non-DM TB)
  • Can mimic community-acquired pneumonia or malignancy → delayed diagnosis
• Multilobar disease with multiple cavities more common
• Elderly DM patients particularly susceptible to lower lobe disease

Drug Interactions (DM + anti-TB)

TB and Glucose Metabolism

• TB itself causes impaired glucose tolerance (IGT)
• India TB-DM Study Group (n=8269): 13% of TB patients had DM (8% known + 5% newly detected)
• Higher prevalence in south India vs north India (20% vs 10%)
• Persistent hyperglycaemia in TB may be due to transient changes in carbohydrate metabolism — improves with anti-TB therapy

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6. Pancreatic TB

Epidemiology

• Very rare despite common abdominal TB
• Miliary TB autopsy (1944): only 14/297 miliary cases had pancreatic involvement
• Pancreatic enzymes may interfere with Mtb seeding (biologically protected)

Pathogenesis

• Most common site: head of pancreas (rich vasculature + lymphatics)
• Route: haematogenous spread (primary); rarely from TB duodenum via reflux/lymphatics

Clinical Presentation

• Obstructive jaundice (mimics pancreatic cancer)
• GI bleeding, acute/chronic pancreatitis, pancreatic abscess
• Portal venous thrombosis → portal hypertension
• Colonic perforation
• Miliary involvement may be initially asymptomatic

Diagnosis

• Non-specific: ↑ CA-125, obstructive LFTs
• USG: hypoechoic lesion with cystic component in pancreatic head
• CT: sharply delineated mass with irregular margins, diffuse enlargement, or peripancreatic lymphadenopathy
• MRI: hypointense on fat-suppressed T1-WI, hypo/hyperintense on T2-WI
• Definitive: EUS/CT-guided biopsy → caseating granulomas, AFB, or positive molecular test
• If inconclusive: laparotomy + frozen section

Treatment

• Standard anti-TB treatment 6–9 months — excellent prognosis, radiological regression on follow-up
• If no improvement: pancreatic excision

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7. Vitamin D and TB

• Pre-antibiotic era: Vitamin D (cod liver oil) used as TB therapy
• TLR2/1 sensing of Mtb → ↑ VDR expression + CYP27B1 in monocytes → Vitamin D₃ → ↑ cathelicidin → kills intracellular Mtb; also promotes phagolysosome formation
• Vitamin D deficiency is pandemic in India → linked to pulmonary TB development
• Higher 25(OH)D₃ = less extensive radiological lesions
• MDR-TB had the lowest 25(OH)D₃ levels; lower levels → longer time to sputum smear negativity
• VDR polymorphisms (FokI, BsmI, TaqI) associated with MDR-TB susceptibility
• Rifampicin and isoniazid both reduce 25(OH)D₃ levels (worsen vitamin D deficiency)

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8. TB and Hypercalcaemia

Frequency

• ~50% of adult TB patients manifest hypercalcaemia
• Shek et al: 6th most common cause and 2nd most common cause after malignancy in Hong Kong

Mechanism (Key Pathogenesis)

• Abnormal Vitamin D metabolism is the primary factor:
  • Granulomatous tissue produces 1α-hydroxylase → converts 25(OH)D₃ to 1,25(OH)₂D₃ (calcitriol)
  • This is not suppressed by the normal negative feedback loop (PTH suppressed, phosphorus normal to high)
  • Regulation of 1α-hydroxylase in granulomatous tissue is driven by lymphokines (similar to sarcoidosis)
  • CD4+ T-lymphocytes from BAL in active TB express 1,25(OH)₂D₃
  • Alveolar macrophages and lymphocytes produce 1,25(OH)₂D₃ in vitro
  • Lung is an extra-renal site of 1,25(OH)₂D₃ synthesis
  • High 1,25(OH)₂D₃ → ↑ intestinal calcium absorption → hypercalcaemia
• Hypercalcaemia may be masked by low serum albumin (measure ionised calcium)

Drug Effects on Calcium Metabolism

• Rifampicin and isoniazid reduce 25(OH)D₃ levels → adversely affect calcium/phosphate metabolism
• Worsened further in vitamin D-deficient populations

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9. Reproductive Endocrine System TB

• Female genital TB → see Chapter 26 (menstrual irregularities, infertility, amenorrhoea)
• Genitourinary TB (male) → see Chapter 27 (epididymo-orchitis, infertility, SIADH)

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Summary Table: Endocrine Complications of TB

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Exam Pearl: Rifampicin is the key culprit in multiple endocrine complications — it induces CYP450 → reduces corticosteroid, vitamin D, and sulphonylurea levels; it can precipitate Addisonian crisis and worsen glycaemic control in type 2 DM patients on sulphonylureas.