Rickets and Osteomalacia 

Rickets in growing children and osteomalacia in adults are skeletal diseases with worldwide distribution. They may result from
1. Diets deficient in calcium and vitamin D
2. Limited exposure to sunlight (in heavily veiled women, and inhabitants of northern climates with scant sunlight)
3. Renal disorders causing decreased synthesis of 1,25 (OH)2-D or phosphate depletion 
4. Malabsorption disorders.

Although rickets and osteomalacia rarely occur outside high-risk groups, milder forms of vitamin D deficiency (also called vitamin D insufficiency) leading to bone loss and hip fractures are quite common in the elderly.

Whatever the basis, a deficiency of vitamin D tends to cause hypocalcemia. When hypocalcemia occurs, PTH production is increased, that ultimately leads to restoration of the serum level of calcium to near normal levels (through mobilization of Ca from bone & decrease in its tubular reabsorption) with persistent hypophosphatemia (through increase renal exretion of phosphate); so mineralization of bone is impaired or there is high bone turnover.

The basic derangement in both rickets and osteomalacia is an excess of unmineralized matrix. This complicated in rickets by derangement of endochondral bone growth.

The following sequence ensues in rickets:
1. Overgrowth of epiphyseal cartilage with distorted, irregular masses of cartilage
2. Deposition of osteoid matrix on inadequately mineralized cartilage
3. Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement and lateral expansion of the osteochondral junction
4. Microfractures and stresses of the inadequately mineralized, weak, poorly formed bone
5. Deformation of the skeleton due to the loss of structural rigidity of the developing bones 

Gross features
• The gross skeletal changes depend on the severity of the disease; its duration, & the stresses to which individual bones are subjected.
• During the nonambulatory stage of infancy, the head and chest sustain the greatest stresses. The softened occipital bones may become flattened. An excess of osteoid produces frontal bossing. Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing the "rachitic rosary." The weakened metaphyseal areas of the ribs are subject to the pull of the respiratory muscles and thus bend inward, creating anterior protrusion of the sternum (pigeon breast deformity). The pelvis may become deformed.
• When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and long bones (e.g., tibia), causing, most notably, lumbar lordosis and bowing of the legs .
• In adults the lack of vitamin D deranges the normal bone remodeling that occurs throughout life. The newly formed osteoid matrix laid down by osteoblasts is inadequately mineralized, thus producing the excess of persistent osteoid that is characteristic of osteomalacia. Although the contours of the bone are not affected, the bone is weak and vulnerable to gross fractures or microfractures, which are most likely to affect vertebral bodies and femoral necks.

Microscopic features

• The unmineralized osteoid can be visualized as a thickened layer of matrix (which stains pink in hematoxylin and eosin preparations) arranged about the more basophilic, normally mineralized trabeculae.

Myocardial infarction (MI)—heart attack

A. Ischemia versus MI: Ischemia is a reversible mismatch between the supply and demand of oxygen. Infarction
is an irreversible mismatch that results in cell death caused by the lack of blood flow (oxygenation). For instance, chest pain caused by ischemia can be relieved by administering nitroglycerin (a vasodilator) to the patient. If the patient has an MI, the pain will not be relieved with nitroglycerin.

1. MIs most commonly occur when a coronary artery is occluded by a thrombus generated in an atherosclerotic artery.

2. Symptoms include:
a. Chest pain, shortness of breath.
b. Diaphoresis (sweating), clammy hands.
c. Nausea, vomiting.

3. Consequences:
a. Death (one third of patients).
b. Arrhythmias (most common immediate cause of death).
c. Congestive heart failure.
d. Myocardial rupture, which may result in death from cardiac tamponade.
e. Thrombus formation on infarcted tissue; may result in systemic embolism.
 

Tuberculosis

Causative organism

-Mycobacterium tuberculosis 
-Strict aerobe 
-Pathogenic strains
-hominis, bovis, avium, murine& cold blooded vertebrate strain 

Koch’s bacillus
-small slender, rod like bacillus, 4umnon-motile, aerobic -high lipid content 
-divides every 16 to 20 hours, an extremely slow rate 
-stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolicacid content of its cell wall 
-can withstand weak disinfectant and survive in a dry state for weeks. 

Demonstrated by 
-ZiehlNeelsenstaining 
-Fluorescent dye method 
-Culture in LJ media 
-Guinea pig inoculation

Modes of transmission

Inhalation , Ingestion, Inoculation , Transplacental

Route Spread 
Local , Lymphatic , Haematogenous , By natural passages, 

Pathogenesis 

- Anti‐mycobacterial CMI, confers resistance to bacteria → dev. of HS to tubercular Ag 
- Bacilli enters macrophages 
- Replicates in phagosomeby blocking fusion of phagosome&  lysosome, continues for 3 weeks →bacteremiabut  asymptomatic 
- After 3 wks, T helper response is mounted by  IL‐12 produced  by macrophages 
- T cells produce IFN, activates macrophages → bactericidal  activity, structural changes 
- Macrophages secrete TNF→ macrophage recruitment,  granuloma& necrosis

Fate of granuloma 
- Caseousmaterial undergo liquefaction---cold abscess 
- Bones, joints, lymph nodes & epididymis---sinuses are formed & sinus tract lined by tuberculousgranulation tissue 
- Dystrophic calcification

Types of TB

1. Primary Pulmonary TB 
2. secondary TB (miliary, fibrocaseous, cavitary) 
3. Extra-pulmonary TB (bone, joints, renal, adrenal, skin… )

Primary TB
Infection in an individual who has not been previously infected or immunised 
Primary complex 
Sites
    -lungs, hilarlymph nodes 
    -tonsils, cervical lymph nodes 
    -small intestine, mesenteric lymph nodes

Primary TB
In the lung, Ghon’scomplex has 3 components: 
1. Pulmonary component -Inhalation of airborne droplet ~ 3 microns. 
    -Bacilli locate in the subpleuralmid zone of lung 
    -Brief acute inflammation –neutrophils. 
    -5-6 days-invoke granulomaformation. 
    -2 to 8 weeks –healing –single round ;1-1.5 cm-Ghon focus. 
2. Lymphatic vessel component 
3. Lymph node component

Fate of primary tuberculosis

- Lesions heal by fibrosis, may undergo calcification, ossification 
    -a few viable bacilli may remain in these areas  
    -bacteria goes into a dormant state, as long as the person's immune system remains active 
- Progressive primary tuberculosis: primary focus continues to grow & caseousmaterial disseminated to other parts of lung 
- Primary miliarytuberculosis: bacilli may enter circulation through erosion of blood vessel 
- Progressive secondary tuberculosis: healed lesions are reactivated, in children & in lower resistance

Secondary tuberculosis

-Post-primary/ reinfection/ chronic TB 
-Occurs in immunized individuals. 
-Infection acquired from 

    -endogenous source/ reactivation 
    -exogenous source/ reinfection 

Reactivation
-when immune system is depressed 
-Common in low prevalence areas. 
-Occurs in 10-15% of patients 
-Slowly progressive (several months) 

Re-infection 
-when large innoculum of bacteria occurs 
-In areas with increased personal contact

Secondary TB

-Sites-Lungs 1-2 cm apical consolidation with caseation 
-Other sites -tonsils, pharynx, larynx, small intestine & skin

Fate of secondary tuberculosis

•Heal with fibrous scarring & calcification 
•Progressive secondary pulmonary tuberculosis: 
    -fibrocaseoustuberculosis 
    -tuberculouscaseouspneumonia 
    -miliarytuberculosis

Complications: 
a) aneurysm of arteries–hemoptysis 
b) bronchopleuralfistula 
c) tuberculousempyema 

MiliaryTB

• Millet like, yellowish, firm areas without caseation 
• Extensive spread through lympho-hematogenousroute 
• Low immunity 
• Pulmonary involvement via pulmonary artery 
• Systemic through pulmonary vein: 
    -LN: scrofula, most common 
    -kidney, spleen, adrenal, brain, bone marrow

Signs and Symptoms of Active TB

• Pulmonary-cough, hemoptysis, dyspnea 
• Systemic: 
• fever 
• night sweats 
• loss of appetite 
• weight loss 
• chest pain,fatigue 

•If symptoms persist for at least 2 weeks, evaluate for possible TB infection

Diagnosis

•Sputum-Ziehl Neelsen stain –10,000 bacilli, 60% sensitivity 
    -release of acid-fast bacilli from cavities intermittent. 
    -3 negative smears : low infectivity 

•Culture most sensitive and specific test.
     -Conventional Lowenstein Jensen media-10 wks. 
     -Liquid culture: 2 weeks 

•Automated techniques within days 
    should only be performed by experienced laboratories (10 bacilli) 

•PPD for clinical activity / exposure sometime in life 
•X-ray chest 
•FNAC

PPD Tuberculin Testing

- Read after 72 hours. 
- Indurationsize -5-10 mm 
- Does not d/s b/w active and latent infection 
- False +: atypical mycobacterium 
- False -: malnutrition, HD, viral, overwhelming infection, immunosuppression 
- BCG gives + result.

Tuberculosis Atypical mycobacteria 

- Photochromogens---M.kansasii 
- Scotochromogens---M.scrofulaceum 
- Non-chromogens---M.avium-intracellulare 
- Rapid growers---M.fortuitum, M.chelonei

5 patterns of disease 

- Pulmonary—M.kansasii, M.avium-intracellulare 
- Lymphadenitis----M.avium-intracellulare, M.scrofulaceum 
- Ulcerated skin lesions----M.ulcerans, M.marinum 
- Abscess----M.fortuitum, M.chelonei 
- Bacteraemias----M.avium-intracellulare as in AIDS

Blastomycosis (North American Blastomycosis; Gilchrist's Disease)

A disease caused by inhalation of mold conidia (spores) of Blastomyces dermatitidis, which convert to yeasts and invade the lungs, occasionally spreading hematogenously to the skin or focal sites in other tissues.

Pulmonary blastomycosis tends to occur as individual cases of progressive infection

Symptoms are nonspecific and may include a productive or dry hacking cough, chest pain, dyspnea, fever, chills, and drenching sweats. Pleural effusion occurs occasionally. Some patients have rapidly progressive infections, and adult respiratory distress syndrome may develop.