SPIROCHETAL DISEASE

Syphilis

A contagious systemic disease caused by the spirochete Treponema pallidum, characterized by sequential clinical stages and by years of latency.

ACQUIRED SYPHILIS

T. pallidum is a delicate spiral organism about 0.25 µm wide and from 5 to 20 µm long, identified by characteristic morphology and motility with a darkfield microscope or fluorescent techniques

In acquired syphilis, T. pallidum enters through the mucous membranes or skin, reaches the regional lymph nodes within hours, and rapidly disseminates throughout the body. In all stages of disease, perivascular infiltration of lymphocytes, plasma cells, and, later, fibroblasts causes swelling and proliferation of the endothelium of the smaller blood vessels, leading to endarteritis obliterans.

In late syphilis, T. pallidum elicits a granulomatous-like (gummatous) reaction causing masses, ulcerations, and necrosis. Inflammation may subside despite progressive damage, especially in the cardiovascular and central nervous systems.

The CNS is invaded early in the infection. During the secondary stage of the disease, > 30% of patients have abnormal CSF and may have symptoms of meningitis

Symptoms, Signs, and Course

The incubation period of primary syphilis can vary from 1 to 13 wk but is usually from 3 to 4 wk. The disease may present at any stage and long after the initial infection

Primary stage: The primary lesion, or chancre generally evolves and heals within 4 to 8 wk in untreated patients. After inoculation, a red papule quickly erodes to form a painless ulcer with an indurated base that, when abraded, exudes a clear serum containing numerous spirochetes

The regional lymph nodes usually enlarge painlessly and are firm, discrete, and nontender. Chancres occur on the penis, anus, and rectum in men and on the vulva, cervix, and perineum in women. Chancres may also occur on the lips or the oropharyngeal or anogenital mucous membranes.

Secondary stage: Cutaneous rashes usually appear within 6 to 12 wk after infection and are most florid after 3 to 4 mo.

Frequently, generalized, nontender, firm, discrete lymphadenopathy and hepatosplenomegaly are palpable. Over 80% of patients have mucocutaneous lesions, 50% have generalized lymphadenopathy, and about 10% have lesions of the eyes (uveitis), bones (periostitis), joints, meninges, kidneys (glomerulitis), liver, and spleen.

Acute syphilitic meningitis may develop, with headache, neck stiffness, cranial nerve lesions, deafness, and, occasionally, papilledema.

Condyloma lata--hypertrophic, flattened, dull pink or gray papules at the mucocutaneous junctions and in moist areas of the skin--are extremely infectious. Hair often falls out in patches, leaving a moth-eaten appearance (alopecia areata).

Latent stage

In the early latent period (< 2 yr after infection), infectious mucocutaneous relapses may occur, but after 2 yr contagious lesions rarely develop, and the patient appears normal. About 1/3 of untreated persons develop late syphilis

Late or tertiary stage: Lesions may be clinically described as (1) benign tertiary syphilis of the skin, bone, and viscera, (2) cardiovascular syphilis, or (3) neurosyphilis.

The typical lesion is a gumma, an inflammatory mass that evolves to necrosis and fibrosis and that is frequently localized but may diffusely infiltrate an organ or tissue

Benign tertiary syphilis of the bones results in either periostitis with bone formation or osteitis with destructive lesions causing a deep, boring pain, characteristically worse at night. A lump or swelling may be palpable.

Cardiovascular syphilis: A dilated, usually fusiform aneurysm of the ascending or transverse aorta, narrowing of the coronary ostia, or aortic valvular insufficiency usually appears 10 to 25 yr after the initial infection

Neurosyphilis

In meningovascular neurosyphilis, brain involvement is signaled by headache, dizziness, poor concentration, lassitude, insomnia, neck stiffness, and blurred vision. Mental confusion, epileptiform attacks, papilledema, aphasia, and mono- or hemiplegia may also occur

Diagnosis:

Two classes of serologic tests for syphilis (STS) aid in diagnosing syphilis and other related treponemal diseases: screening, nontreponemal tests using lipoid antigens detect syphilitic reagin and include the Venereal Disease Research Laboratory (VDRL) and the rapid plasma reagin (RPR) tests. Specific treponemal tests detect antitreponemal antibodies and include fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T. pallidum (MHA-TP), and Treponema pallidum hemagglutination assay (TPHA).

In darkfield microscopy, light is directed obliquely through the slide so that rays striking the spirochetes cause them to appear as bright, motile, narrow coils against a dark background

Iron deficiency anaemia.

Absorption of iron is affected by :
- Iron stores.
- Rate of erythropoiesis
- Acid pH aids absorption.
- Phosphates and phytates in diet impair absorption.

Causes  of deficiency:

- Increased demand:
o    Growth (in children)
o    Menstruation, Pregnancy, lactation.
- Inadequate intake and absorption.
o    Dietary deficiency.
o    Achlorhydria or gastrectomy.
o    Malabsorption states.

- Chronic blood loss
o    Peptic ulcer, bleeding piles
o    Menorrhagia.
o    Hook worm infestation

Features:
- Anaemia.
- Koilonychia.
- Atrophic glossitis and angular stomatitis.
- Dysphagia-Plummer Vinson syndrome.

Blood findings:

- Microcytjc_hypochromic cells, ring cells and pessary cells.
- Anisocytosis and poikilocytosis.
- Low MCV. MCH and MCHC.
- Serum iron is low but iron binding capacity is increased

Bone marrow

Erythroid hyperplasia with imcronormoblasts. Iron stains reveal depleted stores

Differential  diagnosis .-

- Sideroblastic anaemia which is also microcytic hypochromic  but there is excess iron in the erythroid cells .Some are pyridoxine responsive.
- (ii) Thalassaemia
 

Sickle Cell Disease

Sickle cell anemia is a autosomal recessive genetic disorder. It affects the BETA GLOBIN gene on the CHROMOSOME 16. In sickle cell anemia, the hemoglobin abnormality consists of a point mutation in the beta chain gene for hemoglobin; the resulting abnormal gene product is denoted HbS. If you are heterozygous for the HbS gene you will have what is called sickle trait, which is asymptomatic .

 If you are homozygous for the HbS gene  you will get sickle cell disease, which is symptomatic in most patients.
 The problem with HbS is that as it releases oxygen, it polymerizes and aggregates with other HbS molecules, making the red cell stiff and distorted. These distorted, sickle-shaped red cells are fragile so the patient can end up with a hemolytic anemia.
This can occur as pure disease (homozygous) or trait (heterozygous) or with other haemoglobinopathies. It is common. in Negroes. It is due to Hb-s  which is much less soluble than Hb-A  hence deoxygenation insoluble form  sickling of RBC.

This causes:
•    Removal by RE system. 
•    Blockage of microvessels causing  ischaemia.
 

Hyperpituitarism 

Causes  
A. Pituitary; usually anterior lobe

1. Adenoma (the most common cause)
2. Hyperplasia  
3. Carcinoma  

B. Extra-pituitary causes 
1. Hormone producing extra-pituitary tumors (ectopic hormone production)
2. Certain hypothalamic disorders 

Pituitary adenomas are classified according to the hormone(s) produced by the neoplastic cells; these are detected by immunohistochemically-stained tissue sections. Pituitary adenomas can be functional (associated with hormone excess with their related clinical manifestations) or silent. 

Pathogenesis
Guanine nucleotide-binding protein (G-protein) mutations are the best characterized molecular abnormalities. Such mutations eventuate in a persistent increase in intracellular cAMP, which is a potent mitogenic stimulus promoting cellular proliferation and hormone synthesis and secretion. In the setting of MEN-1 syndrome there are mutations in the MEN-1 (menin) gene. 

Gross features

• Adenomas are usually soft & well-circumscribed   
• Larger lesions extend superiorly through the sellar diaphragm compressing the optic chiasm and adjacent structures .  
• Invasive adenomas refer to nonencapsulated tumors that infiltrate adjacent bone, dura, and even brain.

Microscopic features.  

• Adenomas are composed of monomorphic, polygonal cells displayed in sheets, cords, or papillae. Their nuclei may be uniform or pleomorphic but the mitotic activity is scanty. The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic. 
• The connective tissue is scanty that is why many lesions are soft & even gelatinous in consistency.  

Prolactinomas are the most common type of hyperfunctioning pituitary adenoma.
Hyperprolactinemia causes amenorrhea, galactorrhea, loss of libido, and infertility. 

Growth Hormone-Producing Adenomas (somatotroph cell adenomas) are the second most common type of functional pituitary adenoma. Because the clinical manifestations of excessive growth hormone may be subtle, the tumor may be quite large by the time they come to clinical attention. If such tumors occur before closure of epiphyses (prepubertal children), excessive levels of growth hormone result in gigantism. If elevated levels persist, or present after closure of the epiphyses, individuals develop acromegaly. 

Corticotroph Cell Adenomas are mostly small (microadenomas) at the time of diagnosis. They may be clinically silent or cause hypercortisolism referred to as Cushing disease 

Other Anterior Pituitary Neoplasms 
• Gonadotroph adenomas (luteinizing hormone [LH]-producing and follicle-stimulating hormone [FSH]producing)
• Thyrotroph (thyroid-stimulating hormone [TSH]-producing) adenomas 
• Nonfunctioning pituitary adenomas (hormone-negative (null cell) adenomas) Nonfunctioning adenomas constitute approximately 25% of all pituitary tumors; they typically present through their mass effects. 

Hypoparathyroidism

Hypoparathyroidism is a condition of reduced or absent PTH secretion, resulting in hypocalcaemia and hyperphosphataemia. It is far less common than hyperparathyroidism.

The causes of hypoparathyroidism are:
- Removal or damage of the parathyroid glands during thyroidectomy—most common cause of hypoparathyroidism resulting from inadvertent damage or removal.
- Autoimmune parathyroid disease—usually occurs in patients who have another autoimmune endocrine disease, e.g. Addison’s disease (autoimmune endocrine syndrome type 1).
- Congenital deficiency (DiGeorge syndrome)— rare, congenital disorder caused by arrested development of the third and fourth branchial arches, resulting in an almost complete absence of the thymus and parathyroid gland.

The effects of hypoparathyroidism are:
- ↓ release of Ca²⁺ from bones. 
- ↓ Ca²⁺ reabsorption but ↑ PO ₄³⁻ re absorption by the kidneys
- ↓ 1-hydroxylation of 25-hydroxyvitamin D by kidney.

Most symptoms of hypoparathyroidism are those of hypocalcaemia:
- Tetany—muscular spasm provoked by lowered plasma Ca 2+ 
- Convulsions.
- Paraesthesiae.
- Psychiatric disturbances, e.g. depression, confusional state and even psychosis.
- Rarely—cataracts, parkinsonian-like movement disorders, alopecia, brittle nails.

Management is by treatment with large doses of oral vitamin D; the acute phase requires intravenous calcium and calcitriol (1,25-dihydroxycholecalciferol, i.e.  activated vitamin D).

Autoimmune Diseases
These are a group of disease where antibodies  (or CMI) are produced against self antigens, causing disease process.

Normally one's immune competent cells do not react against one's own tissues.
This is due to self tolerance acquired during embryogenesis. Any antigen encountered at
that stage is recognized as self and the clone of cells capable of forming the corresponding antibody is suppressed.

Mechanism of autoimmunity

(1) Alteration of antigen

 -Physicochemical denaturation by UV light, drugs etc. e.g. SLE.
- Native protein may turn antigenic  when a foreign hapten combines with it, e.g. Haemolytic anemia with Alpha methyl dopa.

(2) Cross reaction: Antibody produced against foreign antigen may cross react with native protein because of partial similarity e.g. Rheumatic fever.

(3) Exposure of sequestered antigens: Antigens not normally exposed to immune competent cells are not accepted as self as tolerance has not been developed to them. e.g. thyroglobulin, lens protein, sperms.

(4) Breakdown of tolerance : 
- Emergence of forbidden clones (due to neoplasia of immune system as in lymphomas and lymphocytic leukaemia)
- Loss of suppressor T cells as in old age and CMI defects

Autoimmunity may be
- Organ specific.
-  Non organ specific (multisystemic)

I. Organ specific.
(I) Hemolytic anaemia:
- Warm or cold antibodies (active at 37° C or at colder temperature)
- They may lyse the RBC by complement activation or coat them and make them vulnerable to phagocytosis

(ii) Hashimoto's thyroiditis:
 
- Antibodies to thyroglobulin and microsomal antigens.
- Cell mediated immunity.
- Leads to chronic. destructive thyroiditis.

(3) Pernicious anemia

Antibodies to gastric parietal cells and to intrinsic factor.

2. Non organ specific.

Lesions are seen in more than one system but principally affect blood vessels and connective tissue (collagen diseases).

(I) Systemic lupus erythematosus  (SLE). Antibodies to varied antigens are seen. Hence it is possible that there is abnormal reactivity of the immune system in self recognition.

Antibodies have been demonstrated against:

- Nuclear material (antinuclear I antibodies) including DNA. nucleoprotein etc. Anti nuclear antibodies are demonstrated by LE cell test.
- Cytoplasmic organelles- mitochondria, rib osomes, Iysosomes.
- Blood constituents like RBC, WBC. platelets, coagulation factors.

Mechanism. Immune complexes of body proteins and auto antibodies deposit in various organs and cause damage as in type III hypersensitivity

Organs involved
- Skin- basal dissolution and collagen degeneration with fibrinoid vasculitis.
- Heart- pancarditis.
- Kidneys- glomerulonephritis of focal, diffuse or membranous type 
- Joints- arthritis. 
- Spleen- perisplenitis and vascular thickening (onion skin).
- Lymph nodes- focal necrosis and follicular hyperplasia.
- Vasculitis in other organs like liver, central or peripheral nervous system etc,

2. Polyarteritis nodosa. Remittant .disseminated necrotising vasculitis of small and medium sized arteries

Mechanism :- Not definitely known. Proposed immune reaction to exogenous or auto antigens 

Lesion : Focal panarteritis- a segment of vessel is involved. There is fibrinoid necrosis with initially acute and later chronic inflammatory cells. This may result in haemorrhage and aneurysm.

Organs involved. No organ or tissue is exempt but commonly involved organs are :
- Kidneys.
- Heart.
- Spleen.
- GIT.

3. Rheumatoid arthritis. A disease primarily of females in young adult life. 

Antibodies

- Rheumatoid factor (An IgM antibody to self IgG)
- Antinuclear antibodies in 20% patients.

Lesions

- Arthritis which may progress on to a crippling deformity.
- Arteritis in various organs- heart, GIT, muscles.
- Pleuritis and fibrosing alveolitis.
- Amyloidosis is an important complication.

4. Sjogren's  Syndrome. This is constituted by 
- Kerato conjunctivitis sicca
- Xerostomia
- Rheumatoid arthritis. 

Antibodies

- Rheumatoid factor

- Antinuclear factors (70%).
- Other antibodies like antithyroid, complement fixing Ab etc
- Functional defects in lymphocytes. There is a higher incidence of lymphoma

5. Scleroderma (Progressive systemic sclerosis)
Inflammation and progressive sclerosis of connective tissue of skin and viscera.

Antibodies
- Antinuclear antibodies.
- Rheumatoid factor. .
- Defect is cell mediated.

lesions

- Skin- depigmentation, sclerotic atrophy followed by cakinosis-claw fingers and mask face.
- Joints-synovitis with fibrosis
- Muscles- myositis.
- GIT- diffuse fibrous replacement of muscularis resulting in hypomotility and malabsorption
- Kidneys changes as in SLE and necrotising vasculitis.
- Lungs – fibrosing alveolitis.
- Vasculitis in any organ or tissue.

6.Wegener’s granulomatosis. A complex of:

- Necrotising lesions in upper respiratory tract.
- Disseminated necrotising vasculitis.
- Focal or diffuse glomerulitis.

Mechanism. Not known. It is classed with  autoimmune diseases because of the vasculitis  resembling other immune based disorders.