Molecular techniques

Different molecular techniques such as fluorescent in situ hybridization, Southern blot, etc... can be used to detect genetic diseases.

THYROIDITIS 
The more common and clinically significant thyroidites are:  
1. Hashimoto thyroiditis 
2. Subacute granulomatous thyroiditis
3. Subacute lymphocytic thyroiditis 

Hashimoto thyroiditis 

Hashimoto thyroiditis (Chronic Lymphocytic Thyroiditis) is the most common cause of hypothyroidism. It results from gradual autoimmune destruction of the thyroid gland. There is striking female predominance (10: 1 to 20:1), and is most prevalent around a mean age of 50 years. 

Pathogenesis 
• The dominant feature is progressive destruction of thyroid follicular epithelial cells with gradual replacement by mononuclear cell infiltration and fibrosis. 
• Sensitization of CD4+ T-helper cells to thyroid antigens seems to be the initiating event.
• The reaction of CD4+ T cells with thyroid antigens produces interferon γ  which promote inflammation and activate macrophages. Injury to the thyroid results from the toxic products of these inflammatory cells. 
• CD8+ cytotoxic T cells also contribute to epithelial cells killing as are natural killer cells. 
• There is a significant genetic component to disease pathogenesis. This is supported by 
1.  The increased frequency of the disease in first-degree relatives, 
2.  Unaffected family members often have circulating thyroid autoantibodies.  

Gross features 
• The thyroid shows moderate, diffuse, and symmetric enlargement.
• The cut surface is pale, gray-tan, firm, nodular and somewhat friable. 
• Eventually there is thyroid atrophy 

Microscopic features

• There is widespread, diffuse infiltration of the parenchyma by small lymphocytes, plasma cells.  The lymphocytes are also form follicles some with well-developed germinal centers 
• The thyroid follicles are atrophic and lined by epithelial cells having abundant eosinophilic, granular cytoplasm (Hurthle cells). This is a metaplastic response to the ongoing injury; ultrastructurally the Hurthle cells are stuffed by numerous mitochondria. 
• Interstitial connective tissue is increased and may be abundant.

Hashimoto thyroiditis presents as painless symmetrical goiter, usually with some degree of hypothyroidism. In some cases there is an initial transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones ("hashitoxicosis"). As hypothyroidism supervenes T4 and T3 levels progressively fall & TSH levels are increased. Patients often have other autoimmune diseases and are at increased risk for the development of B-cell non-Hodgkin lymphomas. 

Subacute Granulomatous (de Quervain) Thyroiditis 

Subacute Granulomatous (de Quervain) Thyroiditis is much less common than Hashimoto disease.

- It is most common around the age of 40 years and occurs more frequently in women than in men.

- An upper respiratory infection just before the onset of thyroiditis. Thus, a viral infection is probably the cause.

- There is firm uni- or bilateral enlargement of the gland.

Microscopically, there is disruption of thyroid follicles, with extravasation of colloid. The extravasated colloid provokes a granulomatous reaction, with giant cells.
Thyroid function tests are those of thyrotoxicosis but with progression and gland destruction, a transient hypothyroid phase occurs. The condition is self-limited, with most patients returning to a euthyroid state within at most 2 months.

Subacute Lymphocytic Thyroiditis

Subacute Lymphocytic Thyroiditis may follow pregnancy (postpartum thyroiditis).

- It is most likely autoimmune in etiology, because circulating antithyroid antibodies are found in the majority of patients.

- It mostly affects middle-aged women and present as painless, mild, symmetric neck mass. Initially, there is thyrotoxicosis, followed by return to a euthyroid state within a few months. In a minority there is progression to hypothyroidism.

Microscopically, there is a lymphocytic infiltration and hyperplastic germinal center within the thyroid parenchyma; unlike Hashimoto thyroiditis, follicular atrophy or Hürthle cell metaplasia are not commonly seen.

Riedel thyroiditis 

Riedel thyroiditis is a rare disorder of unknown etiology, characterized by extensive fibrosis involving the thyroid and the surrounding neck structures. The presence of a hard and fixed thyroid mass may be confused clinically with thyroid cancer. It may be associated with idiopathic fibrosis in other sites, such as the retroperitoneum. The presence of circulating antithyroid antibodies in most patients suggests an autoimmune etiology. 

Lupus erythematosus
 - chronic discoid lupus is primarily limited to the skin, while SLE can involve the skin and other systems.
 - pathogenesis: light and other external agents plus deposition of DNA (planted antigen) and immune complexes in the basement membrane.
 Histology:
 - basal cells along the dermal-epidermal junction and hair shafts (reason for alopecia) are vacuolated (liquefactive degeneration)
 - thickening of lamina densa as a reaction to injury.
 - immunofluorescent studies reveal a band of immunofluorescence (band test) in involved skin of chronic discoid lupus or involved/uninvolved skin of SLE.
 - lymphocytic infiltrate at the dermal-epidermal junction and papillary dermis.  

Neutrophilia
Causes
    
-Pyogenic infections.
-Haemorrhage and trauma.
-Malignancies.
-Infarction.
-Myelo proliferative disorders.

Osteomyelitis
This refers to inflammation of the bone and related marrow cavity almost always due to infection. Osteomyelitis can be acute or a chronic. The most common etiologic agents are pyogenic bacteria and Mycobacterium tuberculosis.

Pyogenic Osteomyelitis

The offending organisms reach the bone by one of three routes:
1. Hematogenous dissemination (most common)
2. Extension from a nearby infection (in adjacent joint or soft tissue)
3. Traumatic implantation of bacteria (as after compound fractures or orthopedic procedures). Staphylococcus aureus is the most frequent cause. Mixed bacterial infections, including anaerobes, are responsible for osteomyelitis complicating bone trauma. In as many as 50% of cases, no organisms can be isolated. 

Pathologic features 

• The offending bacteria proliferate & induce an acute inflammatory reaction.
• Entrapped bone undergoes early necrosis; the dead bone is called sequestrum.
• The inflammation with its bacteria can permeate the Haversian systems to reach the periosteum. In children, the periosteum is loosely attached to the cortex; therefore, sizable subperiosteal abscesses can form and extend for long distances along the bone surface.
• Lifting of the periosteum further impairs the blood supply to the affected region, and both suppurative and ischemic injury can cause segmental bone necrosis.
• Rupture of the periosteum can lead to an abscess in the surrounding soft tissue and eventually the formation of cutaneous draining sinus. Sometimes the sequestrum crumbles and passes through the sinus tract.
• In infants (uncommonly in adults), epiphyseal infection can spread into the adjoining joint to produce suppurative arthritis, sometimes with extensive destruction of the articular cartilage and permanent disability.
• After the first week of infection chronic inflammatory cells become more numerous. Leukocyte cytokine release stimulates osteoclastic bone resorption, fibrous tissue ingrowth, and bone formation in the periphery, this occurs as a shell of living tissue (involucrum) around a segment of dead bone. Viable organisms can persist in the sequestrum for years after the original infection.
Chronicity may develop when there is delay in diagnosis, extensive bone necrosis, and improper management. 

Complications of chronic osteomyelitis include
1. A source of acute exacerbations
2. Pathologic fracture
3. Secondary amyloidosis
4. Endocarditis
5. Development of squamous cell carcinoma in the sinus tract (rarely osteosarcoma).

Tuberculous Osteomyelitis

Bone infection complicates up to 3% of those with pulmonary tuberculosis. Young adults or children are usually affected. The organisms usually reach the bone hematogenously. The long bones and vertebrae are favored sites. The lesions are often solitary (multifocal in AIDS patients). The infection often spreads from the initial site of bacterial deposition (the synovium of the vertebrae, hip, knee, ankle, elbow, wrist, etc) into the adjacent epiphysis, where it causes typical granulomatous inflammation with caseous necrosis and extensive
bone destruction. Tuberculosis of the vertebral bodies (Pott disease), is an important form of osteomyelitis.

Infection at this site causes vertebral deformity and collapse, with secondary neurologic deficits. Extension of the infection to the adjacent soft tissues with the development of psoas muscle abscesses is fairly common in Pott disease. Advanced cases are associated with cutaneous sinuses, which cause secondary bacterial infections. Diagnosis is established by synovial fluid direct examination, culture or PCR

Nephrotic Syndrome
The patient will present with a triad of symptoms:
- Proteinuria, i.e. >3g/24hr-3.5g/24 hr
- Hypoalbuminaemia, i.e. <30g/L
- Oedema 
 >80% of cases are due to glomerulonephritis. In this syndrome, there is damage to podocytes 
 
 Clinical signs
- Pitting oedema, particularly in the limbs and around the eyes; may also cause genital oedema and ascites.
- Possible hypertension 

Causes
- Primary causes – these are diagnoses of exclusion that are only made if secondary causes cannot be found
    o Minimal change disease (MCD)
    o Focal segmental glomerulosclerosis
    o Membranous nephropathy
- Secondary causes – note that these fall into the same three categories as above:
    o Minimal change disease – Hep B, SLE, diabetes M, sarcoidosis, syphilis, malignancy
    o Focal segmental glomerulosclerosis –HIV, obesity, diabetes M, hypertensive nephrosclerosis
    o Minimal change disease –drugs, malignancy, particularly Hodgkin’s lymphoma  
    
 - Differential diagnoses include cardiac failure, i.e. increased JVP, pulmonary oedema and mild proteinuria, and liver disease, i.e. reduced serum albumin.
- The condition causes an increased susceptibility to infection – partly due to loss of immunoglobulin in the urine. Patients tend to be prone to streptococcus infection, as well as bacterial peritonitis and cellulitis.
- Nephrotic syndrome also increases the risk of thromboembolism and hyperlipidaemia.
- The former is due to an increase in the synthesis of clotting factors and to platelet abnormalities, and the latter is a result of increased synthesis of these by the liver to counteract reduced oncotic pressure.  

Investigations

- These are the same as those carried out in GN.
- Also, check for cholesterol as part of confirming the presence of hyperlipidemia.
- Renal biopsy – order this for all adults. In children, because the main cause is minimal change GN, steroids are the first-line treatment. Therefore, in children, biopsy is necessary only if pharmaceutical intervention fails to improve the situation.
- The hypercoagulant state seen in the nephrotic syndrome can be a risk factor for renal vein thrombosis. This can present as loin pain, haematuria, palpable kidney and sudden deterioration in kidney function. This should be investigated with Doppler USS, MRI or even renal angiography.
- Once diagnosed, give warfarin for 3 to 6 months.

Management

- Generally, this involves treatment of the underlying condition which is usually GN. Therefore, fluid management and salt intake restriction are priorities. The patient is usually given furosemide along with an ACE inhibitor and/or an angiotensin II receptor antagonist. Prophylactic heparin is given if the patient is immobile. Hyperlipidaemia can be treated with a statin. 

Nephritic Syndrome 

Acute and chronic
forms of the syndrome exist. The main difference between this and nephrotic syndrome is that in nephritic syndrome haematuria is present. There is also proteinuria, hypertension, uraemia, and possibly oliguria. The two standout features are hypertension and RBC casts. The urine will often appear ‘smoky’ in colour due to the presence of RBC casts. Very rarely, it may appear red 

Causes

1. Post-streptococcal
2. Primary:
- Membranous glomerulonephritis
- Rapidly progressive glomerulonephritis
- IgA nephropathy (Berger’s disease)
3. Secondary
- HSP
- Vasculitis

Clinical Features

- Abrupt onset of :
    o Glomerular haematuria (RBC casts or dysmorphic RBC)
    o Non-nephrotic range proteinuria (< 2 g in 24 hrs)
    o Oedema (periorbital, sacral )
    o Hypertension
    o Transient renal impairment (oliguria, uraemia)
- Urinary casts – these are cylindrical structures produced by the kidney and present in the urine in certain renal diseases. They form in the DCT and collecting duct, dislodging and passing in the urine where they are detected by microscopy. RBC casts are usually associated with nephritic syndrome. The presence of RBCs within a cast is always pathologic and strongly indicative of glomerular damage.
- The proteinuria present is often smaller than in nephrotic syndrome, thus a coexistent condition of nephrotic syndrome is not usually present.
- Encepelopathy may be present, particularly in children, due to electrolyte imbalances and hypertension. This type of presentation is indicative of glomerular damage, but requires renal biopsy to determine the exact problem. In this respect it is similar to nephrotic syndrome.
Overlapping of the two syndromes is possible as nephrotic syndrome may precede nephritic syndrome, although not vice-versa.

Mechanisms of the syndrome vary according to cause; both primary and secondary causes exist. Post-infectious GN is the classic illustration of nephritic syndrome, but the condition may be caused by other glomerulopathies and by systemic diseases such as connective tissue disorders 

Two clinical terms to remember:
- Nephritic syndrome; which comprises edema, proteinuria, hypoalbuminemia, hematuria (smoky urine), oligurua and hypertension.
- Nephrotic syndrome; which comprises of albuminuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria.