Granulomatosis with polyangiitis (GPA)

Granulomatosis with polyangiitis (GPA, previously known as Wegener's disease) is an autoimmune multisystem disorder of unknown aetiology. It is characterized by necrotizing granulomatous inflammation and pauci-immune vasculitis affecting small to medium sized blood vessels, most commonly in the airways, lungs and kidneys.

Diagnosis of Systemic Lupus Erythematosus (SLE)

The diagnosis is SLE:
•Raynaud’s phenomenon, myalgia and arthralgia
•Painless mouth ulcers
•The scalp lesion described is discoid lupus
•Leukopenia and lymphopenia
•ANA positive and Ro positive

Cardiac amyloidosis

The commonest cause of death in amyloidosis is secondary to cardiac involvement. It may present with the insidious onset of vague symptoms, such as lethargy. Later peripheral oedema becomes a prominent feature.

Amyloid depositis in the heart produce generalized thickening of the myocardium (as opposed to asymmetrical septal hypertrophy commonly seen in hypertrophic cardiomyopathy) and diastolic dysfunction. This produces a "stiffened" appearance to relaxation in the diastolic phase.

A search for non-cardiac amyloid deposits is usually the most efficient way to coinfirm the diagnosis histologically.

Klinefelter’s syndrome

Klinefelter’s syndrome, which not uncommonly presents in adult life rather than at adolescence. This syndrome is characterised by dysgenesis of the seminiferous tubules and is a common cause of primary hypogonadism and male infertility. Karyotype analysis of unselected newborns has estimated an incidence of 1 per 800 to 1000 males, the most common human chromosomal abnormality.

Patients are phenotypically male with testes of usually < 3cm in length and azoospermia. Gynaecomastia is also common. Karyotype analysis typically demonstrates the 47, XXY karyotype. Patients show poor to normal virilization at puberty and tend to have a tall stature due to disproportionately long legs.
Testosterone levels vary but are usually decreased and gonadotrophins are raised – particularly FSH. Plasma estradiol levels are usually normal or elevated, similarly SHBG.

Undescended testes are 3 times as common as in normal boys. Prepubertal studies indicate that children with the 47, XXY Karyotype have lower birth weights, smaller mean head circumferences, a slightly increased risk of congenital anomalies, height percentiles that increase with age, a lower verbal IQ than normal boys and poor motor and muscle tone.
Associated abnormalities include an increased frequency of diabetes mellitus; 19% of patients have been reported to have impaired glucose tolerance and 8% to be diabetic. 47 XXY patients with gynaecomastia also have an increased predisposition to cancer of the breast. In addition, 20-50% of boys 8 years or older with primary mediastinal germ cell tumours have Klinefelter’s syndrome.
25% of adults with Klinefelter’s have osteoporosis, although this is uncommon in patients on testosterone replacement. Chronic lung disease and varicose veins are also thought to be more common.

It seems that normal complements of germ cells are present in these patients in early foetal life but during late gestation and early infancy there is a dramatic loss of spermatogonia. In adult patients, spermatogenesis may rarely be present but most fertile patients have proved to have sex chromosome mosaicism (46, XY/47 XXY) and often lack the features which distinguish them from typical patients with Klinefelter’s syndrome. The technique of intracytoplasmic sperm injection (ICSI) has been used with some success in this group of patients – however, there is also an increased risk of trisomy 21 in children of patients with Klinefelter’s syndrome.

The mainstay of treatment is testosterone replacement. Patients diagnosed pre-pubertally may be given small doses of testosterone intramuscularly (e.g. 50mg im monthly) to initiate puberty and avoid the psychological and physical consequences of hypogonadism. The dose may be gradually increased (100mg im, monthly) once bone age has advanced to allow full growth potential to be realised. Once the final height has been reached an adult replacement dose of testosterone, e.g. 250mg im 3 weekly. Alternatively testosterone patches or the newer gels or buccal preparations may be used in adults.

Oncogenes

• Initially identified as viral gene
• Proto-oncogenes
• Genes within normal DNA of every cell
• Mutated, activated ￫ Product ￫ Tumour
• Influence is direct or indirect 
• e.g. mitogen-activated protein kinase (MAPK) pathway
• Amino acid substitutions @ 21 or 61 in Ras
• Activating ERK MAPK pathway

video source

Metformin

Metformin is a useful first-line treatment for diabetes and would be particularly appropriate in this overweight patient as it was the only treatment in UKPDS that was weight neutral over long-term therapy and was at least as effective as sulphonylureas in reducing long-term microvascular and macrovascular complications of diabetes. In fact high-dose metformin treatment has been shown to aid weight loss in obese patients. It is contraindicated in significant hepatic, renal or cardiac failure and the dose should be increased slowly to minimise the risk of GI disturbance which are a common side effect and reason for inability to tolerate this treatment. UKPDS showed that treatment of hypertension is at least as important as glycaemic control in prevention of micro- and macrovascular complications of type II diabetes. Having been confirmed on two occasions by his GP it should be aggressively treated. Most hypertensive diabetics will require more than one anti-hypertensive agent to control their blood pressure.

Sulphonylureas

Sulphonylureas promote weight gain as demonstrated in the UKPDS study