Cushing’s syndrome

The symptoms and signs of Cushing’s syndrome are associated with prolonged inappropriate elevation of free corticosteroid levels.

Clinical features

- Central obesity and moon face.
- Plethora and acne.
- Menstrual irregularity.
- Hirsutism and hair thinning.
- Hypertension.
- Diabetes.
- Osteoporosis—may cause collapse of vertebrae, rib fractures.
- Muscle wasting and weakness.
- Atrophy of skin and dermis—paper thin skin with bruising tendency, purple striae.

Aetiopathogenesis — patients with Cushing’s syndrome can be classified into two groups on the basis of whether the aetiology of the condition is ACTH dependent or independent. 

Classification of Cushing's syndrome

ACTH dependent- Iatrogenic (ACTH therapy) Pituitary hypersecretion of ACTH Ectopic ACTH syndrome (benign or malignant non-endocrine tumour)

Non-ACTH dependent - Iatrogenic, e.g. prednisolone Adrenal cortical adenoma , Adrenal cortical carcinoma

ACTH-dependent aetiology:

- Pituitary hypersecretion of ACTH (Cushing’s disease)—bilateral adrenal hyperplasia secondary to excessive secretion of ACTH by a corticotroph adenoma of the pituitary gland.
- Production of ectopic ACTH or corticotrophin- releasing hormone (CRH) by non-endocrine neoplasm, e.g. small cell lung cancer and some carcinoid tumours. In cases of malignant bronchial tumour, the patient rarely survives long enough to develop any physical features of Cushing’s syndrome.

Non-ACTH-dependent aetiology

Iatrogenic steroid therapy—most common cause of Cushing’s syndrome.
Adrenal cortical adenoma—well-circumscribed yellow tumour usually 2–5 cm in diameter.
Extremely common as an incidental finding in up to 30% of all post-mortem examinations. The yellow colour is due to stored lipid (mainly cholesterol) from which the hormones are synthesised. The vast majority have no clinical effects (i.e. they are non-functioning adenomas), with only a small percentage producing Cushing’s syndrome.

Adrenal cortical carcinoma—rare and almost always associated with the overproduction of hormones, usually glucocorticoids and sex steroids. 

Cushing’s syndrome mixed with androgenic effects which are particularly noticeable in women. Tumours are usually large and yellowish white in colour. Local invasion and metastatic spread are common.

Irrespective of the aetiology, the diagnosis is based on clinical features and the demonstration of a raised plasma cortisol level.
The aetiology of the disorder is elucidated through:
- Raised urinary cortisol in the first instance, but further testing is required.
- Low-dose dexamethasone suppression test (suppression of cortisol levels in Cushing’s disease due to suppression of pituitary ACTH secretion, but a lack of suppression suggests ACTH-independent Cushing’s syndrome).
- MRI and CT scan visualisation of pituitary and adrenal glands.
- Analysis of blood ACTH (high = pituitary adenoma or ectopic ACTH source; low = primary adrenal tumour due to feedback suppression).
- Treatment of the underlying cause is essential as untreated Cushing’s syndrome has a 50% 5-year mortality rate.

The therapeutic administration of glucocorticosteroids (e.g. prednisolone) is a common cause of the features of Cushing’s syndrome. 

Hepatitis B virus (“serum hepatitis”)
- Hepatitis B (HBV) may cause acute hepatitis, a carrier state, chronic active disease, chronic persistent disease, fulminant hepatitis, or hepatocellular carcinoma  
- It is caused by a DNA virus, the virions are called Dane particles. 

b. Incubation period: ranges from 4 to 26 weeks, but averages 6 to 8 weeks.
a. Symptoms last 2 to 4 weeks, but may be asymptomatic.
c. The hepatitis B viral structure has also been named the Dane particle.

Transmission is through contact with infected blood or other body fluids. It can be transmitted by sexual intercourse and is frequently transmitted to newborns of infected mothers by exposure to maternal blood during the birth process
- Associated antigens include core antigen (HBcAg) and surface antigen (HBsAg).
The latter is usually identified in the blood for diagnosis. HbsAg is the earliest marker of acute infection.
HBeAg is also associated with the core. Its presence indicates active acute infection; when anti-HBeAg appears, the patient is no longer infective
- HBV is associated with hepatocellular carcinoma; HBsAg patients have a 200-fold greater risk of hepatocellular carcinoma than subjects who have not been exposed. 

Antibodies  
- Antibodies to surface antigen (anti-HBs) are considered protective and usually appear after the disappearance of the virus.
-Antibodies to HBcAg are not protective. They are , detected just after the appearance of HBsAg and are used to confirm infection when both HBsAg and anti HBs are absent (window).
- Antibodies to HBeAg are associated with a low risk of infectivity.

d. Infection increases the risk for hepatocellular carcinoma.

e. Laboratory assay of hepatitis B antigens and antibodies:

(1) HBsAg—present only in acute infection or chronic carriers.
(2) HBsAb—detectable only after 6 months post-initial infection. HBsAb is present in chronic infections or vaccinated individuals. Note: HBsAb is also being produced during acute infections and in chronic carriers; however, it is not detectable via current laboratory methods.
(3) HBcAg—present in either acute or chronic infection.
(4) HBeAg—present when there is active viral replication. It signifies that the carrier is highly infectious.
(5) HBeAb—appears after HBeAg. It signifies that the individual is not as contagious.

f. Vaccine: contains HBsAg.

g. Prevention: immunoglobulins (HBsAb) are available.

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. 

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.