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Pathology -Primary Amenorrhea
This patient has primary amenorrhea — no beginning of menses in a female older than 16 years. This disorder may occur with or without other indicators of puberty and most usually happens as a result of anatomic, hormonal, or genetic abnormality. Anatomic causes include congenital lack of the uterus or vagina, presence of vaginal septum or imperforate hymen, blocked/narrowed cervix, or Müllerian agenesis. Hormonal reasons include pituitary (LH, FSH), ovarian malfunction, or androgen insensitivity. Genetic abnormalities include Turner’s syndrome (45 XO). If secondary sex traits are not present, gonadotropins (FSH, LH) are tested first. If levels are low, hypogonadotropic hypogonadism is present. If FSH and LH are excessive (hypergonadotropic hypogonadism), unresponsiveness of tissues (premature ovarian failure or Turner’s syndrome) is suspected. If secondary sex traits are present (as in the patient in the vignette), ultrasonography assessment of pelvic organs is indicated. If appropriate pelvic architecture is present, uterine outflow blockage is suspected. If aberrant pelvic morphology is identified, this may imply androgen insensitivity throughout fetal life or Müllerian agenesis.
This patient has primary amenorrhea — no beginning of menses in a female older than 16 years. This disorder may occur with or without other indicators of puberty and most usually happens as a result of anatomic, hormonal, or genetic abnormality. Anatomic causes include congenital lack of the uterus or vagina, presence of vaginal septum or imperforate hymen, blocked/narrowed cervix, or Müllerian agenesis. Hormonal reasons include pituitary (LH, FSH), ovarian malfunction, or androgen insensitivity. Genetic abnormalities include Turner’s syndrome (45 XO). If secondary sex traits are not present, gonadotropins (FSH, LH) are tested first. If levels are low, hypogonadotropic hypogonadism is present. If FSH and LH are excessive (hypergonadotropic hypogonadism), unresponsiveness of tissues (premature ovarian failure or Turner’s syndrome) is suspected. If secondary sex traits are present (as in the patient in the vignette), ultrasonography assessment of pelvic organs is indicated. If appropriate pelvic architecture is present, uterine outflow blockage is suspected. If aberrant pelvic morphology is identified, this may imply androgen insensitivity throughout fetal life or Müllerian agenesis.
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Pathology - Addison Disease
Primary adrenocortical insufficiency (Addison disease) develops when there is diminished secretion of all the adrenal cortical hormones. Diagnostic testing includes a cosyntropin (synthetic ACTH) stimulation test, which fails to trigger cortisol release. Low levels of cortisol induce ACTH release, which is responsible for the increased skin pigmentation due to its structural similarities to melanocyte-stimulating hormone. Low cortisol also decreases the ability to maintain blood glucose and produces fasting hypoglycemia. Low aldosterone levels lead to urinary salt loss and volume depletion, causing hypotension and decreased heart size. A compensatory increase in ADH secretion due to hypovolemia induces water retention and hyponatremia. Lack of cortisol makes hypotension worse due to decrease of vasopressor reactivity of blood vessels. Low aldosterone levels also prevent proper potassium excretion and produces hyperkalemia. Loss of libido and pubic hair (especially in females) occur as a result of decreased circulating adrenal androgens. Addison disease is rare and most instances are caused to autoimmune destruction of the adrenal cortex. Secondary adrenal insufficiency, due to decrease of ACTH secretion, is not associated with any pigmentation changes. In this scenario, aldosterone synthesis is preserved by stimulation from the renin–angiotensin axis. Addison disease is treated with glucocorticoid and mineralocorticoid supplements.
Primary adrenocortical insufficiency (Addison disease) develops when there is diminished secretion of all the adrenal cortical hormones. Diagnostic testing includes a cosyntropin (synthetic ACTH) stimulation test, which fails to trigger cortisol release. Low levels of cortisol induce ACTH release, which is responsible for the increased skin pigmentation due to its structural similarities to melanocyte-stimulating hormone. Low cortisol also decreases the ability to maintain blood glucose and produces fasting hypoglycemia. Low aldosterone levels lead to urinary salt loss and volume depletion, causing hypotension and decreased heart size. A compensatory increase in ADH secretion due to hypovolemia induces water retention and hyponatremia. Lack of cortisol makes hypotension worse due to decrease of vasopressor reactivity of blood vessels. Low aldosterone levels also prevent proper potassium excretion and produces hyperkalemia. Loss of libido and pubic hair (especially in females) occur as a result of decreased circulating adrenal androgens. Addison disease is rare and most instances are caused to autoimmune destruction of the adrenal cortex. Secondary adrenal insufficiency, due to decrease of ACTH secretion, is not associated with any pigmentation changes. In this scenario, aldosterone synthesis is preserved by stimulation from the renin–angiotensin axis. Addison disease is treated with glucocorticoid and mineralocorticoid supplements.
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Symptoms and Signs – Differential Diagnosis of Complement deficiency
Congenital e.g. C1 esterase (C1 inhibitor) deficiency (normal C3, reduced C4)
Acquired
Reduced C3 and C4:
SLE, mixed cryoglobulinaemia
Subacute bacterial endocarditis
Serum sickness
Increased Loss/reduced synthesis: malnutrition, nephrotic syndrome, burns, liver failure
Reduced C3
Mesangiocapillary glomerulonephritis, partial lipodystrophy
Gram -ve (endotoxic) shock
Increased C3 and/or C4
Acute phase response
Congenital e.g. C1 esterase (C1 inhibitor) deficiency (normal C3, reduced C4)
Acquired
Reduced C3 and C4:
SLE, mixed cryoglobulinaemia
Subacute bacterial endocarditis
Serum sickness
Increased Loss/reduced synthesis: malnutrition, nephrotic syndrome, burns, liver failure
Reduced C3
Mesangiocapillary glomerulonephritis, partial lipodystrophy
Gram -ve (endotoxic) shock
Increased C3 and/or C4
Acute phase response
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Symptoms and Signs – Differential Diagnosis of Reduced Consciousness
Hypoglycaemia
Hypoxia: cardiac arrest, shock (hypovolaemic, septic), respiratory failure
Infection: meningitis, encephalitis
Inflammation (demyelination)
Toxic: drugs e.g. opiates, alcohol, anxiolytics, antidepressants
Trauma (head injury)
Tumour (increased intracranial pressure)
Vascular: intracranial haemorrhage/infarction
Metabolic: liver failure, renal failure, electrolyte (Na+, K+, Ca2+, Mg2+)
disturbances, endocrinopathies e.g. myxoedema coma, vitamin deficiencies
(e.g. thiamine, B12), hypothermia
Hypoglycaemia
Hypoxia: cardiac arrest, shock (hypovolaemic, septic), respiratory failure
Infection: meningitis, encephalitis
Inflammation (demyelination)
Toxic: drugs e.g. opiates, alcohol, anxiolytics, antidepressants
Trauma (head injury)
Tumour (increased intracranial pressure)
Vascular: intracranial haemorrhage/infarction
Metabolic: liver failure, renal failure, electrolyte (Na+, K+, Ca2+, Mg2+)
disturbances, endocrinopathies e.g. myxoedema coma, vitamin deficiencies
(e.g. thiamine, B12), hypothermia
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Symptoms and Signs – Differential Diagnosis of Constipation
Diet: low fibre, inadequate fluid intake
Drugs: opiates, anticholinergics (tricyclics, phenothiazines), iron
Immobility
Old age
Surgical/gastrointestinal:
Anorectal disease (fissure, stricture, rectal prolapse)
Intestinal obstruction (strictures, e.g. IBD, cancers, diverticulosis, pelvic mass,
e.g. fibroids)
Irritable bowel syndrome
Post-operative
Endocrine: hypothyroidism, hypercalcaemia, hypokalaemia, porphyria, lead
poisoning
Neurological/neuromuscular: autonomic neuropathy, spinal/pelvic nerve injury,
scleroderma, Hirschsprung's disease, Chagas' disease
Diet: low fibre, inadequate fluid intake
Drugs: opiates, anticholinergics (tricyclics, phenothiazines), iron
Immobility
Old age
Surgical/gastrointestinal:
Anorectal disease (fissure, stricture, rectal prolapse)
Intestinal obstruction (strictures, e.g. IBD, cancers, diverticulosis, pelvic mass,
e.g. fibroids)
Irritable bowel syndrome
Post-operative
Endocrine: hypothyroidism, hypercalcaemia, hypokalaemia, porphyria, lead
poisoning
Neurological/neuromuscular: autonomic neuropathy, spinal/pelvic nerve injury,
scleroderma, Hirschsprung's disease, Chagas' disease
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Symptoms and Signs – Differential Diagnosis of Corneal opacification
Corneal ulcer, keratitis
Anterior uveitis (iritis)
Acute angle closure glaucoma
Corneal ulcer, keratitis
Anterior uveitis (iritis)
Acute angle closure glaucoma
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Pathology - Osteomalacia
Osteomalacia may arise from vitamin D insufficiency. In metabolic bone disease there is decreased bone density and diminished bone strength. In osteomalacia the problem is restricted to loss of bone mineralization, but in osteoporosis there is also loss of the collagenous bone matrix. Vitamin D is essential for appropriate mineralization of bone by osteoblasts with calcium phosphate (hydroxyapatite) crystals. Inadequate vitamin D in children causes the irreversible bone abnormalities of rickets, and in adults it causes osteomalacia. Vitamin D is generated in the skin following exposure to UV-B radiation and is also present in the diet. Activation of vitamin D involves 25-hydroxylation in the liver and final conversion to 1,25-(OH)2 D3 (cholecalciferol) in the kidney, under the supervision of PTH. The patient is at great risk for vitamin D insufficiency due to his very restricted diet and avoidance of sunshine. Vitamin D is necessary for appropriate intestinal uptake of calcium and phosphate. Vitamin D insufficiency in this patient accounts for low serum calcium and phosphate levels. Pseudofractures are anomalies detected on radiographs as the periosteum thickens as a healing reaction to an adjacent area of bone demineralization. There are other probable causes of osteomalacia. One example is a mesenchymal tumor type, which releases phosphaturic substances such as fibroblast growth factor-23 (FGF-23), leading to phosphate deficit and bone disease. In children hereditary types of rickets can occur from mutations in either the 1-alpha hydroxylase enzyme for vitamin D activation (rickets type 1), or in the vitamin D receptor (rickets type 2).
Osteomalacia may arise from vitamin D insufficiency. In metabolic bone disease there is decreased bone density and diminished bone strength. In osteomalacia the problem is restricted to loss of bone mineralization, but in osteoporosis there is also loss of the collagenous bone matrix. Vitamin D is essential for appropriate mineralization of bone by osteoblasts with calcium phosphate (hydroxyapatite) crystals. Inadequate vitamin D in children causes the irreversible bone abnormalities of rickets, and in adults it causes osteomalacia. Vitamin D is generated in the skin following exposure to UV-B radiation and is also present in the diet. Activation of vitamin D involves 25-hydroxylation in the liver and final conversion to 1,25-(OH)2 D3 (cholecalciferol) in the kidney, under the supervision of PTH. The patient is at great risk for vitamin D insufficiency due to his very restricted diet and avoidance of sunshine. Vitamin D is necessary for appropriate intestinal uptake of calcium and phosphate. Vitamin D insufficiency in this patient accounts for low serum calcium and phosphate levels. Pseudofractures are anomalies detected on radiographs as the periosteum thickens as a healing reaction to an adjacent area of bone demineralization. There are other probable causes of osteomalacia. One example is a mesenchymal tumor type, which releases phosphaturic substances such as fibroblast growth factor-23 (FGF-23), leading to phosphate deficit and bone disease. In children hereditary types of rickets can occur from mutations in either the 1-alpha hydroxylase enzyme for vitamin D activation (rickets type 1), or in the vitamin D receptor (rickets type 2).
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Pathology - Cushing Syndrome
Cushing syndrome is caused by continuous exogenous glucocorticoid treatment, which is the most common cause of this illness. The term Cushing disease specifically refers to an ACTH-secreting pituitary adenoma, leading to an excess of endogenous cortisol secretion. Nonpituitary ACTH-secreting neoplasms or cortisol-secreting adrenal tumors also result in hypercortisolism. In addition to evaluating ACTH and cortisol levels, a dexamethasone suppression test is used to discriminate between pituitary and extra-pituitary sources: inability to suppress cortisol secretion with high doses of dexamethasone suggests an adrenal tumor. Regardless of causation, high cortisol causes muscle atrophy and leads to hyperglycemia owing to insulin antagonism. Hypertension and hypokalemia reflect stimulation of mineralocorticoid receptors, resulting to renal sodium retention and potassium squandering. Thinning of the skin, poor wound healing, redistribution of body fat, and psychological issues are pathologic outcomes of excess cortisol. Suppression of immunity raises the danger of infections. Treatment depends on the cause of hypercortisolism.
In this instance, moderate reduction in medication dose is necessary (rapid removal risks circulatory collapse due to a persistent condition of adrenal gland suppression from exogenous drug). Cases of pituitary or adrenal tumor are surgically treated.
Cushing syndrome is caused by continuous exogenous glucocorticoid treatment, which is the most common cause of this illness. The term Cushing disease specifically refers to an ACTH-secreting pituitary adenoma, leading to an excess of endogenous cortisol secretion. Nonpituitary ACTH-secreting neoplasms or cortisol-secreting adrenal tumors also result in hypercortisolism. In addition to evaluating ACTH and cortisol levels, a dexamethasone suppression test is used to discriminate between pituitary and extra-pituitary sources: inability to suppress cortisol secretion with high doses of dexamethasone suggests an adrenal tumor. Regardless of causation, high cortisol causes muscle atrophy and leads to hyperglycemia owing to insulin antagonism. Hypertension and hypokalemia reflect stimulation of mineralocorticoid receptors, resulting to renal sodium retention and potassium squandering. Thinning of the skin, poor wound healing, redistribution of body fat, and psychological issues are pathologic outcomes of excess cortisol. Suppression of immunity raises the danger of infections. Treatment depends on the cause of hypercortisolism.
In this instance, moderate reduction in medication dose is necessary (rapid removal risks circulatory collapse due to a persistent condition of adrenal gland suppression from exogenous drug). Cases of pituitary or adrenal tumor are surgically treated.
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Pathology - Polycystic Ovarian Syndrome
While the etiology of this disorder is not well known, overproduction of androgens by the ovaries (and possibly by adrenal glands as well) occurs, creating hirsutism and interrupted menses.
The hyperandrogenic state is further fostered by reduction of sex hormone-binding globulin, which effectively increases the proportion of free circulating androgens. Abnormally high levels of LH develop due to increased frequency of GnRH pulses from the hypothalamus, also increasing androgen excess. This overly abnormal hormonal milieu likely contributes to inadequate follicular development, resulting in the “polycystic” appearance of the ovaries seen with pelvic ultrasound imaging. Insulin resistance is usually detected in these patients due to increased androgen presence and leads to compensatory insulin hypersecretion by the pancreas in order to maintain normoglycemia. Patients often appear with physical indications of these excesses — hirsutism, acne, impaired glucose metabolism, irregular menses, and obesity. Noted in the patient in the vignette is the dermatologic finding of acanthosis nigricans, a darkening of the skin noted most commonly in patients with impaired insulin metabolism.
While the etiology of this disorder is not well known, overproduction of androgens by the ovaries (and possibly by adrenal glands as well) occurs, creating hirsutism and interrupted menses.
The hyperandrogenic state is further fostered by reduction of sex hormone-binding globulin, which effectively increases the proportion of free circulating androgens. Abnormally high levels of LH develop due to increased frequency of GnRH pulses from the hypothalamus, also increasing androgen excess. This overly abnormal hormonal milieu likely contributes to inadequate follicular development, resulting in the “polycystic” appearance of the ovaries seen with pelvic ultrasound imaging. Insulin resistance is usually detected in these patients due to increased androgen presence and leads to compensatory insulin hypersecretion by the pancreas in order to maintain normoglycemia. Patients often appear with physical indications of these excesses — hirsutism, acne, impaired glucose metabolism, irregular menses, and obesity. Noted in the patient in the vignette is the dermatologic finding of acanthosis nigricans, a darkening of the skin noted most commonly in patients with impaired insulin metabolism.
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Pathology - Multiple Endocrine Neoplasia
This is a familial endocrine tumor syndrome that can affect several distinct glands and therefore has diverse presentation. MEN 1 is inherited as an autosomal dominant trait and most patients have mutation in a gene on chromosome 11 called the menin gene. Endocrine tumors arise most commonly in the parathyroid glands (notice this patient has clinically severe hypercalcemia due to excess PTH). The presenting condition in this example is a bleeding peptic ulcer owing to a gastrinoma, however other forms of enteropancreatic tumors also occur.
Pituitary adenomas are also a common characteristic of MEN 1, which was the situation in the patient’s mother. Adrenal tumors and nonendocrine cancers such as lipomas also arise. The additional MEN disorders include MEN 2A and 2B, which are rare and stem from mutations in the ret -oncogene. These disorders likewise have an autosomal dominant pattern of inheritance but are most typically associated with medullary thyroid cancer (secreting calcitonin) and pheochromocytoma (adrenal medullary tumor).
This is a familial endocrine tumor syndrome that can affect several distinct glands and therefore has diverse presentation. MEN 1 is inherited as an autosomal dominant trait and most patients have mutation in a gene on chromosome 11 called the menin gene. Endocrine tumors arise most commonly in the parathyroid glands (notice this patient has clinically severe hypercalcemia due to excess PTH). The presenting condition in this example is a bleeding peptic ulcer owing to a gastrinoma, however other forms of enteropancreatic tumors also occur.
Pituitary adenomas are also a common characteristic of MEN 1, which was the situation in the patient’s mother. Adrenal tumors and nonendocrine cancers such as lipomas also arise. The additional MEN disorders include MEN 2A and 2B, which are rare and stem from mutations in the ret -oncogene. These disorders likewise have an autosomal dominant pattern of inheritance but are most typically associated with medullary thyroid cancer (secreting calcitonin) and pheochromocytoma (adrenal medullary tumor).
