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Pathology - Type 1 Diabetes Mellitus
Type 1 DM is a state of inappropriate hyperglycemia and abnormal metabolism caused by a shortage of insulin secretion. In 95% of type 1 DM patients, the cause is autoimmune destruction of the pancreatic beta-cells that release insulin. In the case vignette, a subacute onset has led in chronic hyperglycemia, evident from the elevated level of glycated hemoglobin (HbA 1c ). Hyperglycemia produces osmotic diuresis, which has resulted in hypovolemia with hypotension, tachycardia, and postural symptoms. Potassium waste from diuresis in combination with metabolic derangements causes to muscle weakness. A shortage of insulin leads to unrestrained glucagon dominance, culminating in hepatic ketone production. Ketosis is evident on urine dipstick and is severe enough to have resulted in ketoacidosis in this case (notice low serum bicarbonate implies metabolic acidosis). Treatment of type 1 DM necessitates replacement of insulin, which commonly combines a long-acting insulin formulation administered at bedtime, with short-acting insulin taken before meals. Patient education is a crucial element of treatment, with the goal of maintaining euglycemia (e.g., indicated when HbA 1c levels are maintained below 7%).
Type 1 DM is a state of inappropriate hyperglycemia and abnormal metabolism caused by a shortage of insulin secretion. In 95% of type 1 DM patients, the cause is autoimmune destruction of the pancreatic beta-cells that release insulin. In the case vignette, a subacute onset has led in chronic hyperglycemia, evident from the elevated level of glycated hemoglobin (HbA 1c ). Hyperglycemia produces osmotic diuresis, which has resulted in hypovolemia with hypotension, tachycardia, and postural symptoms. Potassium waste from diuresis in combination with metabolic derangements causes to muscle weakness. A shortage of insulin leads to unrestrained glucagon dominance, culminating in hepatic ketone production. Ketosis is evident on urine dipstick and is severe enough to have resulted in ketoacidosis in this case (notice low serum bicarbonate implies metabolic acidosis). Treatment of type 1 DM necessitates replacement of insulin, which commonly combines a long-acting insulin formulation administered at bedtime, with short-acting insulin taken before meals. Patient education is a crucial element of treatment, with the goal of maintaining euglycemia (e.g., indicated when HbA 1c levels are maintained below 7%).
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Pathology - Type 2 Diabetes Mellitus
Type 2 DM is a state of inappropriate hyperglycemia and abnormal metabolism caused by a combination of insufficient insulin production and insulin insensitivity in peripheral tissues. Long-term complications of DM, owing to small and large artery disease, include renal failure, blindness, amputations, myocardial infarction, stroke, and peripheral neuropathy. Most people with type 2 DM are overweight or obese. Insulin insensitivity correlates with visceral obesity (notice big waist circumference in this patient) rather than subcutaneous obesity. Adipose tissue releases cytokines (“adipokines”) including tumor necrosis factor and resistin that cause tissue insulin resistance and beta cell loss. A normal blood glucose concentration is initially maintained due to increased insulin secretion, but as the disorder progresses more beta cells are destroyed and this compensatory response begins to fail. Skin discoloration (acanthosis nigricans) is an indication of insulin resistance. Presenting signs such as vulvovaginitis, impaired vision, and peripheral neuropathy are more prevalent presentations of type 2 than type 1 DM. Ketoacidosis seldom develops in type 2 DM because a little insulin response is enough to prevent glucagon from triggering excess hepatic ketone production. Dyslipidemia frequently coexists with hyperglycemia as a consequence of insufficient insulin action. Treatment includes weight loss and exercise, both of which lower insulin resistance. Oral medicines include metformin to decrease hepatic glucose synthesis, sulfonylureas to stimulate insulin secretion, and incretin mimetics to both increase insulin secretion and inhibit glucagon secretion. Subcutaneous insulin injections may also need to be provided as the condition worsens.
Type 2 DM is a state of inappropriate hyperglycemia and abnormal metabolism caused by a combination of insufficient insulin production and insulin insensitivity in peripheral tissues. Long-term complications of DM, owing to small and large artery disease, include renal failure, blindness, amputations, myocardial infarction, stroke, and peripheral neuropathy. Most people with type 2 DM are overweight or obese. Insulin insensitivity correlates with visceral obesity (notice big waist circumference in this patient) rather than subcutaneous obesity. Adipose tissue releases cytokines (“adipokines”) including tumor necrosis factor and resistin that cause tissue insulin resistance and beta cell loss. A normal blood glucose concentration is initially maintained due to increased insulin secretion, but as the disorder progresses more beta cells are destroyed and this compensatory response begins to fail. Skin discoloration (acanthosis nigricans) is an indication of insulin resistance. Presenting signs such as vulvovaginitis, impaired vision, and peripheral neuropathy are more prevalent presentations of type 2 than type 1 DM. Ketoacidosis seldom develops in type 2 DM because a little insulin response is enough to prevent glucagon from triggering excess hepatic ketone production. Dyslipidemia frequently coexists with hyperglycemia as a consequence of insufficient insulin action. Treatment includes weight loss and exercise, both of which lower insulin resistance. Oral medicines include metformin to decrease hepatic glucose synthesis, sulfonylureas to stimulate insulin secretion, and incretin mimetics to both increase insulin secretion and inhibit glucagon secretion. Subcutaneous insulin injections may also need to be provided as the condition worsens.
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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).
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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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Symptoms and Signs – Differential Diagnosis of Chondrocalcinosis/pseudogout
(hyperparathyroidism)
Excess divalent ions: copper (Wilson's disease), iron (haemochromatosis), calcium
Acromegaly
Hypomagnesaemia
Hypophosphataemia
Ochronosis (alkaptonuria)
Osteoarthritis
(hyperparathyroidism)
Excess divalent ions: copper (Wilson's disease), iron (haemochromatosis), calcium
Acromegaly
Hypomagnesaemia
Hypophosphataemia
Ochronosis (alkaptonuria)
Osteoarthritis
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Symptoms and Signs – Differential Diagnosis of Chorea
Wilson's disease
Sydenham's chorea
SLE
Pregnancy
Polycythaemia
Oral contraception
Hypoparathyroidism
Hyperthyroidism
Huntington's disease
Wilson's disease
Sydenham's chorea
SLE
Pregnancy
Polycythaemia
Oral contraception
Hypoparathyroidism
Hyperthyroidism
Huntington's disease
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Symptoms and Signs – Differential Diagnosis of Choroidoretinitis
Toxoplasmosis
Sarcoidosis
Rubella (congenital)
Diabetes mellitus
CMV (congenital)
Toxoplasmosis
Sarcoidosis
Rubella (congenital)
Diabetes mellitus
CMV (congenital)
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Symptoms and Signs – Differential Diagnosis of Raised Creatine Kinase
polymyositis, defibrillation
Myxoedema
Myocardial infarction, myocarditis
Muscular dystrophy
Muscle damage: surgery, trauma, burns, IM injections, rhabdomyolysis, rigorous
Medications: statins, azathioprine, alcohol
exercise, seizures, haematoma, bowel ischaemia, dermatomyositis/
polymyositis, defibrillation
Myxoedema
Myocardial infarction, myocarditis
Muscular dystrophy
Muscle damage: surgery, trauma, burns, IM injections, rhabdomyolysis, rigorous
Medications: statins, azathioprine, alcohol
exercise, seizures, haematoma, bowel ischaemia, dermatomyositis/
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Symptoms and Signs – Differential Diagnosis of Clubbing
Congenital
Acquired
Cardiovascular
Atrial myxoma
Congenital cyanotic heart disease
Infective endocarditis
Respiratory
Cancer: bronchial, mesothelioma
Cryptogenic organizing pneumonia (rare)
Fibrosis (e.g. cryptogenic fibrosing alveolitis)
Suppurative lung disease (abscess, bronchiectasis, empyema)
Gastrointestinal
aneurysm, brachia! AV malformations
Cirrhosis
GI lymphoma, malabsorption e.g. coeliac disease
Inflammatory bowel disease
Others: Thyroid acropachy (thyrotoxicosis), unilateral clubbing: axillary artery
Congenital
Acquired
Cardiovascular
Atrial myxoma
Congenital cyanotic heart disease
Infective endocarditis
Respiratory
Cancer: bronchial, mesothelioma
Cryptogenic organizing pneumonia (rare)
Fibrosis (e.g. cryptogenic fibrosing alveolitis)
Suppurative lung disease (abscess, bronchiectasis, empyema)
Gastrointestinal
aneurysm, brachia! AV malformations
Cirrhosis
GI lymphoma, malabsorption e.g. coeliac disease
Inflammatory bowel disease
Others: Thyroid acropachy (thyrotoxicosis), unilateral clubbing: axillary artery
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Symptoms and Signs – Differential Diagnosis of Cold peripheries
Acute ischaemic limb (thromboembolism)
Drugs: Beta-blockers
Hypothyroidism
Raynaud's phenomenon (vasospasm)
Shock
Acute ischaemic limb (thromboembolism)
Drugs: Beta-blockers
Hypothyroidism
Raynaud's phenomenon (vasospasm)
Shock
