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Hurtle Cells
- Hurthle cells are large, polygonal cells with eosinophilic cytoplasm containing large quantities of mitochondria.
- They are seen in Follicular thyroid Cancer, but are a nonspecific finding, and are also seen in benign adenomas and chronic lymphocytic (Hashimoto) thyroiditis.
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Evaluation of Thyroid Nodule
- Patients without cancer risk factors or suspicious ultrasound findings, but with normal or elevated TSH, should also undergo FNA.
- Patients with low TSH levels should be evaluated with thyroid scintigraphy, preferably with iodine-123.
- A hyperfunctioning ("hot") nodule (increased isotope uptake in the nodule with decreased surrounding uptake) indicates a low cancer risk and may be treated for hyperthyroidism.
- An indeterminate or hypofunctioning ("cold") nodule (decreased isotope uptake compared to surrounding tissue) indicates a higher risk of cancer and should be evaluated further with FNA.
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Clinical Features of VIPOMA
 - Nearly 75% of VIPomas are in the pancreatic tail and 60%-80% have metastasized to the liver by the time of diagnosis.
- Treatment involves intravenous volume repletion, octreotide to decrease diarrhea, and possible hepatic resection in patients with metastasis to the liver.
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Pathophysiology of osteomalacia
- It is due to defective mineralization of the organic bone matrix.
- During new bone formation and remodeling, osteoclasis create a cavity at the bone surface that osteoblasts fill with organic matrix (osteoid).
- Calcium and phosphorus then deposit in the matrix to provide adequate mineralization.
- As a result, calcium or phosphorus deficiency at the mineralization front will lead to inadequate mineralization of the organic matrix.
- In children Vit D deficiency is called rickets where there is defective mineralization of the growth plate .
- X-ray findings include decreased bone density with thinning of cortex, eventual codfish vertebral bodies (concave shape), and pseudofractures (Looser zones).
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Evaluation of Secondary Amenorrhea
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Evaluation of Precocious Puberty
- Precocious puberty is categorized as gonadotropin dependent (central) precocious puberty, gonadotropin-independent (peripheral) precocious puberty, or incomplete precocious puberty.
- Bone age should be performed in all patients with early development of secondary sexual characteristics to assess for advanced skeletal maturation.
- Luteinizing hormone (LH) levels should be measured before and after gonadotropin-releasing hormone (GnRH) stimulation to determine whether the patient's precocious development is peripheral or central.
- In gonadotropin-independent precocious puberty, LH levels are low at baseline and do not increase after stimulation with a GnRH agonist.
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Late-onset (nonclassic) congenital adrenal hyperplasia (CAH)
- It is secondary to 21-hydroxylasedeficiency.
- This enzyme converts 17 -hydroxyprogesterone to 11-deoxycortisol and is deficient in approximately 90% of children with CAH.
- Classic CAH presents in the neonatal period with adrenal insufficiency and/or ambiguous genitalia;
- Late-onset CAH manifests in late childhood with signs of androgen excess.
- Clinical manifestations of late-onset CAH include premature adrenarche/pubarche, severe cystic acne resistant to treatment, accelerated linear growth, and advanced bone age.
- Patients with classic CAH have salt-wasting; those with late-onset CAH have normal electrolytes.
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Idiopathic precocious puberty
- It is characterized by premature activation of the hypothalamic-pituitary-gonadal axis.
- It accounts for 80% of gonadotropin-dependent precocious puberty and occurs almost exclusively in girls.
- Basal levels of LH are usually elevated and will increase with GnRH stimulation, making this diagnosis unlikely.
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Painless thyroiditis (silent thyroiditis)
- It is characterized by acute thyrotoxicosis with mild thyroid gland enlargement and suppressed TSH.
- It is an autoimmune disorder thought to be a variant of Hashimoto thyroiditis, although the latter classically presents with chronic hypothyroidism.
- A similar disorder can also be seen within a year following pregnancy but would be properly termed postpartum thyroiditis.
- The follicular inflammatory reaction in painless thyroiditis may occasionally lead to a persistent hypothyroid phase, but most patients recover normal thyroid function.
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Evaluation of Primary Hyperthyroidism
- Patients with hyperthyroidism and a suppressed TSH should undergo thyroid radioiodine scintigraphy to distinguish painless thyroiditis from Graves disease. With painless thyroiditis, radioiodine uptake is decreased suggesting the release of preformed thyroid hormone.
- In contrast, Graves disease causes hyperthyroidism due to increased synthesis of thyroid hormone. Radioiodine uptake will be diffusely increased, and extra-thyroidal manifestations (eg, exophthalmos, pretibial myxedema) are often present.
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Struma ovarii
- It is a very rare cause of thyrotoxicosis and is due to production of thyroid hormone by an ovarian teratoma.
- It typically presents in women over age 40 with a pelvic mass, ascites, or abdominal pain. The thyroid gland is not enlarged with this condition.
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Common causes of hypogonadotropic hypogonadism in men
- • Gonadotroph cell damage (eg, tumor, trauma, suprasellar surgery or radiation, infiltrative diseases, apoplexy)
- • Prolactinoma
- • Cushing syndrome (endogenous & iatrogenic)
- • Narcotic use
- • Severe systemic illness
- • Diabetes mellitus
- • Hemochromatosis
- • Anabolic steroid & testosterone use
- • Morbid obesity
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Nonfunctioning pituitary adenoma
- It usually arises from the gonadotropin-secreting cells (gonadotrophs) in the pituitary gland.
- Normal gonadotrophs secrete LH and FSH (which are dimeric hormones consisting of a common alpha -subunit and a different beta -subunit), but the dysfunctional cells in most gonadotroph adenomas secrete primarily the common alpha -subunit.
- The clinical symptoms of alpha -subunit overproduction are usually minimal ("nonfunctioning" adenoma), and the diagnosis is not usually apparent until the adenoma is large enough to cause features of mass effect on local tissues (eg, headache, visual field defects, disruption of the surrounding pituitary function)
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Evaluation of a nonfunctioning pituitary adenoma
- Production of most pituitary hormones (eg, TSH, LH) will be decreased due to compression of the neighboring normal pituitary cells.
- By contrast, prolactin levels are often mildly to moderately elevated due to anatomic disruption of the dopaminergic neural pathways that normally suppress prolactin secretion.
- A more significant elevation of prolactin [eg, more than 200 ng/ml] would suggest a prolactin-secreting adenoma (prolactinoma) rather than a nonfunctioning adenoma.)
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Benefit of Obesity in Postmenopausal Women
- During childpearing years, estrogens are mainly formed through the conversion of androgens by the enzyme aromatase, which is primarily present in granulosa cells of the ovary.
- Peripheral fat tissue also contains the enzyme aromatase to a lesser degree.
- After menopause, aromatase activity in the ovaries ceases and the only remaining tissue with aromatase activity is the peripheral fat.
- Patients who are obese will have more estrogen formation.
- This increased estrogen formation may help to alleviate many of the typical menopausal symptoms, such as vaginal dryness or dyspareunia.
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Maternal Thyroid Testing In Pregnancy
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Pregnancy and Hypothyroidism
- Patients with pre-existing hypothyroidism are unable to increase thyroxine production appropriately and are at risk for a worsening hypothyroid state and adverse fetal and maternal effects (eg, gestational hypertension, preeclampsia, premature delivery, postpartum hemorrhage).
- Hypothyroid patients on thyroxine should have their dose increased by approximately 30% at the time the pregnancy is detected. The dose should be adjusted subsequently (typically in 4-week increments) based on TSH using pregnancy-specific norms. Total T4 should also be followed and maintained within pregnancy-specific norms.
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Thyroid hormone production in Pregnancy
- It increases during pregnancy to cope with metabolic demands. This is accomplished by 2 mechanisms:
- • Estrogen stimulates synthesis of thyroxine-binding globulin (TBG) and decreases TBG clearance, leading to an increased pool of bound thyroid hormone. Patients with normal thyroid reserve subsequently increase thyroid hormone production to maintain free hormone levels.
- • hCG (which shares a common alpha subunit with TSH and a very similar beta subunit) directly stimulates TSH receptors. This results in increased hormone production with feedback suppression of pituitary TSH release.
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Congenital Adrenal Hyperplasia
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Congenital Adrenal Hyperplasia
- 21-hydroxylase deficiency prevents progesterone and 17-hydroxyprogesterone from being converted into aldosterone and cortisol, respectively.
- This leads to a mineralocorticoid deficit (hypotension, hyponatremia, hyperkalemia), while the resulting buildup of 17 -hydroxyprogesterone is instead shunted toward adrenal androgen synthesis (virilization of females).
- Severe forms of 21-hydroxylase deficiency can present at birth with salt-wasting, dehydration, and ambiguous genitalia in females.
- Partial deficiencies usually present during childhood with precocious puberty, hirsutism/virilism, medication-resistant acne, or accelerated growth.
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Steroid Synthesis Pathway
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Constitutional growth delay
- It is characterized by a delayed growth spurt, delayed puberty, and delayed bone age.
- It is the most common cause of short stature and pubertal delay in adolescents.
- Affected individuals have a normal birth weight and height, but between 6 months to 3 years of age, the height growth velocity slows, and the child drops percentiles on their growth curve.
- Around 3 years of age, the child regains a normal growth velocity and follows the growth curve at the 5th to 10th percentile.
- Puberty and the adolescent growth spurt are delayed, but eventually occur.
- The child will have a normal growth spurt and reach a normal adult height.
- Bone age radiographs show a bone age that is delayed compared to the chronological age.
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Diagnose and manage DKA
- For making a diagnosis of DKA, three things are necessary: blood glucose level more than 250 mg/dl , pH less than 7.3 or low serum bicarbonate (less than 15- 20 mmol/L), and detection of plasma ketones.
- Essential measures in the management of DKA include the following:
- 1. restoration of intravascular volume: using 0.9% saline (normal saline)
- 2. correction of hyperglycemia: using intravenous regular insulin
- 3. correction of electrolyte abnormalities: Potassium correction is very crucial.
- 4. treatment of precipitating factors such as infections: using antibiotics
- 5. Bicarbonate administration is reserved for DKA patients with severe acidosis (pH less than or equal to 7. 1), plasma bicarbonateless than 5 mEq/L, or severe hyperkalemia.
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Gaucher disease
- Etiology
- • Autosomal recessive, Increase prevalence in Ashkenazi Jews
- • Glucocerebrosidase deficiency leads to glucocerebroside accumulation in macrophages
- Typical features
- • Bone marrow infiltration results in anemia and thrombocytopenia.
- • Splenomegaly is severe and typically more prominent than hepatomegaly.
- • Skeletal involvement causes bony pain.
- • Other common features include failure to thrive (eg, at 5th percentile height and weight for age) and delayed puberty (eg, Tanner stage 1 in a 16-year-old girl).
- Management
- • Enzyme replacement
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Von-Gierkes' disease
- Glucose-6-phosphatase deficiency is also known as type I glycogen storage disease and
- This condition is caused by deficient glucose-6-phosphatase in the liver, kidneys, and intestinal mucosa.
- The typical patient is 3-4 months of age with hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Hypoglycemic seizures may occur.
- The characteristic features include a doll-like face (i.e., fat cheeks), thin extremities, short stature, and a protuberant abdomen (due to the enlarged liver and kidneys). The spleen and heart are normal.
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Pompes' disease
- It is also known as type II glycogen storage disease.
- It is due to Acid maltase deficiency.
- Although patients with this condition also have hepatomegaly, they usually present in the first few weeks of life as a "floppy baby" with feeding difficulties, macroglossia, and heart failure (due to progressive hypertrophic cardiomyopathy).
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Type III glycogen storage disease
- It is caused by a deficiency of glycogen debranching enzyme activity.
- Clinical manifestations (e.g. , hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation) are similar to type I glycogen storage disease: however, their laboratory findings differ.
- Patients with glycogen storage III disease have elevated levels of liver transaminases, fasting ketosis, and normal blood lactate and uric acid concentrations.
- Other pertinent findings are splenomegaly and normal kidneys.
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Type IV glycogen storage disease or amylopectinosis
- It is due to deficiency of branching enzyme activity. The typical patient is in his first 18 months of life with hepatosplenomegaly and failure to thrive.
- The most common pathology is progressive cirrhosis of the liver.
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Hers Disease (Typr VI glycogen Storage Disease)
- These Patients have deficiency of liver phosphorylase
- They have a benign course, and typically present with hepatomegaly and growth retardation early in childhood.
- Mild hypoglycemia, hyperlipidemia, and hyperketosis may occur.
- Lactic acid and uric acid levels are normal.
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Common Causes Of Gynecomastia
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Gynecomastia
- It is enlarged benign glandular tissue of the male breast.
- It can occur in up to 2/3 of pubertal boys and present as unilateral or bilateral firm subareolar nodules (sometimes tender to the touch).
- The breast development is due to transiently increased testicular production of estrogen over testosterone and peripheral conversion of prohormones to estrogen.
- Pubertal gynecomastia resolves in most patients within a few months to 2 years without intervention
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Thyroid Lymphoma
- The risk of thyroid lymphoma is about 60 times higher in patients with Hashimoto's thyroiditis compared to patients without thyroiditis.
- The typical presentation is rapid enlargement of the thyroid gland in patients with preexisting Hashimoto's thyroiditis.
- Compressive symptoms (e.g., dysphagia, voice change) are common.
- CT scan of the neck shows enlargement of the thyroid gland around the trachea: this is also known as the 'doughnut sign.'
- Thyroid ultrasound shows a characteristic pseudocystic pattern.
- The radioactive iodine uptake is reduced.
- Fine needle aspiration biopsy may miss the diagnosis; therefore, core biopsy is often required for making a diagnosis
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Alzheimer's dementia
- It presents with early problems in visuospatial abilities (e.g. getting lost in their neighborhood) and anterograde memory formation.
- Old memories tend to be preserved. Personality and behavioral changes (e.g. hypersexuality, agitation) may occur as the disease progresses.
- Hallucinations and changes in alertness are late findings.
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Normal pressure hydrocephalus (NPH)
- It is a disease characterized by dementia, abnormal gait, and urinary incontinence.
- The gait is broad-based and shuffling and patients tend to be bradykinetic.
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Thiamine Deficiency
- Thiamine deficiency can lead to Wernicke-Korsakoff syndrome.
- This disease presents as ataxia, ophthalmoplegia, and confusion (Wernicke's) in addition to confabulation and amnesia (Korsakoffs). It is particularly common in alcoholics.
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Obesity And Precocious Puberty
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Isolated premature adrenarche
- It is caused by increased adrenal androgen secretion.
- Typical manifestations include body odor. oily hair and skin, acne, pubic hair (pubarche). and axillary hair.
- Laboratory findings may show slightly elevated DHEA S, but testosterone levels are usually low.
- Isolated premature adrenarche is generally benign but is a significant risk factor for polycystic ovarian syndrome (PCOS), type 2 diabetes mellitus and metabolic syndrome, especially in those who are obese.
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Precocious puberty
- It is defined as the development of secondary sex characteristics before the age of 8 in girls and 9 in boys.
- Accelerated bone growth and advanced bone age are also common.
- The causes of precocious puberty can be broken into two categories: central and peripheral.
- Central precocious puberty is the result of early activation of the hypothalamic-pituitary-ovarian (HPO) axis.Therefore, FSH and LH levels are elevated in central precocious puberty.
- Patients with peripheral precocious puberty present with low FSH and LH levels.
- Central precocious puberty is caused by GnRH activation, peripheral precocious puberty is caused by gonadal or adrenal release of excess sex hormones.
- All patients with central precocious puberty should receive brain imaging with CT or MRI. Treatment is with GnRH analog therapy.
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Refeeding syndrome
- It is the constellation of pathologic derangements resulting from a surge in insulin activity as the body resumes anabolism.
- Carbohydrate ingestion, whether enteral or intravenous, causes pancreatic insulin secretion and cellular uptake of phosphorus, potassium, and magnesium.
- Phosphorus is the primary deficient electrolyte as it is required for energy (adenosine triphosphate).
- Deficiencies in potassium and magnesium potentiate cardiac arrhythmias in a heart that is already atrophic from prolonged malnutrition.
- Therefore, aggressive initiation of nutrition without adequate electrolyte repletion can quickly precipitate cardiopulmonary failure.
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Pathogenesis of Refeeding Syndrome
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Primary Hypoparathyroidism
- It is characterized by low calcium and elevated phosphorus levels in the presence of normal renal function.
- Causes of hypoparathyroidism include post surgical, autoimmune parathyroid destruction, and defective calcium-sensing receptor.
- Hypocalcemia is the most common complication seen post thyroidectomy
- Patients with hypocalcemia can be asymptomatic at initial presentation (found incidentally) or may complain only of nonspecific symptoms (eg, fatigue, anxiety, depression).
- Involuntary contractions (tetany) involving the lips, face, and extremities and seizures are seen in severe hypocalcemia.
- Electrocardiogram may show QT -interval prolongation.
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Evaluation of Hypocalcemia
- In asymptomatic patients, a single low serum calcium level must always be confirmed by a second serum calcium value.
- Hypoalbuminemia, hypomagnesemia, and certain drugs (eg, calcium chelators, bisphosphonates, phenytoin) can also cause hypocalcemia and should be considered.
- After hypocalcemia has been confirmed, the next step is to check parathyroid hormone (PTH) level.
- The most common cause of hypoparathyroidism seen in hypocalcemia is due to a recent parathyroid surgery or surgeries involving the surrounding area (eg, thyroidectomy).
- An elevated PTH level is commonly seen in vitamin D deficiency and chronic kidney disease.
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Diagnostic Approach to Hypocalcemia
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