Cheiroarthropathy

- condition of limited joint mobility that occur in diabetics
- characterised by thickening of skin resulting in contracture of fingers
- unable to extend the fingers to fully flatten the hand
- treatment: pain relieve, phystiotherapy, tight glycemic control

Water deprivation test

- Patients are deprived of fluid for 8 hours or until 5% of body weight is loss
- patient should be weighed hourly
- plasma osmolality is measured 4 hourly
- urine volume and osmolality 2 hourly
- then give 2microgram desmopressin IM and check urine volume & osmolality and plasma osmolality over next 4 hours
- Interpretation
 ~ if serum osmolality > 305 mOsmol/kg = diabetes insipidus
 ~ urine osmolality < 300 mOsmol/kg after fluid deprivation and rising to above 800mOsmol/kg after desmopressin = cranial diabetes insipidus
 ~ urine osmolality < 300 mOsmol/kg after fluid deprivation and remains < 300mOsmol/kg after desmopressin = nephrogenic diabetes insipidus
 ~ urine osmolality > 800 mOsmol/kg after fluid deprivation without desmopressin = primary polydipsia
 ~ urine osmolality between 300 and 800 mOsmol/kg = partial DI/polydipsia

Subacute thyroiditis

- a.k.a De Quervain's /granulomatous / viral thyroiditis
- peak incidence 30-50 years, women affected 3 times more common than men
- during initial phase of follicular destrution, there is release of Tg and thyroid hormones, leading to increased circulating T4 and T3 and suppression of TSH (during this stage, radioactive iodine uptake is low or undetectable)
- after several weeks, the thyroid is depleted of stored thyroid hormone and a phase of hypothyroidism typically occurs
- finally thyroid hormone and TSH levels return to normal as disease subsides
- presents with painful and enlarged thyroid, sometimes fever
- malaise and URTI may precede the thyroid related features by several weeks
- patient typically complained of sore throat and pain is often radiated to jaw or ear
- ESR and CRP are markedly elevated
- treatment: NSAIDs (eg: aspirin 600mg QID), or prednisolone 40-60mg gradually tapered over 6-8 weeks
- thyroid function should be monitored every 2-4 weeks using TSH and unbound T4 levels

Incretin

- 2 main incretins, GLP-1 (glucagon-like peptide-1) and GIP (glucose dependent insulinotropic peptide)
- secreted by L cells of ileum and colon
- incretin effect: insulin response to oral glucose is better than intravenous glucose
- promotes glucose induced insulin release from pancreatic beta cells, delays rate of gastric emptying, promotes satiety, reduce appetite in brain
- suppress postprandial glucose secretion
- GLP-1 analogue (exenatide) is given by twice daily subcutaneous injection
- dipeptidyl peptidase 4 (DPP4) rapidly inactivates GLP-1. DPP4 inhibitor (sitagliptin or vildagliptin)

Pseudohypoparathyroidism

- due to mutation of PTH receptor with abnormality of the Gs alpha subunit with reduced cAMP production following a PTH infusion
- hypocalcemia with hyperphosphataemia and elevated PTH
- associated with short stature, low IQ and shortened 4th and 5th metacarpals (Albright's hereditary osteodystrophy)
- pseudopseudohypoparathyroidism is phenotypically similar to pseudohypoparathyroidism but biochemically normal
- both associated with genetic imprinting

Familial hypocalciuric hypercalcemia

- autosomal dominant
- mutation in gene on long arm of chromosome 3 encoding for calcium ion sensing G protein coupled receptor in kidney and parathyroid gland
- characterised by lifelong asymptomatic hypercalcemia associated with a relative hypocalciuria and a tendency to hypermagnesemia
- most are misdiagnosed as hyperparathyrodisim, but difference is in FHH, urinary calcium excretion
is low
- commonest presentation is renal stone, and rarely acute pancreatitis
- PTH levels are normal or slightly raised and urinary calcium is low
- can be differentiated from hyperparathyroidism by the calcium creatinine ratio in blood and urine

Cushing's syndrome

- Cushing's syndrome refers to the sustained overproduction of cortisol which causes centripetal obesity with moon face, Buffalo hump, hirsutism, recurrent infection, osteoporosis, hypokalemia, hyperglycemia, proximal myopathy, acne, striae and psychiatric disturbance

- 4 main causes

  i) exogenous corticosteroids

  ii) Cushing's disease (pituitary adenoma secreting ACTH)

  iii) ectopic ACTH production - hypokalemic alkalosis is typical. Caused by small cell lung CA

  iv) adrenal adenoma

- In the dexamethasone suppression test, normal individuals suppress cortisol level to less than 50nmol/L

- Incomplete suppression of cortisol following high dose of dexamethasone (2mg QID for 48hours) is typical of Cushing's disease (gold standard is inferior petrosal sinus sampling)

- Metyrapone is an inhibitor of 11 beta hydroxylase, inhibit the conversion of 11 deoxycortisol to cortisol, can be used in treatment of CS

Congenital adrenal hyperplasia

- hirsutism, ambiguous genitalia and precocious puberty in boys
- premature epiphyseal closure is a classical feature
- hyperpigmentation and hyperreninaemia

21-hydroxylase deficiency (commonest)
   - raised 17 hydroxyprogesterone is diagnostic
   - excess androgen production due to shunting of 17 hydroxyprogesterone into testosterone and androstenedione production
   - virilisation may result in clitoromegaly and labial fusion in female at birth

11-beta hydroxylase deficiency (second commonest)
   - reduced cortisol leads to increse in ACTH and subsequent increase in production of 11-deoxycorticosterone
   - diagnosis made by raised 11-deoxycortisol




Treatment of CAH
- replacement with dexamethasone/hydrocortisone
- efficacy of treatment is monitored by 17OH progesterone or androstenedione levels

Wolfram syndrome

- DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness)
- autosomal recessive
- mutation in transmembrane gene, WFS1

Hypertension with hypokalemia

Differential diagnosis
1) Renal artery stenosis / Renin secreting tumor (secondary hyperaldosteronism)
- high renin ; high aldosterone

2) Adrenal hyperfunction / Conn's syndrome (primary hyperaldosteronism)
- low renin ; high aldosterone
- adrenal adenoma are usually sensitive to ACTH, thus aldosterone secretion falls during the day as ACTH declines. With bilateral adrenal hyperplasia, aldosterone concentration is higher when patient is erect than supine.

3) Liddle's syndrome

4) Syndrome of apparent mineralocorticoid excess (SAME) / Liquorice usage
- low renin and low aldosterone
- SAME is an autosomal recessive disorder caused by mutation of HSD11B2 which encodes 11-B-hydroxysteroid dehydrogenase (which coverts cortisol to cortisone)
- Liquorice is a temporary form of AME due to its ability to block the enzyme

Diabetes insipidus

- presents with polyuria, nocturia and compensatory polydipsia
- high or high normal plasma osmolality with low urine osmolality ( low osmolality in primary polydipsia)
- high 24-hour urine volume
- failure of urinary concentration with fluid deprivation
- if fluid deprivation causing urine osmolality > 300mOsm/kg, it suggest primary polydipsia ;
  if not, it is either nephrogenic or cranial diabetes insipidus

Nephrogenic DI
- renal tubules are resistant to normal or high levels of plasma vasopressin
- causes : drugs (lithium, demeclocycline, glibenclamide), hypercalcemia, sickle cell disease, hypokalemia
- treatment: amiloride

Cranial DI
- causes: hypothalamic-pituitary surgery, Wolfram syndrome, meningitis, craniopharyngioma
- treatment: synthetic vasopressin analogue desmopressin (intranasal, oral or IM)

Diabetic amyotrophy

- a.k.a proximal diabetic neuropathy
- usually seen in older men with diabetes
- presents with painful wasting, usually asymmetrical of quadriceps muscles
- wasting may be very marked and knee reflexes are diminished
- affected area is often extremely tender
- nerve conduction studies to rule out other conditions
- 50% recover fully in 3-4 months
- often resolves in time with careful diabetic control or transference to insulin therapy

Maturity onset diabetes of young (MODY)

- monogenic diabetes mellitus
- early onset of diabetes with strong family history, often easy to control
- autosomal dominant
- MODY 3 (mutation of HNF-1a) is the commonest (70%), sensitive to treatment with sulphonylureas, raised HDL, preserved insulin sensitivity and glycosuria
- MODY 2 (mutation in glucokinase), usually asymptomatic and does not need treatment, but important to identify as it can lead to reduced birthweight in pregnancy
- MODY 1 (mutation of HNF-4a), presents later in life
- MODY 5 (mutation of HNF-1b), leads to renal cyst and proteinuria
- MODY 4 (IPF-1 mutation) and MODY 6 (NeuroD1 mutation) are rare

*HNF = hepatic nuclear factor
  IPF = insulin promoter factor

Glucagonoma

- rare alpha cell tumor
- 90% associated with skin rash (necrolytic migratory erythema)
- 70% are malignant, metastasis are common at presentation
- treatment: combination chemotherapy (streptazocin and 5-FU)

Autoimmune polyendocrine syndrome

Type 1
- autosomal recessive, rare
- mutation of AIRE gene on chromosome 21
- hypoparathyroidism, addison's disease, chronic mucocutaneous candidiasis
- other associations : hypogonadism, pernicious anemia, hypothyroidism, vitiligo, alopecia, chronic active hepatitis

Type 2 (Schmidt's syndrome)
- Addison's disease, type 1 DM, autoimmune thyroid disease
- other associations: hypogonadism, vitiligo, alopecia, pernicious anemia, chronic active hepatitis, atrophic gastritis, coeliac disease, dermatitis herpetiformis

Phaeochromocytoma

- associated with MEN II , Sturge Weber syndrome and von Hippel Lindau syndrome
- presents with hypertension, headache, palpitation, excessive sweating, anxiety
- symptoms are precipitated by sneezing, stress, surgery, cheese, alcohol, TCA
- rule of 10 - 10% extra-adrenal, 10% bilateral, 10% malignant, 10% familial, 10% not associated with hypertension
- familial phaeochromocytoma almost always arise from adrenal medulla
- adrenal medulla has cells that contain phenylethanolamine-N-methyltransferase that converts norepinephrine to epinephrine. This enzyme is lacking in other sympathetic ganglia.
- diagnosis by raised urinary catecholamines over 24 hours and MIBG (metaiodobenzylguanidine) scan of adrenals
- treatment for hypertension is with alpha-blockade (phenoxybenzamine) prior to beta-blockade

Multiple endocrine neoplasia

- autosomal dominant
- MEN-1 gene is a tumor suppressor gene producing menin (chromosome 11)
- MEN-2 gene is ret proto-oncogen (receptor tyrosine kinase)

MEN-1 (Wermer's syndrome)      "PPP" 
- Parathyroid hyperplasia/adenoma
- Pancreas endocrine tumor (gastrinoma, insulinoma, somatostatinoma, VIPoma, glucagonoma)
- Pituitary prolactinoma or GH secreting tumor

MEN-2A (Sipple syndrome)          "TAP"
- Thyroid (medullary thyroid carcinoma)
- Adrenal (phaeochromocytoma)
- Parathyroid hyperplasia

MEN-2B
- similar to MEN-2A, but parathyroid hyperplasia is rare
- plus mucosal neuroma and Marfanoid appearance

Hypokalemic periodic paralysis

- autosomal dominant
- mutation in muscle voltage gated calcium channel gene (CACLN1A3)
- associated with thyrotoxicosis
- commonly caused by medication (diuretics)
- can occur with hyperkalemia, but less common
- generalised weakness, including bulbar muscles, often starts after a heavy carbohydrate meal or following exertion
- potassium should be given before bicarbonate as bicarbonate can precipitate further hypokalemia

Hereditary hypokalemic tubulopathies

Things to remember for Bartter's , Gitelman's & Liddle's syndrome

- all present with hypokalemia + metabolic alkalosis

- Liddle's syndrome is autosomal dominant and associated with hypertension while the other two are recessive and normotensive. It is caused by mutation of epithelial sodium channel, thus hypertension is very sensitive to diuretics which target on ENaC (amiloride, triamterene)

- Bartter's syndrome is associated with increased urine calcium, and juxtaglomerular apparatus hyperplasia, associated with renal stone and nephrocalcinosis. Secondary hyperaldosteronism is characteristic (plasma volume is low despite normal blood pressure, thus stimulate renin release)

- Gitelman's syndrome is associated with low urine calcium and hypomagnesemia. Treatment is potassium and magnesium supplements.