Endocrinology

Hyperlipideamias and Sex hormones

Introduction

  • Fats are insoluble and must be carried in blood bound within protein molecules and these are called lipoproteins
  • Raised LDL-C carries with it increased risk of coronary disease and stroke
  • HDL-C is protective.
  • Chylomicrons : carry dietary fat in the form of triglycerides from the gut to the liver and TG is removed by lipoprotein lipase to form Intermediate density lipoproteins
  • Low density lipoproteins are formed by removing further TG from IDLS
  • LDLs are the main carriers of cholesterol to the liver and tissues and their level correlates with coronary risk
  • High density lipoproteins carry cholesterol back to the liver from peripheral tissues and correlate with decreased coronary risk
  • Familial combined hyperlipidaemia - Seen in 1 in 250 with a High LDL cholesterol and raised TG and Family history of coronary disease
  • Polygenic hypercholesterolaemia - Commonest cause of raised cholesterol with High fat intake. Treat with diet and statin
  • Familial hypercholesterolaemia

    Introduction

    • Autosomal dominant disorder 1 in 500

    Aetiology

    • Mutation of LDL receptor gene, apolipoprotein B100 gene and subtilisin/kexin type 9 gene Leads to raised LDL-C as LDL half life increased
    • Homozygotes are rare and present in childhood with Cholesterol > 30

    Clinical

    • Heterozygotes present in adulthood with increased coronary risk and TC > 7.8 mmol/l
    • Tendon Xanthomas and Xanthelasma

    Management

    • Treat with diet, weight loss, statins

    Familial hypertriglycerdidaemia

  • Autosomal dominant disorder 1 in 300

    Causes pancreatitis, Eruptive xanthomata, lipaemia retinalis, eruptive xanthomata Elevated VLDL and Triglycerides

  • May be due to lipoprotein lipase deficiency or apoplioprotein C-II deficiency
  • No increased risk of coronary disease and Management is dietary
  • Secondary Hypertriglyceridemia

  • Dietary, Type 2 Diabetes, Alcoholism, Obesity, Hypothyroid
  • Cushing's syndrome, Chronic kidney disease, Pregnancy
  • Causes of an Elevated LDL cholesterol

    • Diet/Obesity, Hypothyroid, drug - steroids, ciclosporin, thiazides
    • Nephrotic syndrome, Chronic liver disease and cholestasis, Alcoholism, Hypothyroid
    • Not Diabetes

    Management of dyslipidaemias

  • Primary prevention : target LDL Cholesterol < 4 mmol/l and Total cholesterol < 5.2 mmol/l and HDL > 1.0 mmol/l
  • Secondary prevention : target LDL Cholesterol < 2.5 mmol/l and Total cholesterol < 4.0 mmol/l
  • Dietary : weight loss and exercise
  • Statins : Inhibit HMG CoA Reductase involved in cholesterol synthesis and so they lower LDL-C and reduce cardiovascular (by 27%) and stroke risk (by 18%) and all mortality (by 15%). Can reduce cholesterol by 50%. May cause myositis and altered liver enzymes. Check CK and AST/ALT and stop if > 2-3 fold rise in AST or ALT. Commonest is Simvastatin but others include Atorvastatin which have slightly more cholesterol lowering effect
  • Fibrates : Reduce LDL and raise HDL and lower Triglycerides. Avoid with liver/renal disease.
  • Nicotinic acid often causes flushing. Lowers Cholesterol and TGs and increases DHL
  • Anion exchange resins e.g. cholestyramine and colestipol Can cause GI Symptoms.
  • Omega 3 fatty acids - Fish oils may be used with raised TGs
  • Porphyrias

    Introduction

    • Deficiency of an enzyme in the heme biosynthesis pathway leads to overproduction of porphyrin precursors which cause symptoms
    • Heme is made from succinyl-coA and glycine by eight enzymic steps and different steps take place in cytoplasm and mitochondria
    • Drugs can induce some of the initial steps in the pathway precipitating attacks of acute symptoms in those with enzyme deficiency

    Clinical

    • Acute attacks may occur with Acute intermittent porphyria and variegate poprhyria with episodes of Neuropathic abdominal pain, Constipation, Neuropsychiatric problems and neuropathy- usually motor or autonomic
    • Attacks may be precipitated by Sulfonamides, Fasting, OCP, Anaesthetic agents, Barbiturates, Alcohol
    • Fragile, photosensitive skin is seen with PCT and VP
  • Different forms
    • Acute Intermittent Porphyria is due to Porphobilinogen-deaminase deficiency seen in 1 in 100. Inherited as an autosomal dominant.
    • Variegate porphyria is due to protoporphyrinogen Oxidase deficiency. Autosomal dominant. Acute and skin manifestations
    • Porphyria cutanea tarda is deficiency of uroporphyrinogen decarboxylase. Is autosomal dominant so a family history may be available but also often sporadic be precipitated by alcohol, smoking, Chronic Hepatitis C, infection, Oestrogen exposure or iron overload Presents to dermatologists Skin fragility and pigmentation No acute symptoms

    Investigations

    • Increased PBG and ALA in urine and Urine darkens to port wine on standing and goes pink with Ehrlich's reagent which remains despite chloroform
    • Porphobilinogen-deaminase is only 40-60% of normal in AIP
    • Faecal porphyrins normal (AIP)
    • Faeces abnormal increase coproporphyrins and protoporphyrins (VP)
    • Hepatitis C serology with PCT
    • PCT : Increased uroporphyrinogen I and III in urine, Increased faecal coproporphyrinogen, Abnormal LFT's and mild iron overload.

    Management

    • In Acute attacks IV haematin may be given
    • Hydration, pain relief and a high carbohydrate diet which inhibits the pathway
    • The treatment of choice for PCT is removal of iron by therapeutic phlebotomy
    • Successful antiviral therapy of chronic Hepatitis C may also produce remission
    • Low-dose therapy with anti-malarial drugs such as chloroquine
  • Sodium and water balance

    Hyponatraemia

    Introduction

    • A low serum Na means a low serum osmolality which causes cellular oedema from osmotic shifts of water into cells. Rapid sudden changes can cause irreversible neuronal damage.

    Clinical

    • Mild < 130 mmol/l :
    • Symptoms of lethargy
    • Moderate < 120 mmol/l : Headchae, nausea, cramps, confusion
    • Severe < 110 mmol/l : Confusion, Seizure, delirium Coma, death

    Investigations

    • U&E - low Na
    • Urinary Na < 20 mmol where there is hypovolaemia and Na retention
    • Urinary Na > 20 mmol where there is no hypovolaemia or there is salt wasting from renal or cerebral disease
    • Check Cortisol levels - Short synACTHen if Adrenal failure considered (low BP and hypovolaemic, pigmentation)
    • Check TFTs

    Management

    • Expert help in difficult cases
    • Water overload : Restritct fluids
    • Salt loss exceeds water loss : IV N-Saline
    • IM Hydrocortisone if adrenal failure considered

    Syndrome of Inappropriate ADH (SIADH)

    Introduction

    • ADH (vasopressin) is a hormone produced in the supraoptic and paraventricular nuclei in the hypothalamus released by the posterior pituitary usually primarily in response to a change in serum osmolality
    • It prevents the loss of water in the collecting ducts
    • There it is released with any rise in plasma osmolality
    • The action is via G receptors in the corticomedullary collecting ducts by which aquaporins are inserted into the cells lining the lumen making them more permeable to water
    • However in some situations ADH is released in high levels inappropriately
    • Before one can make the diagnosis one must be sure that adrenal and thyroid function is normal
    • Patients become water intoxicated.

    Causes

    • Pituitary surgery and Cerebral disease - meningitis, encephalitis, GBS, SAH, Stroke, Bleed
    • Acute intermittent porphyria
    • Drugs - chlorpropamide, barbiturates, anaesthetics, barbiturates, morphine, diuretics, vincristine, vinblastine, cisplatin, cyclophosphamide, and melphalan, Opiates and narcotic analgesics
    • Malignancies - primary brain tumours, haematologic malignancies, intrathoracic non-pulmonary cancers, skin tumours, gastrointestinal cancers, gynaecological cancer, breast-and prostatic cancer, and sarcomas especially small cell lung cancer
    • Respiratory - Positive pressure ventilation, pneumonia, and lung abscess.

    Clinical :

    • Patient is clinically euvolaemic
    • Findings depend on degree of hyponatraemia.
    • Ranges from asymptomatic to those with lethargy, confusion/delirium and even Fits

    Investigations

    • Serum Na low
    • Urine Na > 20 mmol/l
    • Urine osmolality > Serum osmolality
    • Normal TFTs, Adrenal function, Glucose, Renal

    Management

    • Slow controlled correction by fluid restriction to 800-1000 mol/day
    • Refractory cases - demeclocyline to induce nephrogenic diabetes insipidus
    • Too rapid correction can cause quadriplegia and brainstem signs - Central pontine myelinosis

    Cerebral salt wasting

    Introduction

    • A syndrome by which cerebral injury leads to a urinary salt loss with resultant hyponatraemia which must be differentiated form those with SIADH

    Clinical

    • Signs of head injury or SAH. Polyuria
    • Dehydration - hypotension, tachycardia

    Investigations

    • Serum Na low
    • Urine Na > 20 mmol/l and tends to be higher than with SIADH
    • Urine output > 2500 mls/day

    Management

    • The treatment is with salt and volume replacement which is opposite to the fluid restriction needed for SIADH
    • Treatment is water and salt replacement
    • Consider fludrocortisone

    Hypernatraemia

    Introduction

    • Is usually due to excess free water loss
    • Polyuria - measure urine volume > 3 L/day

    Causes

    • Severe dehydration e.g. lost in the desert or immobile and forgotten in the ward side-room
    • Hyperosmolar non ketotic coma (HONK) with severe glycosuria
    • Cranial Diabetes Insipidus, Nephrogenic diabetes insipidus
    • Severe hypercalcaemia, Hyperglycaemia
    • Diuretics, Hypokalaemia
    • Potomania, Renal failure with impaired concentrating ability
    • Post SVT and ANP release

    Management

    • Determine underlying cause
    • Water replacement and rehydration

    Diabetes Insipidus

    Introduction

    • There is a failure to reabsorb water in the collecting tubules due to either an absence of ADH (Cranial) or insensitivity to ADH (Renal).

    Causes

    • Nephrogenic
      • Hypokalaemia, hypercalcaemia, lithium, familial, chronic kidney disease and Demeclocycline.
    • Cranial
      • Usually posterior pituitary damageLocal destructive lesion, trauma, surgical Usually improve with time.

    Clinical

    • Polyuria > 3 L (up to 20 L/day ) /day even despite severe dehydration and serum osmolality > 300 mosm/l
    • Polydipsia

    Investigations

    • Hypernatraemia if water access limited
    • Ensure normal Calcium, K, Glucose
    • Water deprivation will show urine osmolality < 300 mosm/l relative to serum osmolality > 295 mosm/l
    • Beware extreme dehydration (body weight falls > 5%)
    • Those with psychogenic polydipsia will have oliguria.
    • Give desmopressin an analogue of ADH with a longer half life which will reduce polyuria in those with cranial DI
    • MRI of head to look for pituitary or hypothalamic lesion when cranial diabetes diagnosed

    Management

    • Ensure adequate access to free water and if not will need IV rehydration.
    • Cranial
      • Give intranasal desmopressin an analogue of ADH with a longer half life which will reduce polyuria. It is given usually im or intranasal metered dose spray. Be careful of hyponatraemia and water intoxication

    • Nephrogenic
      • Treat cause. Ensure adequate water intake. The polyuria is helped by Bendroflumethiazide 2.5-5 mg / Amiloride 5-10 mg/day and some use Indomethacin. Diuretics to treat polyuria - a paradoxical effects - possibly due to constriction of the vascular space and some animal studies suggest that thiazides have a specific effect of increasing collecting duct water uptake. The role of the amiloride is to avoid hypokalaemia which can worsen polyuria

    Male Hypogonadism

    Introduction

    • Male Hypogonadism refers to reduced gonadal function which is due to either a primary testicular problem or a secondary (pituitary/hypothalamic) disorder.
    • Testicular (Primary) Causes - Klinefelter's syndrome, Cryptorchidism, Previous Orchitis, Previous chemotherapy or radiotherapy, Testicular trauma, Bilateral testicular torsion, Alcohol excess, Chronic illness
    • Non Testicular (Secondary) Causes - Hypothalamic tumours, Kallmann's syndrome, Idiopathic hypogonadotropic hypogonadism, Pituitary disease

    Clinical

    • Small testes, not fully formed genitalia
    • Loss of libido, Infertility, Impotence
    • Decreased shaving, Muscle weakness
    • Delayed puberty, Gynaecomastia
    • High-pitched voice, a small scrotum, Decreased phallic and testicular growth
    • Sparse pubic and axillary hair, and an absence of body hair
    • Absent secondary sexual characteristics
    • Osteoporosis, Absent beard growth and male pattern baldness in male
    • Poor muscle bulk, Female fat distribution in male
    • Anosmia (Kallmann's)

    Investigations

    • Low testosterone seen in primary and secondary
    • Low FSH/LH seen in secondary pituitary dysfunction
    • Prolactin may be high with prolactinoma
    • Sperm count reduced
    • Sex Hormone Binding globulin enables calculation of free testosterone index
    • Pituitary MRI may be needed

    Causes

    • Testicular hypogonadism - Klinefelter's syndrome, Mumps
    • Secondary male hypogonadism - Kallmann's syndrome, Haemochromatosis, Prader-Willi syndrome

    Management

    • Assess cause
    • Testosterone via im or orally, transdermally or implant for males
    • Treatment with GnRH can help restore fertility with secondary disease

    Hirsuitism

  • Causes
    • Polycystic ovary syndrome
    • Congenital adrenal hyperplasia
    • Ovarian tumour or Adrenal tumour
    • ACTH dependent Cushing? s disease

    Clinical

    • Hirsuitism, menstrual problems, acne
    • Virilisation ? male pattern baldness, increase muscle bulk, deep voice, clitoromegaly

    Investigations

    • Elevated testosterone and androstenedione and an elevated DHEAS
    • CT abdomen and pelvis ? Ovarian and adrenal masses

    Management

    • Surgical removal of adrenal or ovarian tumour
    • Oral contraceptive suppresses androgen production
    • Glucorticoids for CAH
    • Spironolactone and Cyproterone acetate
    • Metformin for PCOS
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