Metabolic Medicine Flashcards
Vitamin D is relatively inactive. List the Vitamin D activation steps
Vitamin D is made in the skin following UV exposure to sunlight.
1,25(OH)2 vitamin D is made from vitamin D (D2 or D3 forms).
Both vitamin D2 and D3 undergo 25-hydroxylation in the liver and α-hydroxylation in the kidney to produce the activated form ,25(OH)2 vitamin D.
The rate-limiting step is the α-hydroxylation.
Calcium - sites of reabsorption
Kidney - calcium is reabsorbed in the distal convoluting tubule
Gut - calcium is reabsorbed in duodenum and upper jejunum
Calcium, PTH, Vitamin D Axes - what happens if there is a drop in calcium serum level
Low blood Ca
Release of PTH by parathyroid gland
Increased vitamin D hydroxylation
Increased bone resorption
Increased Ca reabsorption in kidneys
Decrease in PO4 levels (increased excretion)
Effects of PTH at high levels
High levels of PTH + poor control of serum phosphate and calcium-phosphate product in CKD causes increased cardiovascular disease risk and vascular calcification.
Calcific uraemic arteriolopathy (calciphylaxis), a painful ulcerating skin condition carrying a high mortality, is also a risk factor in patients with chronic kidney disease.
Effects of Vitamin D
- Gut: multiple actions on different proteins serve to increase absorption of calcium and phosphate.
- Kidney: inhibits its own synthesis by reduced 1α-hydroxylase activity.
- Parathyroid glands: inhibits PTH synthesis.
- Bone: at high concentrations, activated vitamin D increases osteoclastic activity, promoting bone
resorption.
Hypercalcaemia - what are calcium levels adjusted and why are they necessary?
Calcium is protein-bound
Adjusted calcium concentration = Measured calcium + [(0.02 × (42-albumin level in g/L)].
A low adjusted calcium may be found in patients with severe hypoalbuminaemia, while true ionised calcium levels are normal.
At what level will hypercalcemia be symptomatic? List the symptoms of hypercalcemia.
- Adjusted calcium concentration >3.8 mmol/L carries risk of arrhythmias.
Adjusted calcium concentration >3.0 mmol/L, usually causes symptoms.
BONES
STONES
ABDOMINAL GROANS
PSYCHIC MOANS - malaise, polyuria, polydipsia, nocturia, renal calculi, bone pain (due to osteitis fibrosa cystica), abdominal pain, nausea, constipation, dehydration, low mood and confusion.
- Adjusted calcium concentration >3.8 mmol/L carries risk of arrhythmias.
Causes of hypercalcemia [8]
Primary and tertiary hyperparathyroidism
Malignancy (cytokine release & production of PTH related peptide or calcitriol)
Thyrotoxicosis
Hypoadrenalism
Thiazide diuretics, excess Vit D, Milk-alkali syndrome
Immobility
Sarcoidosis
Familial hypocalciuric hypercalcemia
Primary, secondary & tertiary hyperparathyroidism
Why does secondary hyperPTH not cause hypercalcemia?
- Primary hyperparathyroidism:
◆ Increased PTH due to parathyroid adenoma(s) or hyperplasia.
◆ 80% due to a benign solitary adenoma.
◆ MEN types 1 and 2A (2%)
◆ Characterised by high corrected serum and urine calcium, and low serum phosphate. - Tertiary hyperparathyroidism: autonomous secretion with high PTH despite hypercalcaemia.
(Secondary hyperparathyroidism does not cause hypercalcaemia but is characterised by increased
PTH in response to hypocalcaemia with low active vitamin D levels because of renal disease or dietary deficiency.
Hypercalcemia Ix [10]
- History: exclude iatrogenic causes and immobility; ask about symptoms of malignancy.
- Examination: look for signs of malignancy and investigate as appropriate.
- Blood tests for urea and electrolytes (to exclude renal impairment), calcium, PTH, vitamin D,
phosphate and magnesium. - Urine test for calcium (ideally a 24-hour collection) and calcium:creatinine ratio to exclude familial
hypocalciuric hypercalcaemia. - X-rays: look for characteristic sub-periosteal resorption of distal phalanges, tapering of distal
clavicles, ‘salt and pepper pot’ skull lucencies and brown tumours of long bones. - If PTH levels are appropriately suppressed in the face of a normal PTH axis, check thyroid
stimulating hormone (TSH), protein electrophoresis, urinary Bence–Jones protein and consider a Synacthen® (tetracosactide) test. - Parathyroid technetium (99mTc) sestamibi scan to identify parathyroid adenomas in primary
hyperparathyroidism. - If all aforementioned tests are negative, investigate further for malignancy.
- Dual energy X-ray absorptiometry (DEXA) scan for evidence of resulting osteoporosis.
Hypercalcemia Treatment
Mild - monitor for renal stones
Moderate - fluid resuscitation, loop diuretic (furosemide)
Primary hyperparathyroidism - surgical resection
Cinacalcet
Glucocorticoids for cancer, sarcoidosis, vitamin D toxicity
Bisphosphonates
Calcinet for hypercalcemia
Mechanism of action? Indications?
Cinacalcet is a calcium sensing receptor agonist- acts on the parathyroid cells, mimics effect of hypercalcaemia, suppressing PTH synthesis and secretion.
Indications: tertiary hyperparathyroidism due to chronic kidney disease, primary hyperparathyroidism unsuitable for surgery and hypercalcaemia from malignancy not responding to treatment.
The combined use of vitamin D and calcimimetics has reduced the need for parathyroidectomy in the management of renal bone disease.
Bisphosphonates for hypercalcemia
Mechanism of action? What is used in emergency? Chronic severe?
- Bisphosphonates inhibit osteoclastic activity
- prevent calcium release from bone.
- Intravenous pamidronate - emergency situations.
- Chronic severe hypercalcaemia may benefit from a bisphosphonate with a longer half-life (e.g. risedronate or zoledronic acid).
Hypocalaemia - severity classification into mild, moderate, severe
- Adjusted calcium concentration 2.0–2.5 mmol/L is often asymptomatic.
- Adjusted calcium concentration <2.0 mmol/L may cause symptoms
- Adjusted calcium concentration <.8 mmol/L may result in arrhythmias or seizures, especially with a rapid fall in serum calcium.
Symptoms of hypocalcemia
Give 3 points
- Neuromuscular excitability, tetany and paraesthesiae of the extremities and perioral area, along with cramps and tetany.
- Trousseau and Chvostek signs may be demonstrated
- ECG may show a prolonged QTc interval.
Causes of hypocalcemia Part 1
Causes of hypocalcaemia
Give 8 points
- Lysis syndromes- rhabdomyolysis, tumour lysis syndrome, widespread release of phosphate from damaged cells binding to calcium, lowering serum levels.
- Osteoblastic metastases with calcium uptake
- Rx
- DiGeorge syndrome (Ch22)
- Acute pancreatitis (marker of severity)
- Diet
- CKD
- Underactivity of PTH and vitamin D axes
- Magnesium deficiency impairs PTH secretion and promotes resistance to the actions of PTH.
Causes of hypocalcemia: Part 2
Which cancers are associated?
How does infusion of citrate blood products cause hypocalcaemia?
How does CKD cause hypocalcaemia?
Prostate, breast or bladder cancers cause osteoblastic mets with calcium uptake.
Infusion of citrate-containing blood products that can cause pronounced hypocalcaemia due
to citrate complexing with calcium.
CKD causes underactivity of axes:
Reduced hydroxylation of vit D > lack of active Vit D > unable to feedback to PTH to increase levels. Reduced phosphate excretion inhibits Vit D.
What other causes can result in inactivity of PTH and vitamin D axes?
- Hypoparathyroidism: associated with parathyroid damage, surgical removal (e.g. during
thyroidectomy), autoimmune polyglandular endocrine syndromes and various mutations affect-
ing the calcium sensing receptor. - Pseudohypoparathyroidism (Albright’s hereditary osteodystrophy): hypocalcaemia with
measureable PTH, caused by end-organ resistance to the effects of PTH due to mutations.
Hypocalcaemia: Investigation
History: ?chronic kidney disease, longstanding hypertension, diabetes mellitus, malabsorption and family history. Review medication.
Examination: ?malignancy, features of
chronic kidney disease or Albright’s hereditary osteodystrophy
- Blood tests: bone profile, Mg, vitamin D, urea & Cr, LFTs, CK.
- Urinary calcium and PO4 excretion.
- Imaging: growth plate abnormalities in children, pseudofractures (Looser’s zones), reduced bone mineral density (BMD) on DEXA.
Management of hypocalcaemia
CKD? Hypophosphatemic rickets? Oncogenic osteomalacia
- CKD - 1-alpha hydroxylated vitamin D and alfacalcidiol corrects hypocalcaemia and suppresses PTH synthesis & secrertion.
- Oncogenic osteomalacia requires tumour resection.
Osteomalacia - bone profile?
low vitamin D levels
low calcium, phosphate (in around 30%)
raised alkaline phosphatase (in 95-100% of patients)
Osteomalacia
Definition
Cause
Features
Osteomalacia
* Osteomalacia describes softening of the bones because of low vitamin D levels
* If this occurs in growing children it is referred to as rickets, with the term osteomalacia preferred for adults.
* vitamin D deficiency
* Features: bone pain, bone muscle tenderness, femoral neck fracture, proximal myopathy > waddling gait
Osteomalacia
Radiological signs
translucent bands (Looser’s zones or pseudofractures)
Treatment includes loading dose vit D with ca supplementation
Inherited metabolic disorders
Phenylketonuria
an inability to convert phenylalanine into tyrosine due to lack of phenylalanine hydroxylase. This results in hyperphenylalaninaemia and increased excretion of its metabolite, phenylpyruvic acid (‘phenylketone’) in the urine.
Causes of hypoglycaemia
- Most common: drug treated DM by sulfonylureas, insulin.
- Rx: quinine, indoetacin
- Alcohol inhibits gluconeogenesis
- Hepatic failure impairs gluconeogenesis & glycogen storage
- Hormonal deficiencies e.g., hypoadrenalism, GH, glucagon, thyroid deficiency
- Insulinoma
- Malignancies that consume glucose
- NIPHS
- Bariatric surgery
- Neonatal
- Genetic
Hypoglycaemia
What is NIPHS?
Non insuloma pancreatogenous hypohlycaemia syndrome
- Hypertrophy and new formation of pancreatic islets cause increased insulin production & typically post-prandial hypoglycaemia.
Hypoglycaemia: investigation in a non-diabetic adult
Non diabetic adult with glc <4mmol/L
* Insulin, c-peptide, anti-insulin antibodies
* Determine if there is endogenous hyperinsulinism - insulinoma
* If not, exogenous causes (rx), sepsis, malnutrition, end organ failure, hormone deficiency
High density lipoprotein (HDL) vs LDL
HDL - transports cholesterol to liver
* Ways to increase HDL - reduce weight, increase exercise, alcohol in moderation, smoking cessation.
LDL - increased risk of atherosclerosis by entering vascular wall, being oxidised and promoting entry and activation of macrophages
* Way to decrease LDL & TC - reduce dietary fat & cholesterol, increase fibre
Familial Hypercholesterolemia
- AD inheritance
- Xanthomata in tendon, iris
- Associations: early onset CVD
- Diagnosis confimed by genetic analysis
- Mx: statins
Drugs used in hyperlipidemia
- 3-HMG COA reductase inhibitors
- Fibrates
Mechanism of action, side effects, interactions
- Competitive inhibition of enzyme involved in production of cholesterol from LDL. Statins may cause myositis, potentiates warfarin
- Works on PPAR in liver increasing enzymes that clear triglyceride rich proteins from the blood, potentiates warfarin
Ezetimibe
MOA: inhibits gut cholesterol absorption
Inherited metabolic disorders
Phenylketonuria
- usually presents by 6 months e.g. with developmental delay
- child classically has fair hair and blue eyes
- learning difficulties
- seizures, typically infantile spasms
- eczema
- ‘musty’ odour to urine and sweat*
Inherited metabolic disorders
Phenylketonuria
Diagnosis [3]
Management [3]
Diagnosis
* Guthrie test: the ‘heel-prick’ test done at 5-9 days of life - also looks for other biochemical disorders such as hypothyroidism
* hyperphenylalaninaemia
* phenylpyruvic acid in urine
Management
* poor evidence base to suggest strict diet prevents learning disabilities
* dietary restrictions are however important during pregnancy as genetically normal fetuses may be affected by high maternal phenylalanine levels
* Sapropterin is a new drug that activates residual phenylalanine hydroxylase, leading to improvement
of phenylalanine metabolism and decreasing phenylalanine concentrations
Inherited Metabolic Disorders
Alkaptonuria
Pathophysiology, Presentation
- Due to a deficiency of homogentisate dioxygenase (which is also part of the phenylalanine/tyrosine breakdown pathway).
- Results in accumulation of homogentisic acid in cartilage and other tissues (ochronosis):
◆ blue/black discolouration of ear cartilage and sclera;
◆ spine and large joint arthritis;
◆ cardiac valve disease;
◆ renal calculi.
Inherited Metabolic Disorders
Alkaptonuria
Diagnosis, Treatment [3]
- Diagnosed by elevated homogentisic acid in urine; homogentisic acid also causes urine to turn red/
black on standing. - Treatment is with a low phenylalanine and tyrosine diet. Vitamin C is a mild antioxidant.
- Nitisinone, which blocks an upstream pathway in phenylalanine/tyrosine breakdown, is currently
being evaluated for treatment.
Inherited Metabolic Disorders
Homocystinuria
Presentation [5]
- Due to a deficiency of cystathionine beta-synthase, a vitamin B6-dependent enzyme, involved in the breakdown of homocysteine to cysteine.
Presentation: - often patients have fine, fair hair
- Marfanoid body habitus: arachnodactyly etc osteoporosis, kyphosis
- neurological: may have learning difficulties, seizures, ocular downwards (inferonasal) dislocation of lens, severe myopia
- increased risk of arterial and venous thromboembolism
- also malar flush, livedo reticularis
Inherited Metabolic disorders
Homocystinuria
Investigations, Management
- Diagnosis: elevated methionine and homocysteine (reduced sulphydryl monomer form) concentrations in plasma and increased homocystine (oxidised disulphide) concentration in urine.
- cyanide-nitroprusside test: also positive in cystinuria
- Depending on the exact genetic mutation, patients may respond to high dose vitamin B6, vitamin B12, folic acid, betaine or a methionine-restricted diet.
Urea Cycle Disorders
Causes of hyperuricemia
3 mechanisms
- Underexcretion - most common
* Decreased glomerular filtration (hypothyroidism, lead toxicity)
* Decreased renal tubular secretion (DKA)
* Increased renal tubular reabsorption (DI, anti-uricosuric drugs like diuretics) - Overproduction
* Exogenous from diet like offal, game.
* Endogenous sources - HGPRT deficiency, Lesch-Nyhan syndrome. - Combined mechanisms
Inherited Metabolic Disorders: Urea cycle disorders
Causes of hyperuricema with combined mechanisms
combined mechanisms: Under-excretion and overproduction, 2 points
◆ Most commonly alcohol consumption that results in accelerated hepatic breakdown of ATP and the generation of organic acids that compete with urate for tubular secretion.
◆ Enzymatic defects such as glucose-6-phosphatase deficiency (Type I [von Gierke] GSD).
Gout Management
Acute episodes, long term management
- Treatment is with NSAIDs and colchicine for acute episodes.
- NSAIDS or colchicine may be contraindicated or poorly tolerated by some groups patients (eg CKD)
- Longer-term lowering of uric acid is achieved with allopurinol. Febuxostat (selective nonpurine xanthine oxidase inhibitor) has also been shown to effectively lower serum uric acid levels
- Hyperuricaemia is associated with increased cardiovascular risk
Gout management
What are alternatives if NSAIDs are not suitable for the patient?
short courses of oral steroids, or a long-acting intramuscular steroid injection, can be prescribed as an alternative.
Osteoporosis vs Osteomalacia vs Pagets Disease on blood tests
PTH, Ca, PO4
Osteoporosis - doesnt affect blood tests
Osteomalacia -
* vitamin D low
* Low Ca
* Low phosphate
* Raised ALP
Pagets disease- ALP isolated rise
