Lect 7: Nutritional & metabolic disorder in ageing & neurological disorder

Osteoporosis

  • Decreased Ca salt deposition in bone
  • Fragility fractures of vertebrae, proximal femur
  • Hip fractures -> embolism of marrow ->ends up in lungs -> pneumonia & death
  • Dowager’s hump -> osteomalacia -> severe loss of Ca salts in bone

Risk factors

  • Smoking
  • Ca intake
  • Vitamin d deficiency
  • Family history
  • Parathyroid hormone
  • Decreased in obesity/ increased in low BMI

Ca regn

  • Parathyroid gland detects plasma Ca via Ca sensing receptor to release PTH when Ca is low
  • PTH stimulates osteoclasts to reabsorb bone & release Ca
  • PTH stimulates kidney to reduce Ca excretion & increase phosphate excretion
  • PTH increases VitD 1alpha-hydroxlase to increase 1,25(OH) VitD pdn in kidney
  • Balance
  • Increased phosphatase & 1,25(OH) VitD stimulates FGF23 pdn
  • FGF23 stimulates kidney to reduce phosphate reabsorption -> by reducing VitD 1alpha hydroxylase & decreases PTH

Vitamin D

DEXA- dual x-ray absorptiometry

  • Osteoporosis diagnosis
  • 2 x rays of diff energies to detect
    • Fat/soft tissue
    • Bone

Clinical biochemistry -> markers for showing increased risk/has osteoporosis

  • Bone reabsorption
    • C & N terminal collagen -> useful marker of increased bone deposition
    • Urinary calcium
  • Bone formation
    • Bone alkaline phosphatase
    • Osteocalcin
    • Markers of therapy

Metabolism

  • From diet -> dairy pdts
  • Goes to liver -> pro vitamin D in blood converted in kideny to 1,25(OH) VitD
  • Into blood stream where it is bound to vitamin D binding protein -> activates vitamin D receptor -> increase gene transcription -> increase of ca trpter in gut & kidney

Treatment

  • Ca supplementation + vitamin D
  • Biphosphonates -> inhibit bone resorption (etidronate,zoledronate)
  • Oestrogen Receptor Modulation ->inhibit bone resorption (HRT)
  • Hormone treatment ->PTH (teriparatide)

Neurological problems from osteoporosis ->involve nerve entrapment & severe spinal problems

  • Severe curving of spine -> Osteroporosis kyphosis
    • 2 danger points in cervical cord & lumbar cord
  • Cervical listhesis
    • Severe case of osteoporosis
    • MRI -> damage to spine & column shifted to one side -> major disability in arms & severe pain
  • Paget’s disease
    • Osteoporosis of skull
      • Primary progressive deafness/tinnitus
      • Vertigo -> cochlear lose Ca
      • Primary tooth loss
      • Secondary osteonecrosis of jaw from bisphosphonates

Iron

Disordered iron metabolism

  • Iron deficiency anaemia

  • Decreased muscle func & cognitive func


  • Transfusional overload (thalassaemia, sickle cell anaemia) - Diabetes, endocrine dysfunc


Iron uptake

  • Uptake regulated in gut
  • Fe3+ converted to 2+ -> comes in with metal trpter into entrhocyte -> some used internally, some stored
  • Goes into blood stream where it is converted to 3+ -> bind to binding protein Transferrin & circulates in body
  • Iron loss->unregulated
  • Absorption in upper GI
  • Reg by body iron store by hepcidin
  • Fe exported to plasma by Ferroportin & Haephestin
  • Bound to plasma Transferrin

Hemochromatosis

  • Common genetic disorder
  • Elevated transferrin iron saturation
  • Commonly recessive HFE mutations

  • Diabetes, cardiomyopathy



    Iron & neurological disorders

  • Freidreich’s ataxia
  • All extremely rare

Brain iron uptake

  • Periphery gets its own iron from Transferrin
  • BBB in brain -> reg everything
  • System on blood vessels of brain->Transferrin binds -> drops off iron onto endothelial cells and into brain itself
  • Another transferrin system -> circulates all the Fe in brain
  • Closed system
  • Transferrin dep
  • Highly expressed on neurons
  • Mitochondrial oxidative metabolism (IDA)
    • Brain takes 20% of body’s O2 ->high metabolic demand from mitoc oxidation of glucose; since mitoch FE rich -> hv high req for FE
  • Accum of Fe with age in glia

Fe deficiency anaemia (IDA)

  • Increases with age
  • Primary: diet; Secondary: GI disease (inflammatory disorders like Coeliac disease -> reduces Fe absorption)

  • Also due to chronic inflammatory disease


  • Improved EEG measures with Fe supplementation

  • Improved quality of life


  • X RCT (randomised clinical trial) of anaemia treatment in elderly



Clinical Fe biochemistry

  • Ferritin -> better marker for Fe stores

Folate & B12 deficiency

  • Similar clinically
  • Dietary & age related GI problems -> Coeliac
  • Neurological problems
  • Hyperhomocystinaemia -> relates to dementia
  • Macrocytic Hypochromic Anaemia
    • RBCs larger in size but reduced Hb content
  • Fatigue, muscle weakness
  • Cognitive impairment, depression
  • Paraesthesia, ataxia
  • Visual impairment

Folate

Folate deficiency

  • 1 in 10 over 75 -> 2% anaemic
  • Folate comes from green leafy vegetables

Folate uptake

  • Proton coupled folate trpter in proximal jejunum at low pH
  • Reduced folate carrier at near neutral pH
  • Folate receptor helps with cellular uptake

Risk factors

  • Poor diet
  • Coeliac disease
    • Water soluble vitamin
  • Congestive heart failure
    • Diuretics so increase water output -> lose folate
  • Alcohol abuse

Vitamin B12

Vitamin B12 deficiency

  • Plasma B12
  • 1 in 10 over 75 -> deficient
  • Only 10% show clinical signs of deficiency
  • Found in high meat diets

Vitamin B12 uptake

  • Vitamin B12 from food broken down -> binds to Haptocorrin in stomach
  • Haptocorrin deg in upper GI & B12 binds Gastric Intrinsic Factor (GIF)
  • Forms complex with Cubilin on surface of gut cells & enters cell via endocytosis
  • Proteins deg in lysosomes
  • B12 exported to blood via MBD1
  • Binds to transcobalamin for distribution

Treatment

  • B12 injection
  • Folate supplementation

Diagnosis

  • Sural nerve biopsy in folate deficiency neuropathy
    • Severe reduction of large myelinated fibres

Smith AD (2016)

  • Loss of folate seem to correlate with homocysteine
  • B vitamin supplementation -> cognitive decline in early dementia patients