12. Plasma Proteins and amino acid disorders

Define dysproteinaemia

Change in serum protein levels/fractions (excluding fibrinogen)

Normal total plasma protein

60 – 80 g/L

Basic screening test for dysproteinaemia

Serum protein electrophoresis

Albumin: share and main functions

~55–65% of protein

Maintains oncotic pressure (keeps water in vessels) + transports insoluble molecules

Why does hypoproteinaemia cause oedema?

↓ albumin → ↓ oncotic pressure → fluid leaves capillaries into the interstitium

α1-globulins

α1-antitrypsin, α1-acid glycoprotein, HDL, thyroxine-binding globulin

⚠ Your notes said: 'tyrosine-binding protein' and no α1-antitrypsin.

α2-globulins

α2-macroglobulin, haptoglobin, ceruloplasmin, α2-antiplasmin, VLDL

β-globulins

Transferrin, LDL, complement C3

γ-globulins

Immunoglobulins (IgG, IgA, IgM)

⚠ Your notes said: γ-globulin = Factor VIII.

Serum vs plasma electrophoresis difference

Serum lacks fibrinogen (consumed in clotting)

Relative vs absolute hyperproteinaemia

Relative: haemoconcentration (dehydration)

Absolute: real ↑ globulins (inflammation, infection, paraproteins)

Define paraprotein (M-protein)

Monoclonal immunoglobulin or fragment made by a single clone of plasma/B cells

Causes of paraproteinaemia (monoclonal gammopathy)

Multiple myeloma, Waldenström's macroglobulinaemia, MGUS (also some lymphomas)

⚠ Your notes said: 'caused by leukaemia, lymphoma' — the classic cause is multiple myeloma.

Causes of hypoproteinaemia

• ↓ intake (malnutrition)

• ↓ synthesis (liver cirrhosis/hepatitis)

• ↑ loss (nephrotic syndrome, protein-losing enteropathy, burns)

• ↑ catabolism (cancer)

Electrophoresis in acute inflammation

↑ α1 and α2 (acute-phase proteins)

Electrophoresis in chronic inflammation

↑ γ, broad polyclonal

Electrophoresis in nephrotic syndrome

↓↓ albumin, ↑ α2 (α2-macroglobulin too big to be filtered)

Electrophoresis in liver cirrhosis

↓ albumin, ↑ polyclonal γ, β–γ bridging

Electrophoresis in multiple myeloma

Narrow M-spike, usually in the γ region

General mechanism of inherited amino acid disorders

Single gene/enzyme defect → block in a pathway → substrate accumulates and/or product is deficient (or transport defect)

PKU — enzyme defect

Phenylalanine hydroxylase (phenylalanine → tyrosine)

Autosomal recessive

PKU — consequences

↑ phenylalanine (neurotoxic) + ↓ tyrosine → ↓ catecholamines, melanin, thyroxine

PKU — clinical features

Intellectual disability, seizures, growth restriction, vomiting, fair skin/hair, musty odour

Homocystinuria type I

Cystathionine β-synthase deficiency (homocysteine → cystathionine)

Autosomal recessive

Homocystinuria type II

Defective methylcobalamin synthesis → ↓ methionine synthase (homocysteine → methionine)

⚠ Your notes said: 'converts homocysteine to methylcobalamin'.

Homocystinuria type III

MTHFR defect — can't make 5-methyl-THF (methyl donor for homocysteine → methionine)

Homocystinuria — clinical features

Ectopia lentis, marfanoid skeleton, intellectual disability, thromboembolism (homocysteine damages endothelium)

Hartnup disease — defect

Defective Na⁺-dependent neutral amino acid transporter (e.g. tryptophan) in gut and proximal tubule

Hartnup disease — consequence

↓ tryptophan → ↓ niacin (B3) → pellagra (dermatitis, diarrhoea, dementia)

Plasma protein fractions (g/L): albumin _____, α1 _____, α2 _____, β _____, γ _____

35–55 | 1–3 | 6–10 | 7–14 | 7–16

Normal fibrinogen and CRP

Fibrinogen 2–4 g/L

CRP < 3–5 mg/L (acute-phase marker)

Haptoglobin (α2) — function

Binds free haemoglobin released by haemolysis so it isn't lost in urine

↓ in haemolytic anaemia

⚠ Your notes said: α2-globulins are 'involved in binding of Hb to O2'.

Monoclonal vs polyclonal gammopathy

Monoclonal: one clone → one M-protein (myeloma, MGUS, Waldenström, amyloidosis)

Polyclonal: many clones → broad γ rise (chronic infection, autoimmune disease e.g. SLE, chronic liver disease)

Causes of hypogammaglobulinaemia

Primary immunodeficiency (Bruton, CVID), protein loss (nephrotic syndrome), immunosuppressive drugs, lymphoid malignancy (CLL, myeloma suppresses normal Ig)

Acute-phase proteins — what and why

Liver proteins whose levels change in inflammation (driven by IL-6)

↑ CRP, fibrinogen, haptoglobin, ceruloplasmin, α1-antitrypsin, serum amyloid A

↓ albumin, transferrin ('negative' APPs)

How does oestrogen change plasma proteins?

↑ hepatic synthesis of binding globulins — SHBG, TBG, CBG (pregnancy, oral contraceptives)

EXAMINER ASKS: Why does a cirrhotic patient have low albumin but high gamma-globulins?

Damaged hepatocytes make less albumin

Portal-systemic shunting lets gut antigens bypass Kupffer cells → B-cell stimulation → polyclonal ↑ γ (β–γ bridging)

EXAMINER ASKS: Why is PKU screened at birth?

Treatable: a low-phenylalanine diet started in the first weeks prevents brain damage (Guthrie / heel-prick test)

15-MINUTE NOTES / Write your note sheet for essay 12 Plasma proteins and amino acid disorders

1. Definition of dysproteinaemia + normal total protein

2. The 5 electrophoresis fractions with their proteins and ranges

3. Hyperproteinaemia: relative vs absolute; polyclonal vs monoclonal (paraproteins)

4. Hypoproteinaemia: 4 mechanisms (intake, synthesis, loss, catabolism)

5. Electrophoresis patterns (acute/chronic inflammation, nephrotic, cirrhosis, myeloma)

6. Amino acid disorders: mechanism; PKU, homocystinuria I–III, Hartnup

Draw: a normal electrophoresis curve (albumin peak, α1, α2, β, γ) and an M-spike next to it