Mesangiocapillary glomerulonephritis (MCGN)

- Type I: associated with mesangial cell proliferation and mainly subendothelial immune complex deposition (tramline appearance). Associated with hepatitis B or C infection and reduced plasma C3, C4. Classical complement activation (reduced C4 levels)
  Type I more common than type II

- Type II: idiopathic or after measles infection. Characterised by mesangial cell proliferation with electrodense, linear intramembranous deposits that stain positive for C3. Presents with hematuria, proteinuria, nephrotic syndrome or renal failure.
   Immune complex deposition is predisposed to by C3 nephritic factor rise in MCGN type II, which stabilise C3bBb and activates the alternative complement pathway

autoimmune hepatitis

- inflammatory liver disease of unknown cause characterised by suppressor T cell defects with autoantibodies directed against hepatocyte surface antigens
- 25% present with acute hepatitis and signs of autoimmune disease (fever, malaise, urticarial rash, polyarthritis, pleurisy or glomerulonephritis)
- Type I: occur in associated with other autoimmune disorder. Positive antinuclear antibodies, anti smooth muscle autoantibody (ASMA) and anti-actin antibodies
- Type II: occurs in association with anti liver/kidney mircosomal (LKM) antibodies. Most frequently in girls and young women.
- Type III: occurs in association with anti soluble liver-kidney antigen
- Liver biopsy : necroinflammatory process (mononuclear infiltrate of portal and periportal areas & piecemeal necrosis, fibrosis or cirrhosis)
- Treatment: prednisolone followed by azathioprine, or liver transplantation

Paget's disease

- a.k.a osteitis deformans
- focal disorder of bone remodelling
- most are asymptomatic and incidence up to 10% of individuals radiologically affected by age of 90
- symptoms: bone pain, bowed tibia, skull changes, joint pain (when bone involved close to joint)
- most common site = pelvis
- complications: nerve compression (deafness from CN VIII involvement), high output cardiac failure, pathological fracture, osteosarcoma
- X-ray: osteoporosis circumscripta in skull is characteristic
- raised ALP and normal calcium & phosphate
- treatment: bisphosphonates

microvascular cranial nerve palsy

- one of the most common causes of double vision in elderly with diabetes and hypertension
- a.k.a diabetic palsy
- occurs when perfusion to abducen, oculomotor or trochlear nerve is affected
- presented with diplopia, drooping eyelid or mydriasis
- benign prognosis
- treatment: eye patch, treat underlying diabetes and hypertension

Valproate (side effects)

VALPROATE

V: Vomiting
A: Alopecia
L: Liver toxicity
P: Pancreatitis/Pancytopenia
R: Retention of fat (weight gain)
O: Oedema
A: Appetite increase
T: Tremor
E: Enzyme inducer (liver)

Bile acid malabsorption

- can occur in long standing Crohn's disease (which involves terminal ileum) / ileal resection
- increased bile acids in colon reduce absorption of water and electrolytes and at higher concentration induce colonic secretion and increase motility.
- diagnosis by SeHCAT test (radiolabelled bile acid analogue is administered and percentage retention at 7 days is measured - less than 19% is abnormal)
- can be diagnosed by 14C glycolate test also
- treatment: cholestyramine

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

Hypertrophic cardiomyopathy (HCM)

- associated with Friedreich's ataxia, WPW, phaeochromocytoma, familial lentiginosis
- features: jerky pulse, double apical impulse, LSE systolic thrill with harsh ESM
- ESM increase with Valsalva manoeuvre, GTN, digoxin, standing (decrease venous return) and decrease with squatting, beta blockers, handgrip (increase venous return)
- 45% mutation in B-myosin heavy chain on chromosome 14 , 35% mutation in cardiac myosin binding protein C
- diastolic dysfunction
- echo: asymmetrical septal hypertrophy (left ventricular myocardial segment of 1.5cm or greater thickness) , left ventricular outflow tract gradient, systolic anterior motion of anterior mitral valve cusp
- 12 leads ECG abnormal in 80%, most common are ST segment and T wave abnormalities, followed by left ventricular hypertrophy
- microscopic findings: myocardial cell disarray with myocardial hypertrophy and gross disorganization of muscle bundles
- annual mortality = 1%
- 5 poor prognostic markers of sudden death
 i) syncope
 ii) family history of HCM + sudden death
 iii) maximum left ventricular wall thickness > 3cm
 iv) BP decrease during peak exercise / stress test
 v) non sustained VT
       *No consistent relationship of outflow gradient with risk of sudden death
- treatment : beta blockade reduce outflow gradient during exercise thus reduce risk of rhythm disturbance. ICD (implantable cardioverter defibrillator) is considered for patient with history of collapse (VT). Myomectomy is indicated for patient with significant outflow obstruction and is usually reserved for failed medical therapy

Porphyria

- Porphyrias are group of inherited disease resulting from deficiencies in haem biosynthetic pathway
- Acute porphyrias : acute intermittent porphyria, variegate porphyria, hereditary coproporphyria
- Non acute porphyria : cutaneous hepatic porphyria, congenital porphyria, erythropoeitic protoporphyria
- precipitants of acute attacks are: stress, infection, pregnancy, menstruation, starvation, drugs (sulphonamides, barbiturates, phenytoin)
- Haematin can help as it acts as negative feedback operator on the porphyrin synthetic pathway
- enzyme inducer exacerbate porphyria as they induce the pathway
- Ehrlich's test: add one volume of Ehrlich reagent to one volume of urine and urine turns red. Add two volumes of chloroform and red colour stays in upper layer
- Variegate porphyria is associated with raised urinary & fecal protoporphyrins
- Hereditary coproporphyria is associated with raised urinary & fecal coproporphyrins

Essential MRCP facts about porphyria
- All porphyrias have autosomal dominant inheritance except congenital porphyria
- Only acute porphyrias develop neurological consequence (ALA is neurotoxic)
- All porphyrias are photosensitive, except acute intermittent porphyria
- If the name sound's "inherited" eg.congenital porphyria or hereditary coproporphyria, then it is extremely rare.







Porphyria cutanea tarda
- most common subtype of porphyria
- deficient activity of enzyme uroporphyrinogen decarboxylase, causing accumulation of uroporphyrinogen III
- most common presenting sign is fragility of sunexposed skin after mechanical trauma, leading to erosion and bullae on dorsal hand, forearm and face
- diagnosis is by increased plasma and urinary porphyrins
- treatment: chloroquine, venesection

Klinefelter syndrome

- 47 XXY
- most common chromosomal disorder associated with male hypogonadism and infertility
- poor sexual development, small or undescended testes, scanty pubic hair, gynaecomastia and infertility
- testes are firm due to fibrosis and hyalinisation of seminiferous tubules
- involves loss of Leydig cell and seminiferous tubular dysgenesis
- associated with increased risk of male breast cancer
- low serum testosterone, high serum FSH & LH (primary hypogonadism)
- diagnosis: chromosomal analysis

Neurofibromatosis

- a.k.a von Recklinghausen disease (NF-1)
- autosomal dominant

Criteria for diagnosis of NF-1 ( CALBORN ) - at least 2

C - Cafe au lait spot (6 or more, 5mm in < 10 years old, 15mm for >10 )
A- Axillary freckels
L - Lisch nodule
B - Bony lesion (eg: sphenoid dysplasia)
O - Optic glioma
R - Relative (first degree family history)
N - Neurofibroma

- mild learning disabilities are common
- incidence of seizure is 20 times that of normal population
- associated with phaeochromocytoma and syringomyelia

- NF-1 is due to mutation of neurofibromin (chromosome 17) - 90%
- NF-2 is due to mutation of merlin (chromosome 22) - 10%. Hallmark of NF-2 is hearing loss due to bilateral acoustic neuroma

Polymyositis

- disorder of muscle characterised by necrosis of muscle fibers, regeneration and inflammation
- presents with proximal muscle weakness and wasting, muscle pain and tenderness and arthralgia
- also associated with dysphagia due to esophageal spasm
- polymyositis + rash (heliotrope rash, Gottron's papules) = dermatomyositis
- associated with malignancy (esp elderly) 
- raised muscle enzymes (creatinine kinase, aldolase)
- raised ESR, anemia, and positive RF and ANA
- EMG: spontaneous fibrillation
- diagnosis: muscle biopsy
- treatment: prednisolone / immunosuppressives




- Mechanics hand is associated with anti-Jo 1 antibodies and should check for interstitial lung disease

Botulism

- presynaptic neuromuscular junction disorder caused by anaerobic Clostridium botulinum
- transmitted through food contaminated with toxin / IVDU
- blocks release of acetylcholine from motor nerve terminal
- incubation period from 4-14days
- 2 forms: food borne or wound botulism
- presents with cranial neuropathies, autonomic dysfunction (dry mouth, urinary retention), descending limb weakness and depressed reflexes
- NO sensory signs
- respiratory failure is a common complication
- diagnosis: demonstrate toxins in serum, stool or vomitus
- edrophonium test false positive in 1/3 cases
- repetitive nerve stimulation: progressive increase in amplitude of potentials
- treatment: supportive, Botulinum antitoxin (trivalent antiserum), guanidine hydrochloride, penicillin and metronidazole

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.

Churg-Strauss syndrome

- eosinophilic granulomatous inflammation of respiratory tract with small and medium vessels necrotizing vasculitis
- pANCA is positive (50%)
- leukotriene inhibitor allow steroid doses to be lowered and this may unmask underlying vasculitis
- causing focal segmental glomerulonephritis
- principle cause of morbidity and mortality are myocarditis and myocardial infarction secondary to coronary arteritis
- serum IgE is commonly elevated and correlates with disease severity
- treatment: glucocorticoids, azathioprine, cyclophosphamide
- with treatment, 1 year survival is 90% and 5 year survival is 62%

mnemonic : BEAN SAP


BE: Blood Eosinophilia
A  : Asthma
N  : Neuropathy (mononeuritis multiplex) - usually common peroneal nerve
S  :  Sinus abnormality
A  : Allergies
P  : Perivascular eosinophils / vasculitis

juvenile myoclonic epilepsy

- most common primary generalised epilepsy
- genetically linked to short arm of chromosome 6
- absence seizure during childhood
- in adolescent, presents with myoclonic jerks in the morning after waking (Kellogg's jerk) and generalised tonic clonic seizure.
- worsened by sleep deprivation and alcohol
- EEG: generalised spike and polyspike wave activity
- treatment: valproate (extremely respond well) and lamotrigine (lower rate of drug interaction)
- lifelong drug treatment is usually necessary to avoid relapse in patients who achieve seizure free status on medication

Lambert-Eaton syndrome

- autoimmune disorder caused by antibodies against the voltage-sensitive calcium channels of the motor nerve terminals
- males more than female, with underlying malignancy (majority small lung lung CA)
- typically presents with weakness improved with exercise
- reduced/absent reflex (cardinal sign), because less transmitter is released, but reflexes may increase after maximum voluntary contraction (post-tetanic potentiation)
- also presents with autonomic symptoms (dry mouth)
- nerve conduction studies: compound motor action potential have small amplitude which after exercise or with repetitive stimulation will immediately increase by 100%
- voltage gated calcium channel antibodies are seen in almost 100% of LEMS patient with cancer and 90% of LEMS patient without cancer
- treatment: 3-4 diaminopyridine 20mg 5 times/day (potassium channel blocker, which helps maintain depolarisation of the nerve terminal by preventing repolarisation, leading to more calcium enter nerve terminal) or IVIG
 

Cystinuria

- autosomal recessive
- defective tubular reabsorption and jejunal absorption of cysteine and dibasic amino acids (COAL - cysteine, ornithine, arginine, lysine)
- commonest cause of renal stone in children where a metabolic cause is identified
- presents with chronic backache, recurrent urinary stones
- cysteine is highly insoluble at acid pH and form radio-opaque calculi
- urine FEME: pathognomonic hexagonal crystal

- management: large fluid intake, alkalinisation of urine and penicillamine / tiopronin /captopril

Polymyalgia rheumatica

- inflammatory soft tissue condition characterised by persistent pain and stiffness of neck, shoulder girdle and pelvic girdle
- female aged more than 50 years
- proximal muscle pain (shoulder or pelvic) without weakness + early morning stiffness
- Lab findings: raised ESR(more than 40), raised CRP, abnormal LFT (ALP,GGT), anemia
- Response to corticosteroid is dramatic and prompt (within 24-72 hours). Optimal starting dose is 15mg od for first month.
- The risk of relapse is higher with smaller dose and risk of adverse event increased with larger dose.
- Initial dose reduction should be 2.5mg fortnightly until 10mg daily and reduce 1mg each 6 weeks until 5-7mg daily. Maintenance dose 5-7mg daily for 12 months provided symptoms controlled. Subsequently prednisolone can be reduced by 1mg every 6-8 weeks.

hereditary angioedema

- autosomal dominant
- mutation at C1 inhibitor gene, causing low levels of C1 esterase inhibitor
- painless, non pruritic, non pitting swelling of skin
- characterised by recurrent self limited attacks involving skin, subcutaneous tissue, upper respiratory tract, gastrointestinal tract
- reduced C1, C2 and C4 levels (reduced C4 level even between attacks), normal C3
- treatment: C1 esterase inhibitor concentrates 1000-1500 unit IV over 20-30mins, danazole (induce liver enzymes to synthesize C1 esterase inhibitor), fresh frozen plasma (potential to aggravate the condition as it replaces all the complement components, not just C1 inhibitor)

Fragile X syndrome

- a.k.a Martin-Bell syndrome
- X-linked recessive
- trinucleotide repeat disorder (in FMR 1 gene)   - genetic anticipation
- most common cause of inherited intellectual disability
- second most common known cause of mental retardation in males
- expansion of CGG on X-chromosome

• 6-55 : normal
• 55-230 : premutation carrier
• 230->1000 : disease state / full mutation

- features: elongated face, prognathism, macroorchidism, large low set floppy ear, short stature, hyperflexible joints, high arched palate, ADHD, autism

G6PD deficiency

- X-linked recessive
- G6PD oxidises glucose-6-phosphate to 6-phosphogluconolactone with reduction of NADP to NADPH. Thus G6PD is to protect red cell from oxidative damage
- On exposure to infection, fava beans, certain drugs, patient will develop intravascular hemolysis with hemoglobinuria
- Blood film : bite cells (degmacytes), blister cells with Heinz bodies (oxidized denature hemoglobin) removed by spleen
- Treatment: stop the offending drug, maintain a high urine output and transfuse if necessary