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Derm > Metabolic and nutritional > Flashcards

Metabolic and nutritional Flashcards

1
Q

What is a porphyrin?

A
  • Tetrapyrrole and is aromatic
  • It incorporates iron to create haem, and undergoes the haem biosynthesis pathway to get there
  • When there is an issue with one of the enzymes, then there is accumulation in the substrates
  • Porphyrins get excited by the Soret Band which is 408 nm
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2
Q

Overarching Porphyria pathophysiology

A
  • The Soret band excites the molecule into an excited singlet state
  • The singlet state results in:
    • Hydroxy radical production which directly damages tissue
    • Complement production, which you see on IF
    • Mast cell degranulation
    • MMP activity
  • Particular to certain subtypes:
    • EPP: PPP is lipophilic so it hands out in the endothelial cells, so the pathology is mainly in the upper dermal blood vessels so you get pain from sun exposure
    • PCT: UPP is more water soluble, so it diffuses to surrounding tissue –> this causes lysis of the cells in the superficial dermis, resulting in a blister under the basal lamina (coalescing of vacuoles)
    • VP: this has both CPP and PPP but for some reason the hydrophilic component predominates more
  • There is no correlation between porphyrin concentration and association with cutaneous disease
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3
Q

Porphyria histology

A
  • In the dermis, eosinophilic hyaline is deposited in and around the vessel walls - its pink, and is PAS positive and diastase resistant. There is lots in EPP
  • In bullous lesions: sub-epidermal bullae which is cell poor, and the dermal papilla prottrudes into the blister cavity called festooning or caterpillar
  • IF –> IG at DEJ
  • Electron microscopy: reduplication of vascular basal lamina
  • Particular:
    • EPP: vessel wall changes are more pronounced, deposition can be extensive and look like colloid milium
    • PCT: basement membrane zone changes predominate here
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4
Q

Porphyria Photoprotection principles

A
  • The Soret wavelength light is at 408 nm so they need broad spectrum protection
  • They basically need long shirts, hats, etc
  • Sunscreens: physical blockers (titanium, zinc, iron) but these aren’t enough
  • Dihydroxyacetone paint –> induces formation of light-absorbing brown pigment in the stratum corneum
  • Clear window films can absorb UV light –> car, home windows
  • If requiring surgery, for certain types, filters over lights in theatre
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5
Q

Acute attacks of porphyria + triggers

A
  • This occurs with HP, AIP and VP (HAV), and is most common in AIP
  • It is triggered when something induces CYP450 –> this exacerbates the inability of the liver pathway to respond adequately because of PGB deaminase deficiency
  • Triggers:
    • Drugs –> metabolised by CYP450
    • Hormones –> menstrual cycle (affects women:men 5:1)
    • Recreational –> alcohol, cannabis
    • Stress, infection, fasting
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6
Q

Clinical features of acute attacks of porphyria

A
  • Gastrointestinal: abdominal pain, vomiting, constipation
  • Metabolic: hyponatraemia
  • Neurological: convulsions, acute autonomic neuropathy, motor neuropath
  • Respiratory: paralysis
  • Psych: abnormal behaviour, confusion, generalised anxiety
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7
Q

Diagnosis and treatment of acute attacks of porphyria

A 
- Increased urinary PBG, and the higher it is the more likely the acute attack
Treatment
- admit
- fluid management
- Haem arginate
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8
Q

Congenital erythropoietic porphyria AKA Gunther Disease clinical

A
  • Deficiency of UP cosynthetase
  • Autosomal recessive
    Clinical
  • wide spectrum
  • In utero: hydrops fatalis
  • At birth:
    • Brown amniotic fluid
    • Blistering on light –> photherapy can be triggering
    • Secondary infections
  • Scarring, erosion of terminal phalanges, onycholysis, destructive change, pseudosclerodermatous
  • Hypertrichosis
  • Hypo + hyperpigmentation
  • Later onset as adult - associated with haematological –> BM myelodysplasia
  • Extracutaneous:
    • Haem - haemolytic anaemia
    • Bones and teeth
    • Eyes
  • Earlier life expectancy ~40 years
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9
Q

Gunther disease investigations

A

Investigations –> elevated everywhere

  • Tissue: accumulation of UP and CP
  • Red cell and urine: large amount of UP and CP
  • Faeces: increased CP
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10
Q

Gunther management

A
  • Photoprotection
  • Prevention of secondary infection
  • Haem:
    • hypertransfusion
      • complicated by iron overload
    • Allogenic BM transplant
      • difficult, need to find HLA-compatible donor
  • Prognosis:
    • reduced life span (40 years)
  • Genetic counselling:
    • chance of sibling having 25%
    • can detect in utero via amniotic fluid or chorionic villous biopsy
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11
Q

PCT types

A
  • Deficiency of UROD
    Types
  • 1: 75% of population, sporadic mutation, enzyme deficiency is in the liver only
  • 2: 25%, familial, autosomal dominant with low penetration, in all tissues of the body
  • 3: rare, hereditary enzyme deficiency localised to the liver
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12
Q

PCT pathophysiology

A
  • accumulated uroporphyrin (hydrophilic) diffuses from plasma into surrounding tissues
  • causes phototoxic reaction in the upper dermis of the skin –> cell lysis in the superficial dermis, formation of membrane limited vacuoles which merge to produce a blister
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13
Q

Risk factors for PCT

A
  • Haemachromatosis
  • Infectious: HCV, HIV, HAV, HBV
  • Alcohol
  • Oestrogens: OCP, HRT, tamoxifen
  • Less common:
    • haemodialysis
    • NIDDM, SLE, dermatomyositis
    • Haem: malignancy, sideroblastic anaemia, thalassaemia
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14
Q

PCT Clinical

A
  • Blistering, skin fragility, bullae, atrophic scars, milia, hyper and hypopigmentation
  • Type 1 - arises in middle aged people
  • Other cutaneous features: scarring alopecia, hypertrichosis, hyperpigmentation, morphoea-like plaques (possible induction of collagen synthesis by uroporphyrin)
  • Nails: photo-distributed onycholysis
  • Variants:
    • Homozygous form of familial is HEP –> 90% reduction in UROD. This is severe, with photosensitivity at birth, blisters, mutilating scarring, hypertrichosis, shortened phalanges, milder haemolysis than CEP. Life expectancy is normal.
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15
Q

Liver implications of PCT

A
  • Accumulated porphyrins are carcinogenic to the liver
  • Liver biopsy: stainable iron, fatty change, intracellular porphyrin crystals
  • 15% develop cirrhosis
  • 3% develop hepatocellular carcinoma
  • Risk factors for carcinoma are:
    • symptomatic >10 years
    • severe changes on histology
    • HCV
    • Male
    • > 50 yrs
  • requires monitoring of liver via USS and alpha-fetal protein
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16
Q

PCT investigations

A
  • Remember - it is a liver disorder with secondary effects on the skin
  • Urine: positive, particularly UP
  • Faeces: positive, particularly isocoproporphyrin
  • Histology:
    1. Subepidermal bullae with sparse inflammatory infiltrate
    2. Festooning of the dermal papillae in the bullae: the papillae protrude up
    3. Thickened uppder dermal capillary walls: this is due to deposition of fibrillar glycoprotein, is PAS positive and diastase negative
    4. May have caterpillar bodies in the blister roof: linear, eosinophilic PAS positive globules composed of basement membrane material and degenerating keratinocytes
  • Liver biopsy is warranted
17
Q

Management of PCT

A
  1. Prevention
    1. Photoprotection
    2. Eliminate risk factors
    3. Genetic counselling: difficult to justify screening as no acute attacks
  2. Physical methods
    1. Venesection
      1. ~500 mL every 1-2 weeks
      2. takes blistering 2-3 months to resolve, and skin fragility 6-9 months
      3. relapse 2.5 years later
    2. Excision and graft of sclerodermoid lesions
  3. Medical
    1. Hydroxychloroquine
      1. Low dose 100 mg twice weekly
      2. promotes uroporphyrin excretion in bile
    2. Desferrioxamine
      1. Chelates hepatic ion, requires S/C pump at night
      2. Expensive
    3. Erythropoieitin
      1. Treatment of choice in renal failure
18
Q

EPP definition

A

Ferrochelatase deficiency - final enzyme of the pathway. It hurts rather than blisters.

Epidemiology

  • super rare
  • some have been associated with haem malignancy
19
Q

EPP clinical

A
  • Baby:
    • usually only physical sign is oedema, with severe attacks they can have purpuric lesions, crusted erosions and vesicles
    • immediate pain to bright light –> crying in pram, worse in spring and summer
    • pain, tingling, discomfort, itching
    • partial relief with cold water and wet clothes
  • Older:
    • Signs: thickening over MCP and IP joints, vermicular scarring on nose, shallow linear/punctate/circular scars on cheeks, forehead, radial scars around lips, skin roughened and pebbly
    • 50% still have no physical signs
    • Psychosocial ++
    • May improve with pregnancy due to anaemia
    • Variant: associated with palmar keratoderma
  • Liver:
    • PPP can precipitate and form gallstones in ~ 12% patients
    • PPP is also hepatotoxic –> 1% severe liver damage, some may require liver transplant but can still get disease back in graft
20
Q

EPP investigations

A
  • Red cell-free protoporphyrin is increase which is diagnostic. This makes sense as its vascular
  • Faecal: increased protoporphyrin in 60%
  • Urinary: normal
  • Biopsy:
    • endothelial damage in superficial dermal vessels in acute phase
    • chronic phase: deposition of hyaline material (PAS positive) in walls of blood vessels of upper dermal and papillary vascular plexuses –> can be so extensive looks like coloid milia
    • IF: IgG
21
Q

EPP management

A
  • Prevention:
    • Photoprotection
    • Monitoring - LFTs and red cell PPP checked annually
    • Genetic counselling: autosomal dominant with incomplete penetrance, probability of offspring acquiring and suffering is under 10%, testing for partner is now available
  • Acute attacks
    • analgesia
    • severe –> admission
  • Medical therapy:
    • Oral beta-carotene
      • believed to scavenge free radicals involved in the acute phototoxic reaction
      • can cause reversible skin pigmentation
    • PUVA
      • may be useful in that it induces epidermal thickening and pigmentation
    • Afamelanotide
      • alpha-melanocytic stimulating hormone analogue –> has shown promising results
  • Physical:
    • Allogenic bone marrow transplant
    • Liver transplant in liver issues
22
Q

Hereditary coproporphyria

A
  • Autosomal dominant inherited deficiency of CPP oxidase
  • puberty onwards
  • 10-2% have cutaneous fragility and blistering, however it is mostly non-cutaneous
  • Investigations: increased UPP and CPP in urine and CPP in faeces
23
Q

Variegate porphyria epi

A
  • Really common in South Africa –> 1/20, much less in Europe and elsewhere
  • at least 80% of south africans carry a pathogenic mutation of VP but are asymptomatic
24
Q

Variegate pathophysiology

A
  • Autosomal dominant inherited deficiency of PPP oxidase

- Accumulated CPP and PPP inhibit PBG –> resulting in acute attacks

25
Q

Varigate porphyria clinical

A
  • Cutaneous
    • 70% have cutaneous involvement
    • adolescence/young adulthood onset
    • indistinguishable from PCT: skin fragility, tense blistering in photo-distributed sites, pigment changes, scarring, scleroderma, milia, hypertrichosis
    • Nail: occasionally photo-onycholysis
    • No seasonal variation
    • Acute photosensitivity when hepatic injury (due to increased porphyrins I guess)
  • Extracutaneous
    • Intercurrent biliary obstruction –> exacerbated cutaneous diease
    • Increased lifetime risk of hepatocellular carcinoma
    • Acute attacks –> occurs more in women, declined in recent times due to prophylactic measures
  • Sometimes goes into clinical and biochemical remission in old age
  • Variants:
    • homozygous VP mutation –> clinically much worse, occurs in neonates and have significant neurological issues –> epilepsy, delayed development, nystagmus, hand deformities
26
Q

VP diagnosis

A

Plasma spectrofluorimetry peak: 626 nm –> this is diagnostic in the absence of a raised free red cell porphyrin

27
Q

VP Management

A
  • Prevention
    • Photoprotection
    • Avoid medications and low calorie diets and alcohol
    • Emergency identification bracelet
    • Genetic counselling:
      • identify relatives - negative test is uninformative but positive means they have it
      • Risk of passing to offspring is 50%, 20% of those will have symptoms
  • Medications
    • Beta-carotene and canthaxanthin? limited protection
  • Physical
    • Liver transplant for acute attacks
28
Q

Pseudoporphyria

A
  • Not actually porphyria, and is clinically and histologically indistinguishable from PCT
  • Cause:
    • Photosensitising drugs - FIND
      • Frusemide
      • Isotretinoin
      • NSAIDS - naproxen, nabumetone
      • Dapsone, doxycycline (other tetracyclines)
    • Haemodialysis
    • Sunbeds
  • Clinically indistinguishable from PCT, however less likely to see hyperpigmentation, hypertrichosis and sclerodermoid changes
  • DDx: PCT, EPP, bullous dermatoses
  • Ix: normal porphyrins, histo identical to PCT
  • Management: key is to remove provoking factor and photoprotection
29
Q

How do you diagnose and treat vit A deficiency

A

Serum retinol <20

Rx: 50 000-200 000 iu daily

30
Q

How do you diagnose and treat pellagra

A

24 hour urinary niacin + clinical

Rx: nicotinamide 500 mg a day for 3-4 weeks - neuropsych improves within 24-48 hrs

31
Q

Medications that can decrease zinc absorption

A

Diuretics
Penicillamine
Valproate

32
Q

Zinc mutation for acrodermatitis enteropathica

33
Q

Investigations to do for zinc deficiency

A

Albumin - when it’s low can contribute
ALP is a zinc dependent enzyme
Low zinc <70 fasting or <65 non fasting
Histo: psoriasiform hyperplasia

34
Q

Zinc deficiency treatment

A

Acquired: 0.5-1 mg/kg/day for kids, 15-30 mg daily for adults
AE 3 mg/kg/day forever

Derm (57 decks)

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