Gilbert’s syndrome

Gilbert’s syndrome is an hereditary, chronic/episodic, mild unconjugated hyperbilirubinemia.  Due to impaired hepatic bilirubin clearance (glucuronyltransferase deficiency).  Otherwise liver function is normal.

It does not cause chronic liver disease. Non pruritic.  Jaundice may be provoked by fasting, surgery, dehydration, alcohol ingestion, infectious illnesses, heavy physical exertion, and lack of sleep.  Symptoms eg tiredness are due to exacerbating condition, not high bilirubin!

Common, 2–10% of the general population, many undiagnosed. At least 30% of people with Gilbert’s syndrome never develop symptoms.

Gilbert’s syndrome can be diagnosed when the person has:

  • Unconjugated hyperbilirubinemia (on at least 2 occasions, and not progressing).  Conj bilirubin may be sl high but always less than 20% of total.
  • Bilirubin is less than 3x upper limit of normal (approx 60).
  • No evidence of haemolysis (normal full blood count, reticulocyte count, blood film, Coombs’ test, haptoglobin level, and lactate dehydrogenase level).
  • Normal liver enzyme levels.
  • No clinical evidence of liver disease.
  • Commonly homozygous for allele 7.

Differential is Crigler Najjar type 2 – can cause persistent jaundice in childhood (cf type 1 = severe jaundice in first few days of life).

No treatment is required.

Some drugs should be used with caution in people with Gilbert’s syndrome:

  • Atazanavir and indinavir.
  • Gemfibrozil.
  • Irinotecan.
  • Statins when combined with gemfibrozil.

[NICE clinical knowledge summary]

Parent/family information at https://childliverdisease.org/liver-information/childhood-liver-conditions/gilberts-syndrome/

Sudden Unexpected Death in Infancy (SUDI)

Or Cot death?  Or SIDS (Sudden infant death syndrome)?

It is well recognised that some babies go to sleep apparently healthy, and then don’t wake up in the morning.  Even after a full post mortem (PM) investigation, no cause is found.  This unexplained phenomenon however has some very well recognised features eg age 2-6 months, prematurity, maternal smoking, poor socio-economic conditions, prone sleeping.

SUDI was originally defined by CESDI (Confidential Enquiry into Stillbirths and Deaths in Infancy) as death between 7 and 365 days where unexpected and unexplained at autopsy, during an acute illness that was not recognised as life-threatening, due to an acute illness of less than 24 h duration in a previously healthy infant (or death after this if life had only been prolonged by intensive medical care); definition also includes deaths from a pre-existing occult condition, and deaths from any form of accident, trauma or poisoning.

I find SUDI most useful for describing the initial situation one may find oneself in, particularly from the point of view of bereavement, need for medical and police investigation.  Interestingly, many of the same risk factors pertain to both deaths unexplained (ie SIDS, or strict SUDI) and to accidental deaths (with the exception of prone sleeping).

SIDS is the ICD recognized term, so is what is generally put on a death certificate.  However pathologists vary in their use of the terminology, some will use “Unascertained” to mean SIDS, others will use SIDS but reserve Unascertained for cases where there are additional factors that somehow cast doubt on the diagnosis.

Similarly, overlying (smothering) as a cause of SUDI is often inferred from the history, but may be specified on the death certificate to differentiate from SIDS.

PM finds a cause in about a 1/3 of cases) eg

  • Infection
  • Cardiomyopathy, anomalies of coronaries
  • Ion channelopathies
  • Metabolic disorders eg MCAD

See also Prevention, and Sudden unexpected postnatal collapse.

Nephrotic Syndrome

Clinical picture, whereby kidneys leak protein, leading to hypoalbuminaemia. This results in oedema, particularly noticeable around the eyes, but also peripherally and as ascites. Mechanism is thought to be loss of negative charge on basement membrane. Usually idiopathic, mostly Minimal change glomerulonephritis. Otherwise can be focal segmental gomerulosclerosis (10-20%), secondary (eg HSP, SLE).

Mostly boys, 2 to 1 ratio. 5% go on to Chronic Renal Failure. Hypertension unusual so consider non minimal change glomerulonephritis if hypertensive at presentation. Classic features are:

  • Urinary protein:creatinine (PCR) more than 200mg/mmol (0.2g/mmol), and usually more than 500 (early morning sample is more reliable)
  • Strict definition is protein loss more than 1g/m2/d but noone collects 24hr urines anymore!
  • Low albumin (<25g/l)
  • Oedema
  • High Hb
  • Low Calcium

Check FBC, U&Es, creat, albumin, LFTs, varicella IgG (to check status before starting steroids), cholesterol, HBV/HCV, C3/4. Urinalysis, urine culture, protein:creatinine ratio. Urine sodium <10mmol/l indicates hypovolaemia.

Complications

  • Oedema – if symptomatic, give albumin (see below).
  • Intravascular depletion (despite massive oedema) – BP not useful as paradoxical hypertension may be seen; instead, judge by heart rate, perfusion, urinary sodium (<10 = hypovolaemia).
  • Infection – at risk due to loss of complement and immunoglobulins, esp cellulitis, primary pneumococcal peritonitis. Consider antibiotic prophylaxis with penicillin V if severe proteinuria.
  • Risk of thrombosis – loss of anti-thrombin III and other anti-coagulants, +/- hypovolaemia.  Esp renal vein thrombosis (pain, haematuria, worse renal function, palpable kidney. Do USS)
  • Hypocalcaemia – adjusted or ionised value.
  • Hyperlipidaemia  – characteristic, so part of diagnosis!  Only seen during flare, so only needs treated if other risk factors or frequent relapses.

Those with minimal change tend to be responsive to steroids and do not need a biopsy. But if atypical or unresponsive (allow 4 weeks) then biopsy indicated; or if:

  • Age under 1 yr, over 10yrs
  • Hypertensive
  • Elevated creatinine
  • Macroscopic haematuria (microscopic sometimes seen with minimal change)

Treatment

  • Steroids – Cochrane suggests at least 3 months.  PREDNOS trial did not find benefit from 16 weeks cf 8 (median time to relapse 139 vs 87 days. RHC protocol is:
    • 60mg/m2 for 4 weeks (max 80mg)
    • 40mg/m2 alt days for 4 weeks (max 60mg)
    • Wean by 5-10mg/m2 weekly for a total of 12 weeks treatment
  • Low salt diet, fluid restriction eg 50-70%.  Beware thirst driving consumption of wet foods to cheat restriction! Or drinking with tooth brushing, showering.
  • Albumin: not for low albumin itself, but for hypovolaemia or severe, symptomatic oedema (esp scrotal, where skin starts to break down). If shock, give 4.5% albumin as resuscitation fluid (without diuretic!). Otherwise, 1g/kg 20% albumin (=5ml/kg) over 4-6 hours, with IV frusemide (2mg/kg) mid-infusion.
  • Diuretics – not usually regular.  Some need, metazolone and spironolactone are synergistic with frusemide.
  • Varicella protection – check serology at diagnosis.  Vaccinate when on low dose; consider vaccinating close contacts.  May need post exposure prophylaxis if susceptible.

Remission defined as 3 consecutive days neg or trace protein. Most remit within 1 month, refer if no response by then – allow 8/52 before labelling steroid resistant .

Prognosis

1/3 no relapse, 1/3 infrequent, 1/3 frequent. Nephrotic relapse defined as 3+ protein for 3 days, but also refer if 2+ for 7 days. Treat relapse with prednisolone 2mg/kg until proteinuria suppressed for 3 days, then taper over 4-8 weeks.  In frequent relapsers (ie 2+ within first 6 months, or 4+ within any 12 month period), may become steroid dependent (ie relapses during weaning) so consider Levamisole (2.5mg/kg alternate days, SE reversible neutropenia), cyclophosphamide, ciclosporin etc.

As with any condition requiring high dose steroids, remember vaccinations, varicella, bones.

Children with steroid-resistant nephrotic syndrome who are homozygous or compound heterozygous for NPHS2 (podocin) mutations do not respond to standard steroid treatment and have a reduced risk for recurrence of nephrotic syndrome (with focal segmental glomerulosclerosis) after renal transplantation. Available through UK Genetic Testing Network for children with nephrotic syndrome that is resistant to treatment with steroids, presents in the first 3 months of life or has a histological picture of focal segmental glomerulosclerosis on renal biopsy.

Sudden Unexpected Postnatal Collapse

Identified as a group by BPSU, led by Julie-Clare Becher in Edinburgh.  As with SUDI, previously well appearing baby suddenly suffers cardiorespiratory failure, with death or severe neurological disability as a result.

Her 2011 report highlighted an association with prone position and breast feeding.  One third of of cases had an underlying pathological or clinical condition but over half probably due to accidental suffocation, frequently unrecognised by parents themselves.

Some suggestion that cases are underreported, and that cases are increasing due to increased early skin-skin practices without adequate supervision.  In a big survey from Sweden, most happen within first 2 hours of birth, often during first breast feeding attempt.

The process of referral to procurator fiscal, bereavement support, prolonged delay in post mortem report etc is common to SUDI, even if only a few of the underlying risk factors are shared.

A BAPM protocol is available, detailing elements of history eg family tree, drug/alcohol/smoking history, obstetric history; plus investigations eg Kleihauer, placental histology, skeletal survey, PHOX2B gene (congenital central hypoventilation syndrome), fibroblast culture from skin biopsy.  In a death, most if not all should be done routinely by pathology.

In terms of prevention, standard SUDI precautions are emphasized – avoid prone position, co-bedding, head covering, beware sedating drugs etc.  Education of parents regarding warning signs and upper airway control.  Better non-obtrusive monitoring.

[Arch Dis Child Fetal Neonatal Ed 2012;97:F30−F34. doi:10.1136/F30 adc.2010.208736; Translational Stroke Research , Volume 4, Issue 2, pp 236-247]

 

Prednisolone allergy

Both type I and type IV allergic reactions associated with corticosteroids have been reported in the literature.  Due to drug itself, the excipients making up the drug, or both?

Corticosteroids have been classified into 5 different categories based on their structural and chemical properties:

Group Agents
A Hydrocortisone

Methylprednisolone

Prednisolone

B Budesonide

Triamcinolone

C Betamethasone

Dexamethasone

D1 Mometasone furoate

Fluticasone propionate

Cross-reactivity outside of these groups has only really been seen with group D2, which includes only lesser known steroids eg hyrdocortisone 17 butyrate, and group A.  Budesonide has also been described to exhibit some cross-reactivity with group D2, due to a stereoisomer, rather than its group conformation.  There is also some cross-reactivity with sex hormones, although the clinical significance is unclear – there is a type of cyclical dermatitis which is thought to be related to endogenous progesterone sensitivity.

[Allergy. 2009 Jul;64(7):978-94. doi: 10.1111/j.1398-9995.2009.02038.x]

Oral allergy syndrome

Used interchangeably with Pollen food syndrome, although PFS is probably a better name because it is more specific and more closely represents what is going on. Only described in 1942!

Pollen Food Syndrome (PFS) refers to fruit and/or nut allergy, associated with birch pollen allergy (ie hayfever).  The food allergy part of the deal however is usually mild, eg itching/tingling/scratching/numbness, of lips/tongue/throat (sometimes ears) only, which distinguishes it from primary peanut or tree nut allergy. Peri-oral rash, nausea, abdo pain are sometimes reported. Mild angioedema of tongue and lips can occur, as can cough – you would be more nervous about assuming PFS in this situation, of course.

Peeling root vegetables is a trigger in those who have vegetable types of PFS! Another reason why PFS is a better name.

Extremely common – probably 40% of children with birch pollen related hay fever (and more than 70% of adults)! Getting more common too – climate change related hay fever season, and more allergenic pollen (thought to be related to ozone levels, hence cities can be worse)…

Due to cross reactions between birch pollen and similar proteins (most commonly PR-10 group – also oak, beech, alder) found in fruit, particularly those fruit with pips inside and a peel eg apple, pear, peach – this group of fruit is known as Rosaceae and includes nectarine, cherry, apricot, plum.

Other fruits involved include Kiwi, Mango, Melon, Tomato, Raspberry, Strawberry. Kiwi and banana still quite common primary allergies. Can be both, of course!

Peanut, Hazelnut and almond most common nuts involved in PFS in UK. 

Sometimes vegetables (Carrot, Celery, Potato, Asparagus, Pepper). Poppy seed, herbs and spices (Aniseed, Camomile, Coriander, Cumin, Fennel, Parsley).

Profilin group (Bet v2) about 20% of PFS in UK, more common in Southern Europe. Birch and oak too, but also olive tree, London plane, grasses (Phl p12), ragweed. Watermelon profilin cross reacts with melon, kiwi, peach.

There are other similar allergy syndromes including celery-spice-mugwort syndrome and latex allergy

You may find that you can eat the fruit if peeled, tinned, cooked or processed (eg jam). The ripeness, even the specific species, can matter too. Cold storage may increase the risk of reactions. Freezing doesn’t seem to make any difference.

Some affected individuals even put up with the itching because they prefer not to miss out on their favourite fruit!

Often emerges in later childhood or early adulthood, and only after hay fever develops. Seen in up to 25% of kids, but they don’t always recognise it themselves! Big variations geographically, obviously related to distribution of birch.

The main impetus for making the diagnosis is to select patients with a lower risk of anaphylaxis, even if nut allergic.  However, not always possible, and certainly not 100% reliable.  Thought that about 3% of PFS patients have systemic rather than just oral symptoms, and 1-2% will have anaphylaxis.  Potential confusion too because people who have primary IgE mediated peanut or nut allergy may of course also report isolated oral symptoms if low dose exposure.  In the original description of oral allergy syndrome, 50% progressed to systemic reactions!

So, important to differentiate –

  • primary IgE peanut or tree nut allergy who have only had oral symptoms so far (but are are risk of severe reactions, due to sensitisation to storage proteins, typically found in seed/kernel)
  • benign PFS, where allergic to Bet v 1, its homologues (eg Ara h 8, Cor a 1 – see peanut allergy) or other PR-10 or Profilin.  These proteins are usually in the pulp of the fruit. Soya (Gly m 4) is an exception where soya milk can cause severe reactions.
  • PFS with potential for systemic reactions where allergic to LTP (typically found in the peel)

BSACI peanut and tree nut allergy guidance is to go with typical history and only test if:

  • Atypical/severe reactions
  • reactions to processed rather than raw plants (including roast nuts)
  • Soya products other than soya milk
  • Tree nuts other than hazelnut, almond, walnut
  • Legumes other than peanut

BSACI guideline says beware younger children (under 8) with kiwi, melon or banana allergy, even if otherwise typical history – PFS unlikely.

Testing could be Prick to prick tests (important to get skin and pulp!), or else consider:

  • Pru p 3 for LTP allergy– if reacts to cooked food or other atypical features (even if not peach specifically!)
  • Gly m 4 if soya milk negative (PR-10 but can be severe reactions).  Gly m 5/6/8 if atypical
  • For hazelnut and almond, best to do prick to prick, for raw AND roast; if positive, do Cor a 1 (PR-10, so PFS) with 9 and 14 (which would suggest primary)
  • Ara h 2 if any standard tests for peanut positive (should be negative in PFS) – if negative, Ara h 1/3/6
  • Jug r 1 if walnut tests positive, Ber e 1 for brazil nut.

Oral challenges only possibly needed if avoiding multiple foods.

Pollen subcut immunotherapy does not seem to help PFS, unfortunately.  Insufficient evidence about pollen sublingual immunotherapy.  Some work around oral immunotherapy with fresh food or with isolated proteins.

The risk of anaphylaxis in PFS is quoted as 10%, but this is perhaps misleading as it usually relates to very high doses such as smoothies, tofu, soya milk. Other possible risk factors include:

  • severe seasonal asthma
  • Acid suppression therapy!
  • Jackfruit!

Adrenaline autoinjectors are rarely justified.

But there are reports of anaphylaxis to peanut despite being exclusively Ara h 8 sensitised and passing an oral challenge – but had big dose on empty stomach! [https://doi.org/10.1111/cea.12425]

Golden Delicious, Granny Smith and Cox’s the worst of the fruit, with the most Mal d 1 (Bet v 1 homologue).

BSACI does not mention whether prick to prick with frozen is effective, only that you can still react to frozen fruit/veg.

More severe reactions described with jackfruit! Beware smoothies, protein shakes, edamame beans!

Bean sprouts, mange tout and sugar snap mentioned specifically as usually only lightly cooked, or just raw.

[Isabel Skypala, BSACI PFS guidance, Clin Exp Allergy 2022]

Long QT Syndrome (LQTS)

16 genes now known, most incomplete penetrance. Important in drug induced Torsades too. LQTS probably accounts for many sudden unexpected deaths, some evidence for SUDI too.  Some genes associated with epilepsy. Triggers for cardiac event seem to vary from 1 gene to another eg exercise (LQT1), sudden loud noise (LQT2).

Variable expressivity too, so 1 normal ECG not adequate.

Other ECG clues are bradycardia, T wave alternans or biphasic, abnormal U waves. T wave changes with posture or exercise may also be seen. Allow at least 3 consecutive beats to measure, to allow for sinus arrhythmia.

Consensus diagnostic criteria

Any of:

  1. LQTS risk score >=3.5 (in the absence of an alternative cause) – score is complex, but involves QTc, Torsades, T wave abnormalities, syncope, cong deafness, FH.
  2. Pathogenic mutation in a LQTS gene
  3. QTc >500 on repeated ECG
  4. QTc 480-499 (repeated) PLUS unexplained syncope.

Treatment is with beta blockers, avoidance of triggers.

[Current Opinion in Pediatrics. 26(6):727-33, 2014 PMID: 25313972].

Attention Deficit & Hyperactivity Disorder

ADHD defined as at least 6 months of

  • Inattention,
  • Hyperactivity,
  • Impulsivity.

ICD requires all 3, DSM requires just 1.

Plus,

  • social and/or academic difficulties not explained by anxiety or depression,
  • child should be under 7 yrs.

DSM does not give guidance on assessing severity. UK guidelines do not mention mild ADHD.

Commonly associated with peer rejection, increased risk of injury. Long term, less likely to enter higher education or find employment, more likely to have delinquent/criminal behaviour, more likely to smoke, use alcohol and illegal drugs.

There is high concordance for monozygotic twins, which supports a genetic cause. There are also MRI/PET lesions, which support a physical cause (cortical abnormalities in the frontal, temporal, and parietal lobes, Lancet 2003). It is 3 times more common in boys. It may be related to traumatic experience in infancy.

There are rating scales eg Conner’s ADHD index, which is 94% sensitive.

Examples of inattention:

  • Careless mistakes
  • Does not seem to listen when spoken to directly
  • Does not follow through instructions (NOT simply oppositional)
  • Avoids sustained mental effort
  • Loses things necessary for tasks/activites

Examples of hyperactivity/impulsivity:

  • Fidgets, squirms, leaves seat when expected to remain
  • Runs about, climbs in appropriate situations
  • Acts as if “driven by a motor”
  • Blurts out answers before question finished
  • Interrupts, intrudes on others

There should be impairments in at least 2 settings eg school and home.

Management

Parent training programmes are effective for preschool children.

Methylphenidate, a dopamine agonist, is effective, esp for concentration, hyperkinesis and impulsiveness. Clonidine has been suggested.

Behaviour modification (NOT cognitive behavioural) is effective for age 6yr+ only when combined with medication.

Hyperactivity tends to improve over time, but there are associated antisocial behaviours and learning difficulties long term. The longest trial showed better performance up to 8yrs after entry (compared with baseline), but still underperforming compared with peers.

A diagnosis can help parents but also carries stigma: children with ADHD are perceived as lazier and less clever by peers, and teachers/parents have lower academic expectations.

BMJ 2013;347:18a

Sepsis

See also Sepsis6.

In reviews of child deaths, most significant recurrent avoidable factor is failure to recognize severe illness, most often at point of first contact with health services (Why children die, Pearson Arch Dis Child doi:10.1136/adc.2009.177071)

American College of critical care medicine 2007 shock update – central venous and arterial monitoring, dopamine within 15 mins, then warm vs cold shock, etc.  2009 Paed intensive care society audit in UK found majority of children (62%) targets were not met, for reasons that remain unclear. OR for death 3.8 where shock still present at time of PICU admission.

In 2011 goal directed therapy study, less intubations and inotropes, half the number of deaths. (But less severe group?) [Andrea Cruz, Pediatrics 2011;127;e758; DOI: 10.1542/peds.2010-2895]

Chinese study of antibiotic timing found reduced time to reversal of shock where given within 1 hour.

Definition of risk group – Paed CCM international consensus conference – at least 2 of the following 4, 1 must be abnormal temp (reported within 4 hours of admission if afebrile at presentation)

  • Core temp <36 or > 38.5
  • Tachycardia
  • Bradycardia
  • Tachypnoea
  • Leucocyte count elevated for age or >10% immature neutrophils

(Not clear why different criteria used for sepsis6)

Def of inappropriate tachycardia?

Studies continue to be done looking for predictive factors esp young infants.

Management

  • Give high flow O2, regardless of sats!
  • Titrate fluids over 5-10 mins, repeat if necessary. Aim to reverse shock.
  • Early inotropic support viz adrenaline (make up during 3rd bolus). 0.3mg/kg in 50ml 5% dextrose, 1ml/hr (0.1mcg/kg/min)
  • 15 mins ideal, within 60mins acceptable.

Headaches and exertion/sport

Not uncommon. Tension headaches tend to get better with exertion, in any case mild by definition so unlikely to be a problem. Some specific exertion-related headaches eg Primary headache with raised cardiac output – pulsating in quality, can last just a few minutes but up to 48 hours! Primary headache with raised venous pressure is related to valsalva manoeuvre eg weight lifting, can last just seconds, rarely more than 30 minutes.

Do MRI, ECG to exclude underlying cause.

Could try more gentle aerobic warm up, NSAID prophylactically, Else triptan/NSAID treatment as required. Beta blockers (esp Non-selective eg propanolol) appear to have some negative effects on aerobic exercise capacity (except when used for treating cardiac failure). They are also banned in competitive sports (due to their use by precision sports athletes eg archery). [Sports Med. 1988 Apr;5(4):209-25. PMID   2897710]