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Anorexia nervosa, re-
feeding syndrome and
  endocrine sequelae
      Mark Daly
Why this talk…..
Traditionally eating disorders have been looked after
by either gastro-enterologists or endocrinologists
with the support of psychiatry

There are few conditions where such strong
leadership is necessary in the best interests of the
patient and may go counter to the instincts or wishes
of members of staff
Anorexic woman from Wales
to be force fed, judge orders
A woman with "severe" anorexia who wanted to be
allowed to die is to be force fed in her "best
interests" by order of a High Court judge.

She was being looked after in a community hospital
under a palliative care regime whose purpose was to
allow her to die in comfort

Treatment - "does not merely entail bodily intrusion
of the most intimate kind, but the overbearing of E's
will in a way that she experiences as abusive".
A not unusual pathway
      of care…..
19 yr old girl, admitted BMI of 12

Intermittent institutionalised care since age 9 with
Anorexia nervosa

Admitted because of recent further weight loss,
minimal intake for 1 week

Agreed for a voluntary admission
Admission criteria
Based on recent change in the context of absolute
BMI, physiological and functional parameters
Physical concern
                    Concern        Admit
BMI                 <14            <12
Wt loss (kg/week)   >0.5           >1
BP                  <90/70         <80/60
Postural drop       >10            >20
Pulse               <50            <40
Temp                <35            <34
Muscular            Uses arms to   Can’t stand
strength            stand
WBC                 <4             <2
Hb                  <11            <9
Plts                <130           <110
Physical concern(2)
            Concern       Admit
NA+         <135          <130
K+          <3.5          <3.0
Mg2+        If depleted   If depleted
Po4-        If depleted   If depleted
ECGqtc      >450msec      >450 or
                          arrhythmia
ALT         >45           >90
Bilirubin   >20           >40
Alk phosp   >110          >200
Albumin     <35           <32
O/E
Well presented

Gross cachexia

Hypotensive and bradycardic

Pre-pubertal
Initial investigations
Hb 11.0,WCC 2.0, Plts 78

Na+ 127, K+ 3.1, urea 1.8, creat 38, PO4- 0.75

ECG bradycardia, long QT
Initial plan
Medical
  Initial assessment
     Na+, K+, Urea, Creat, glucose, CRP
     Mg2+, PO4-, Ca2+
     Albumin, liver enzymes, INR
     FBC, ferritin, folate, B12
     FSH, LH Oest or testo
  Thiamine 300mg daily, vit b complex strong 2 tabs
  od, multivit generic, sandophosp 2 tabs tds
  Pabrinex
Initial plan
Nutritional
   5 kcal per kg stepping up over 5-7days to weight gain
   levels (+500kcal over estimates from Henry equation
   (10kcal per kg if BMI>16)
   Menu plans agreed with patient
Initial plan
Behavioural/other restrictions
   Normal foods in preference to supplements
   Bed rest/commode/wheelchair
   Away from window, no fans
   Restrictions according to Mental health status
   Compliance essential
Progress
Day 3, non-compliance with feeding plan

Non-compliance with activity

Reviewed with psych

Formal section

Advised likely need to progress to NG feeding in
absence of compliance and/or weight gain

Informed of need to search belongings
Progress
Day 5, intermittent compliance with feeding plan

Reviewed with psych

Razor blades and salt sachets removed

NG feeding under restraint, NG re-
positioned/replaced 5 times first 24 hrs

Bolus feeds under restraint during periods of non-
compliance
Progress
Day 8

Hypokalaemia and hypophosphataemia requiring IV
replacement

Subsequent weight gain back to BMI 15

Established weight stability at BMI 15 on oral intake
and basic mobility

Discharged to OP ED services
Anorexia nervosa
What is anorexia nervosa?
Anorexia nervosa is defined as:
  intense fear of weight gain

  Weight consistently < 85th percentile for age and height
(In women) three consecutive missed periods

 Together with one of following:
     refusal to admit seriousness of weight loss
     undue influence of shape or weight on one’s self-image
     disturbed experience in one’s shape or weight




                                                          DSM-IV-TR
Types of Anorexia
• Purging
  – Weight loss achieved by
    vomiting, laxatives, or
    diuretics



                              Restricting
                                 Weight loss achieved by
                                 restricting calories
                                    Following diets, fasting, and exercising to
                                    excess
Causes
Anorexia Nervosa patients tend to have
   Low self-evaluation
   Come from competitive, high-achieving, and protective
   families
   Set perfectionist standards
   Intensely concerned with how others perceive them
   Fear falling short of expectations
   Genetics
   Culture
   Idealize thinness
   Have poor body image
   Feel shame, depressed, and dissatisfied with their own
   bodies
Symptoms
Dramatic weight loss

Preoccupation with
weight, food, calories, fat grams, and
dieting

Refusal to eat certain foods, or whole
categories of food (e.g. no carbohydrates)

Denial of hunger

Excessive, rigid exercise regimen

Withdrawal from usual friends and
activities

Weight loss and dieting become primary
concerns in life.

Constant excuses to avoid mealtimes

Anxiety about gaining weight or being fat
Epidemiology
UK
     1 in 250 females
     1 in 2000 males

SMR 9.5

Mortality of 0.6% per year

Higher in those presenting after age 20
50 years of treatment
                  outcomes
Comparison of outcomes 1950-1999 to gauge whether any
improvement over time.
119 studies conducted 1950-1999
5,590 patients, adolescents and adults
Follow-ups clustered into three time frames:
       - fewer than 4 years after hospitalization;
       - 4-10 years;
       - more than 10 years after




                                         Steinhausen HC. Am J Psychiatry. 2002.
Outcome measures
Broad outcome measures: death, recovery, improvement,
chronicity.
Symptom normalization measures: weight, menstruation,
eating behavior
Psychopathologies such as affective disorders, OCD,
anxiety, substance abuse.




                                   Steinhausen HC. Am J Psychiatry. 2002
“The mortality rate was much
lower in the group of younger
patients than that in the group
with a much wider age at onset
of illness. The rates of
recovery, improvement, and
chronicity were more favorable
in the group with the younger
patients.”

Outcome of Anorexia Nervosa
in 119 Patient Series by Duration
of Follow-Up and Age at Onset.

A total of 577 patients had less
than 4 years of follow-up, 2,132
had 4–10 years of follow-
up, and 438 had more than 10
years of follow-up.




  Steinhausen HC. Am J Psychiatry. 2002
“Anorexia nervosa did not
lose its relatively poor
prognosis in the
20th century.”


Outcome of Anorexia Nervosa
in 119 Patient Series by
Duration of Follow-Up and
Time Period of Study.

A total of 577 patients had less
than 4 years of follow-up, 2,132
had 4–10 years of follow-
up, and 438 had more than 10
years of follow-up.



   Steinhausen HC. Am J Psychiatry. 2002.
Re-feeding syndrome
First described in American Japanese POW

Precipitated cardiac failure

clinical features of refeeding syndrome
   rhabdomyolysis, leucocyte dysfunction, respiratory
   failure, cardiac
   failure, hypotension, arrhythmias, seizures, coma, and
   sudden death

Driven by low serum phosphate (<0.5)
Re-feeding syndrome -
  pathophysiology
insulin is decreased due to a reduced oral carbohydrates.

fat and protein stores are catabolized

Intracellular loss of electrolytes, esp. phosphate.

intracellular phosphate stores can be depleted despite normal
serum phosphate concentrations

a sudden shift from fat to carbohydrate metabolism -secretion
of insulin increases -stimulates cellular uptake of phosphate,

usually occurs within four days of starting to feed again.

Phosphate is necessary for ATP from ADP and AMP
How do we manage it?
Risk is obvious

Degree of risk is not

Assume risk is reduced after 1 week of good intake
AND weight gain

Often use telemetry – some centres use it
continuously for all patients

ECG daily is essential
Exeter protocol
(with thanks to Roderick Warren)
 Assume high risk in all cases. Medical inpatients with
 anorexia nervosa who require inpatient feeding are
 almost always at high risk of refeeding syndrome.
 However, NICE guidance (2006 – CG32) states that the risk
 is high if:
 • One of: BMI<16, weight loss >15% in last 3-6 months, little
 or no nutrition >10 days, low
 potassium/phosphate/magnesium levels prior to feeding.
 • Two of: BMI <18.5, weight loss >10% in last 3-6 months,
 little or no nutrition >5 days, history of alcohol abuse or
 use of insulin/chemotherapy/antacids/diuretics/(laxatives)
Exeter protocol
Bloods before feeding:

Sodium, potassium, urea, creatinine, glucose, CRP

Magnesium, phosphate, calcium

Albumin, liver enzymes, INR

FBC, ferritin, folate, B12

FSH, LH, oestradiol (females) or testosterone (males)

Thiamine: 300mg per day
Vitamin B Complex (Strong): 2 tablets, once per day Multivitamins:
generic, 1 tablet, once per day Phosphate-Sandoz: 2 tablets, three
times daily
Exeter protocol
Daily bloods while risk of refeeding syndrome is high:
•
Sodium, potassium, urea, creat, glucose, magnesium, phosphate
, calcium
Bloods once-twice weekly when stable (after 3-4 days of
sustained feeding and no electrolyte abnormalities):
Sodium, potassium, urea, creatinine, glucose
Magnesium, phosphate, calcium
Albumin, liver enzymes
FBC
Exeter protocol

Mild deficiency (3.0 – 3.5 mmol/L)

• Sando-K or equivalent, 4-8 tablets daily

Moderate-severe deficiency (<3.0 mmol/L)
• Intravenous, using pre-prepared bags of 1 litre 0.9%
saline with 40 mmol potassium chloride, given over
at least 4 hours (but usually longer e.g. 12 hours).

Anorexic patients may be chronically hypokalaemic.
Exeter protocol
Mild deficiency (>0.5 mmol/L and not falling rapidly) • Phosphate-Sandoz 2 tablets,
three times daily

Moderate-severe deficiency (<0.5 mmol/L, or higher but falling)
• Intravenous, using pre-prepared bags of Phosphates Polyfusor, 500ml over 24
hours.

– monitor calcium. Will precipitate if co-infused with calcium – always avoid infusing
magnesium or calcium through the same cannula.

– check levels after 24 hours.

IV phosphate. Various recommendations suggest 9, 12 or 18 mmol administered over
12 hours. However, the use of an entire Polyfusor bag (containing 50 mmol
phosphate) has been shown to be a simple, effective and safe approach. Mild
hyperphosphataemia is not uncommon (levels up to 1.57 mmol/L have been seen) –
consider a smaller dose (e.g. 250 ml over 12 hours) for less severe
hypophosphataemia.
Exeter protocol

Mild deficiency (>0.6 mmol/L)
   Magnesium glycerophosphate 2 tablets, twice daily.
   May cause GI irritation/diarrhoea. Avoid with co-admin with
   phosphate

Moderate-severe deficiency (<0.6 mmol/L)
   IV magnesium sulphate, 20 mmol over 12 hours, or 40 mmol
   over 24 hours. Can be given faster in emergencies
   Will precipitate if co-infused with phosphate – always used a
   separate cannula.

Magnesium levels may drop rapidly after correction -
several days of IV replenishment may be required before
they become stable.
Exeter protocol- calcium
rarely necessary. Correction of hypomagnesaemia may improve calcium
levels. Administration of phosphate may lower calcium levels.

Asymptomatic mild-moderate deficiency

Calcichew, 1-3 tablets daily.

Do not administer at same time as phosphate – insoluble CaPO4 will form.
Symptomatic or severe deficiency

• IV calcium chloride or calcium gluconate, 10 mmol over at least 10 min
(but usually longer e.g. 1 hour).

Followed by infusion of 40 mmol over 24 hours.

Must be diluted before administration
A more unusual case….
Douglas

To GP, Feb 2010

Weight loss feeling tired

Recent junior Exeter chiefs player

Creat high at 110, glucose 2.1, Hb12.6, WCC 3.4

Subsequent fall in WCC, rise in ALT
Douglas
Ft4 12.3, cortisol 594, fsh 0.6, lh 0.4, PRL 208, testo 0.8
GH 15.1, IGF1 8.6
68kg BMI 20.9, prior weight 111kg 6 mths earlier
Clinically cachectic, lanugo hair, but post-pubertal
Admitted – psych confirmed significant AN
Weight regain to 76kg, BMI 23
Partial recovery of pancytopaenias, no recovery of
gonadotrophins despite weight regain and 2 trials of
testosterone cessation
Anorexia and fertility
Very little data in men for longer term

Testo crashes during acute illness

Seems to be less marked than in females

Partly an adaptive response

Many recovered anorexic patients go on to
successful pregnancies
Conlcusions
Behaviourally challenging

Strong leadership

Need to be physiologically alert

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Eating disorder presentation

  • 1. Anorexia nervosa, re- feeding syndrome and endocrine sequelae Mark Daly
  • 2. Why this talk….. Traditionally eating disorders have been looked after by either gastro-enterologists or endocrinologists with the support of psychiatry There are few conditions where such strong leadership is necessary in the best interests of the patient and may go counter to the instincts or wishes of members of staff
  • 3. Anorexic woman from Wales to be force fed, judge orders A woman with "severe" anorexia who wanted to be allowed to die is to be force fed in her "best interests" by order of a High Court judge. She was being looked after in a community hospital under a palliative care regime whose purpose was to allow her to die in comfort Treatment - "does not merely entail bodily intrusion of the most intimate kind, but the overbearing of E's will in a way that she experiences as abusive".
  • 4. A not unusual pathway of care….. 19 yr old girl, admitted BMI of 12 Intermittent institutionalised care since age 9 with Anorexia nervosa Admitted because of recent further weight loss, minimal intake for 1 week Agreed for a voluntary admission
  • 5. Admission criteria Based on recent change in the context of absolute BMI, physiological and functional parameters
  • 6. Physical concern Concern Admit BMI <14 <12 Wt loss (kg/week) >0.5 >1 BP <90/70 <80/60 Postural drop >10 >20 Pulse <50 <40 Temp <35 <34 Muscular Uses arms to Can’t stand strength stand WBC <4 <2 Hb <11 <9 Plts <130 <110
  • 7. Physical concern(2) Concern Admit NA+ <135 <130 K+ <3.5 <3.0 Mg2+ If depleted If depleted Po4- If depleted If depleted ECGqtc >450msec >450 or arrhythmia ALT >45 >90 Bilirubin >20 >40 Alk phosp >110 >200 Albumin <35 <32
  • 8. O/E Well presented Gross cachexia Hypotensive and bradycardic Pre-pubertal
  • 9. Initial investigations Hb 11.0,WCC 2.0, Plts 78 Na+ 127, K+ 3.1, urea 1.8, creat 38, PO4- 0.75 ECG bradycardia, long QT
  • 10. Initial plan Medical Initial assessment Na+, K+, Urea, Creat, glucose, CRP Mg2+, PO4-, Ca2+ Albumin, liver enzymes, INR FBC, ferritin, folate, B12 FSH, LH Oest or testo Thiamine 300mg daily, vit b complex strong 2 tabs od, multivit generic, sandophosp 2 tabs tds Pabrinex
  • 11. Initial plan Nutritional 5 kcal per kg stepping up over 5-7days to weight gain levels (+500kcal over estimates from Henry equation (10kcal per kg if BMI>16) Menu plans agreed with patient
  • 12. Initial plan Behavioural/other restrictions Normal foods in preference to supplements Bed rest/commode/wheelchair Away from window, no fans Restrictions according to Mental health status Compliance essential
  • 13. Progress Day 3, non-compliance with feeding plan Non-compliance with activity Reviewed with psych Formal section Advised likely need to progress to NG feeding in absence of compliance and/or weight gain Informed of need to search belongings
  • 14. Progress Day 5, intermittent compliance with feeding plan Reviewed with psych Razor blades and salt sachets removed NG feeding under restraint, NG re- positioned/replaced 5 times first 24 hrs Bolus feeds under restraint during periods of non- compliance
  • 15. Progress Day 8 Hypokalaemia and hypophosphataemia requiring IV replacement Subsequent weight gain back to BMI 15 Established weight stability at BMI 15 on oral intake and basic mobility Discharged to OP ED services
  • 17. What is anorexia nervosa? Anorexia nervosa is defined as: intense fear of weight gain Weight consistently < 85th percentile for age and height (In women) three consecutive missed periods Together with one of following: refusal to admit seriousness of weight loss undue influence of shape or weight on one’s self-image disturbed experience in one’s shape or weight DSM-IV-TR
  • 18. Types of Anorexia • Purging – Weight loss achieved by vomiting, laxatives, or diuretics Restricting Weight loss achieved by restricting calories Following diets, fasting, and exercising to excess
  • 19. Causes Anorexia Nervosa patients tend to have Low self-evaluation Come from competitive, high-achieving, and protective families Set perfectionist standards Intensely concerned with how others perceive them Fear falling short of expectations Genetics Culture Idealize thinness Have poor body image Feel shame, depressed, and dissatisfied with their own bodies
  • 20. Symptoms Dramatic weight loss Preoccupation with weight, food, calories, fat grams, and dieting Refusal to eat certain foods, or whole categories of food (e.g. no carbohydrates) Denial of hunger Excessive, rigid exercise regimen Withdrawal from usual friends and activities Weight loss and dieting become primary concerns in life. Constant excuses to avoid mealtimes Anxiety about gaining weight or being fat
  • 21. Epidemiology UK 1 in 250 females 1 in 2000 males SMR 9.5 Mortality of 0.6% per year Higher in those presenting after age 20
  • 22. 50 years of treatment outcomes Comparison of outcomes 1950-1999 to gauge whether any improvement over time. 119 studies conducted 1950-1999 5,590 patients, adolescents and adults Follow-ups clustered into three time frames: - fewer than 4 years after hospitalization; - 4-10 years; - more than 10 years after Steinhausen HC. Am J Psychiatry. 2002.
  • 23. Outcome measures Broad outcome measures: death, recovery, improvement, chronicity. Symptom normalization measures: weight, menstruation, eating behavior Psychopathologies such as affective disorders, OCD, anxiety, substance abuse. Steinhausen HC. Am J Psychiatry. 2002
  • 24. “The mortality rate was much lower in the group of younger patients than that in the group with a much wider age at onset of illness. The rates of recovery, improvement, and chronicity were more favorable in the group with the younger patients.” Outcome of Anorexia Nervosa in 119 Patient Series by Duration of Follow-Up and Age at Onset. A total of 577 patients had less than 4 years of follow-up, 2,132 had 4–10 years of follow- up, and 438 had more than 10 years of follow-up. Steinhausen HC. Am J Psychiatry. 2002
  • 25. “Anorexia nervosa did not lose its relatively poor prognosis in the 20th century.” Outcome of Anorexia Nervosa in 119 Patient Series by Duration of Follow-Up and Time Period of Study. A total of 577 patients had less than 4 years of follow-up, 2,132 had 4–10 years of follow- up, and 438 had more than 10 years of follow-up. Steinhausen HC. Am J Psychiatry. 2002.
  • 26.
  • 27. Re-feeding syndrome First described in American Japanese POW Precipitated cardiac failure clinical features of refeeding syndrome rhabdomyolysis, leucocyte dysfunction, respiratory failure, cardiac failure, hypotension, arrhythmias, seizures, coma, and sudden death Driven by low serum phosphate (<0.5)
  • 28. Re-feeding syndrome - pathophysiology insulin is decreased due to a reduced oral carbohydrates. fat and protein stores are catabolized Intracellular loss of electrolytes, esp. phosphate. intracellular phosphate stores can be depleted despite normal serum phosphate concentrations a sudden shift from fat to carbohydrate metabolism -secretion of insulin increases -stimulates cellular uptake of phosphate, usually occurs within four days of starting to feed again. Phosphate is necessary for ATP from ADP and AMP
  • 29. How do we manage it? Risk is obvious Degree of risk is not Assume risk is reduced after 1 week of good intake AND weight gain Often use telemetry – some centres use it continuously for all patients ECG daily is essential
  • 30. Exeter protocol (with thanks to Roderick Warren) Assume high risk in all cases. Medical inpatients with anorexia nervosa who require inpatient feeding are almost always at high risk of refeeding syndrome. However, NICE guidance (2006 – CG32) states that the risk is high if: • One of: BMI<16, weight loss >15% in last 3-6 months, little or no nutrition >10 days, low potassium/phosphate/magnesium levels prior to feeding. • Two of: BMI <18.5, weight loss >10% in last 3-6 months, little or no nutrition >5 days, history of alcohol abuse or use of insulin/chemotherapy/antacids/diuretics/(laxatives)
  • 31. Exeter protocol Bloods before feeding: Sodium, potassium, urea, creatinine, glucose, CRP Magnesium, phosphate, calcium Albumin, liver enzymes, INR FBC, ferritin, folate, B12 FSH, LH, oestradiol (females) or testosterone (males) Thiamine: 300mg per day Vitamin B Complex (Strong): 2 tablets, once per day Multivitamins: generic, 1 tablet, once per day Phosphate-Sandoz: 2 tablets, three times daily
  • 32. Exeter protocol Daily bloods while risk of refeeding syndrome is high: • Sodium, potassium, urea, creat, glucose, magnesium, phosphate , calcium Bloods once-twice weekly when stable (after 3-4 days of sustained feeding and no electrolyte abnormalities): Sodium, potassium, urea, creatinine, glucose Magnesium, phosphate, calcium Albumin, liver enzymes FBC
  • 33. Exeter protocol Mild deficiency (3.0 – 3.5 mmol/L) • Sando-K or equivalent, 4-8 tablets daily Moderate-severe deficiency (<3.0 mmol/L) • Intravenous, using pre-prepared bags of 1 litre 0.9% saline with 40 mmol potassium chloride, given over at least 4 hours (but usually longer e.g. 12 hours). Anorexic patients may be chronically hypokalaemic.
  • 34. Exeter protocol Mild deficiency (>0.5 mmol/L and not falling rapidly) • Phosphate-Sandoz 2 tablets, three times daily Moderate-severe deficiency (<0.5 mmol/L, or higher but falling) • Intravenous, using pre-prepared bags of Phosphates Polyfusor, 500ml over 24 hours. – monitor calcium. Will precipitate if co-infused with calcium – always avoid infusing magnesium or calcium through the same cannula. – check levels after 24 hours. IV phosphate. Various recommendations suggest 9, 12 or 18 mmol administered over 12 hours. However, the use of an entire Polyfusor bag (containing 50 mmol phosphate) has been shown to be a simple, effective and safe approach. Mild hyperphosphataemia is not uncommon (levels up to 1.57 mmol/L have been seen) – consider a smaller dose (e.g. 250 ml over 12 hours) for less severe hypophosphataemia.
  • 35. Exeter protocol Mild deficiency (>0.6 mmol/L) Magnesium glycerophosphate 2 tablets, twice daily. May cause GI irritation/diarrhoea. Avoid with co-admin with phosphate Moderate-severe deficiency (<0.6 mmol/L) IV magnesium sulphate, 20 mmol over 12 hours, or 40 mmol over 24 hours. Can be given faster in emergencies Will precipitate if co-infused with phosphate – always used a separate cannula. Magnesium levels may drop rapidly after correction - several days of IV replenishment may be required before they become stable.
  • 36. Exeter protocol- calcium rarely necessary. Correction of hypomagnesaemia may improve calcium levels. Administration of phosphate may lower calcium levels. Asymptomatic mild-moderate deficiency Calcichew, 1-3 tablets daily. Do not administer at same time as phosphate – insoluble CaPO4 will form. Symptomatic or severe deficiency • IV calcium chloride or calcium gluconate, 10 mmol over at least 10 min (but usually longer e.g. 1 hour). Followed by infusion of 40 mmol over 24 hours. Must be diluted before administration
  • 37. A more unusual case…. Douglas To GP, Feb 2010 Weight loss feeling tired Recent junior Exeter chiefs player Creat high at 110, glucose 2.1, Hb12.6, WCC 3.4 Subsequent fall in WCC, rise in ALT
  • 38. Douglas Ft4 12.3, cortisol 594, fsh 0.6, lh 0.4, PRL 208, testo 0.8 GH 15.1, IGF1 8.6 68kg BMI 20.9, prior weight 111kg 6 mths earlier Clinically cachectic, lanugo hair, but post-pubertal Admitted – psych confirmed significant AN Weight regain to 76kg, BMI 23 Partial recovery of pancytopaenias, no recovery of gonadotrophins despite weight regain and 2 trials of testosterone cessation
  • 39. Anorexia and fertility Very little data in men for longer term Testo crashes during acute illness Seems to be less marked than in females Partly an adaptive response Many recovered anorexic patients go on to successful pregnancies