Nutritional disorders

 

Assessing nutritional status

Working out body mass index

The Body Mass Index (originated by Quetelet, so sometimes called the Quetelet Index): BMI = weight / (height)² Overweight = BMI > 25. Obese = BMI > 30.

For example, an individual weighing 80 kg and with a height of 1.70 metres has a BMI = 80/(1.7 x 1.7) = 80/2.89 = 27.7.

Waist circumference measurement is also worth doing – it is used as a component of some definitions of the metabolic syndrome (3 or more of: BP>130/85; fasting glucose >6.1; triglycerides > 1.7; HDLchol <1.3 and waist circumference > 102 cm in men and > 88 cm in women). It is measured with the patient standing and the tape measure circling the abdomen parallel to the floor at the level of the iliac crest.¹

Undernutrition can also be evaluated clinically – apart from body mass, look for evidence of protein deficiency (thin hair) and vitamin deficiencies – crazy paving skin changes on legs suggesting B group deficiency, perifollicular haemorrhages suggesting Vitamin C deficiency, and pallor suggesting B12 or folate deficiency.

Perspective – the metabolic syndrome

The metabolic syndrome is increasingly viewed as an important risk component in cardiovascular disease. It is defined differently by various bodies,² but generally comprises the elements of insulin resistance with fasting glucose of >6.1 mM, hypertension (>135/85), central obesity as defined above, dyslipidaemia (HDLC <1, TG>1.7 mM) and a pro-inflammatory state (raised CRP and decreased adiponectin). Its actual relevance remains to be defined, although an observational study³ of patients with acute MI showed higher in hospital mortality and greater likelihood of developing cardiac failure in the 46% who fulfilled the diagnostic criteria for the syndrome (3 of the 4 features of raised BP, dyslipidaemia, hyperglycaemia and central obesity). In spite of recent hype, lifestyle modification is better at reducing incidence than is metformin.⁴ (Three year cumulative incidence 51% for placebo, 45% for metformin, and 34% for lifestyle modification.)

Obesity

Mortality and morbidity in obesity

The mortality rate is clearly increased in those with a BMI above 35,⁵ but is less clearly increased in those with lesser degrees of obesity, perhaps reflecting improvements in cardiovascular care in the US over the periods studied. The relationship between BMI and mortality is J-shaped⁶ – the group with weights well below a BMI of 20 includes individuals with cancer and AIDS, and thus the curve tips up below 20 to form the toe of the J. Even after excluding the effect of comorbidity and smoking, the relative risk of death is 2.68 times higher in extremely obese males than in those of normal BMI – for instance, males with a BMI of 25 had a mortality rate of 962 per 100 000 per year, whereas those with a BMI of more than 40 had a rate of 2578. (The corresponding figures for women were 682 and 1289.)

A simpler way of expressing this is that the mortality hazard ratio of 2 (for an obese individual relative to a normal weight individual) translates, for a 40 year old, into a reduction in life expectancy of about 7 years.⁷ Weight reduction has been demonstrated to benefit morbidity in obese individuals in the following: type 2 diabetes, hypertension, dyslipidaemia, obstructive sleep apnoea, asthma coronary artery disease, obesity related cardiomyopathy, non-alcoholic fatty liver disease, osteoarthritis, and polycystic ovary syndrome⁸.

History and examination in obese patients

The medical illnesses faced by obese people are fairly well discussed in standard texts. Some difficulties arise, however, with symptom interpretation and physical examination, and with the use of diagnostic tests in such patients. In reality it is sometimes necessary to make management decisions in the absence of the usual diagnostic clues.

A history of dyspnoea and ankle swelling is almost invariable. The point of interest is whether these symptoms have changed – a recent exacerbation would be relevant.

Ask about features suggestive of sleep apnoea (snoring, daytime somnolence)

Low back pain and knee and hip joint pain are very common in ambulant obese people. Try to avoid chronic use of non-steroidal anti-inflammatories.

On examination, the JVP is invisible, the apex impalpable, and BP recording difficult. Remember to use an especially wide cuff, and if this is unavailable, taking an average of 15 mmHg from the systolic and 10 from the diastolic is a reasonable approximation. If the only available cuff keeps on popping off, a lightly applied crepe bandage on top may help. Fore-arm cuff use may be the only alternative.

Checking for abdominal visceromegaly is difficult but do try, as the presence of localised pain may be of value. Remember that the position of the umbilicus is not a reliable guide to the localisation of the intra-abdominal quadrants, and you must work ‘from the edges’ – rib margins and anterior superior iliac spines.

Cardiomegaly on CXR may be due to a pushed up diaphragm and epicardial fat. Echocardiography may be impossible. The ECG may show left axis deviation.

In the face of these challenges, consider the following:

• It is still worth looking for the JVP and the apex, even though the task appears daunting – every now and then you can be pleasantly surprised.
• Concentrate hard on the nature of the crackles in the lungs, if present – in the absence of other clues, the finding of fine inspiratory crackles that persist after coughing is very valuable. (LVF!)
• Taking blood involves looking for a little vein on the volar side of the wrist, or sometimes an invisible but easily palpable antecubital vessel. The tiny very visible elbow veins are often quite difficult. Femoral puncture is sometimes tempting, but also often not as easy as one might think. Superficial neck veins are worth considering, but aren’t very common and tend to be difficult to fixate. Radial arterial puncture is always an option, but think about it carefully.
• Venous access for fluids in the shocked very obese patient should be by a central line unless peripheral veins are immediately obvious. A lot of valuable time can be wasted trying to insert an impossible drip.
• Very frequently, management will be guided by therapeutic trials, so try to keep the regimen as ‘pure’ as possible. (i.e. a response after giving a bronchodilator and a diuretic together is difficult to interpret)
• Don’t forget about heparin prophylaxis.

Which patients warrant further investigation for the obesity?

Most obesity is constitutional, and looking for a reversible endocrine cause is futile. An individual who was obese as a child and had obese parents probably does not have an endocrinopathy. There are a number of conditions associating mental retardation with obesity (Prader-Willi – hypotonia and diabetes, Laurence-Moon-Biedl – retinitis pigmentosa and polydactyly) or associating obesity and hypogonadism (Froehlich). These are generally obvious from history and examination, and the majority of obese mentally retarded individuals simply eat too much. Be alert for:

• Rapid onset obesity on history or purple striae on examination.
• New constitutional symptoms (tiredness, malaise).
• Hirsutism (Cushing’s and polycystic ovary syndrome.)

If in doubt, a TSH and 24 hour urinary cortisol are relatively cheap, and will screen in the majority of that very small group with hypothyroidism or Cushing’s that is not obvious clinically. Also take a drug history (corticosteroids, valproate, tricyclics, insulin). Investigations worthwhile in most patients are:

• Check the blood pressure with an appropriate sized cuff
• Cholesterol and triglycerides as part of workup for dietary intervention
• Blood glucose level.

Interventions for obesity

Life style modification and diets

Many clinicians appear rather defeatist about the possibility of achieving weight loss in obese individuals, in spite of the obvious benefits:

• Improved blood pressure control.
• Better glycaemic control in diabetics.
• Reduced risk of IHD associated with reduced cholesterol.
• Less knee osteoarthritis.
• Improvement in psychosocial outcome measures (happier and more integrated).

Lifestyle modification is about more than just going on a diet for a few weeks – it is really about achieving a change in mindset. Improved health is seen as under the control of the individual concerned. Modest calorie restriction combined with a bit of exercise and perhaps joining one of the many commercial obesity support groups now available will probably achieve a lot more than cycling through fad diet after fad diet. Much of the literature on the subject involves trials of less than a year, and the remarkable weight reduction achieved is not sustained. In resource-constrained environments, access to medication and fancy diets purported to induce weight loss is also difficult.

Energy restriction

Basal metabolism requires quite a lot of energy; the increment required to shift from couch potato to active labourer is only about 20%. Equally, the energy expended from mild exercise by the very obese is easily recaptured by relatively minor increases in energy intake. Exercise and calorie restriction need to be linked.

Suggest: Restrict carbohydrate to a single ‘portion’ per meal – e.g. two slices of bread, half a cup of cooked rice. Avoid all obvious fat – no fried food, remove skin from chicken before cooking. Cheaper alternatives such as cabbage, spinach, and tomatoes vary in individual palatability and seasonal availability.

Walking is cheap and relatively safe if you aren’t mugged.

Collaborative groups where there are team weight loss goals and interpersonal competitions (e.g. Weigh-Less^®, Weightwatchers^®) are usually accessible geographically in peri-urban areas but practically impossible in rural areas. They are not cheap. Special commercial diets are very expensive and rarely effective in the long term.

Make a habit of weighing patients who are obese and whom you are seeing regularly – it allows the setting of goals and carries the message that you are genuinely interested in weight reduction.

Perspective – dietary advice

‘Standard’ servings of food from take-away establishments in the US have more than doubled in size over the last five decades, perhaps reflecting a change in cultural norms of what is regarded as ‘normal’. Total energy intake is what is critical – not just fat intake, and reductions in fat may not lead to energy intake reduction. For instance some versions of low fat peanut butter contain the same energy content as the regular version, and the regular versus low fat kiloJoule content of 100ml frozen yoghurt was 435 versus 418, of a low fat muffin 577 versus 548, and of a cereal bar was 586 versus 544⁹.

The key difficulty is ‘movement inertia in an obesogenic environment’¹⁰ complicated by mechanical dysfunction (arthritis and back pain), and psychological dysfunction (low self-esteem compensated for by increased eating).

Perspective – success of diets

A narrative review¹¹ suggested an overall median success rate of 15% for sustaining weight loss of 10 kg or more for 3 years or more. A RCT¹² looking at the independent effect of exercise on weight loss in young individuals showed that males lost on average 5 kilograms, whereas women remained at the same weight over 16 months. A meta-analysis of 46 trials of the effect of dietary counselling¹³ confirmed this 5 kg weight loss (they expressed it as a reduction in BMI of 1.9, 95% CI 1.5-2.3) at one year, but noted that about half of this loss was regained after three years. This translates into 3 kg at three years, which is rather disappointing, but bear in mind that this is the mean figure – some individuals may do considerably better.

Perspective – success of medications.

The field contains a remarkable number of medications that have been used and then removed because of side-effects. A review¹⁴ suggested pooled weight loss of 4 kg for sibutramine, and 3 kg for orlistat, fluoxetine and bupropion. More recently, GLP-1 receptor agonists seem to have changed this field considerably, with early long term results looking promising.¹⁵

Prescribing in obesity

For those medication prescribed according to lean body mass, height is a surrogate marker. A very rough approximation is ideal weight = 50 + 0.75(height – 150 cm) for males. Subtract a further 5 kg for females. There are numerous other formulae, all trading complexity against accuracy.

Antibiotic prescribing in obesity is not straightforward. One suggestion¹⁶ is that aminoglycosides, ciprofloxacin, and anti-tuberculous medications should be dosed on adjusted body weight, and vancomycin on total body weight. Penicillins and cephalosporins are not usually dosed by weight, but it is suggested that ‘higher’ doses be used in very obese patients. (One suggestion is to double the normal dose but there is little empiric evidence that this is correct.) Meropenem dosing is unchanged.

Many medications may lead to weight gain, with the regularly mentioned culprits being valproate, atypical antipsychotics, lithium, sulphonylureas, beta-blockers and corticosteroids, with some suggestions that weight gain may contribute to poor adherence with these agents¹⁷. Information about this should, however, be seen in the light of the 0.5 to 1 kg annual weight gain seen in the normal population, with figures of up to 5 kg gain per year seen in obese persons.

Starvation

• There is reduced cardiac output.
• There is reduced glomerular filtration rate, and reduced ability to excrete a sodium load.
• There is also a reduced ability to handle hot or cold environments, and reduced ability to respond to infection by mounting a temperature or a leukocytosis.
• There may be small bowel stasis with intestinal overgrowth and excess gas production (one of the causes for the swollen abdomen).

In some individuals kwashiorkor develops. This oedematous state is associated with but not due to hypoalbuminaemia, and probably represents a situation similar to the so-called sick cell syndrome sometimes found in severely ill patients with multiple organ failure or septicaemia. This is an incompletely understood syndrome associated with ‘leaky’ cell membranes and increased sodium flux.

Re-feeding syndrome

Of particular clinical importance is the re-feeding syndrome, which occurs about 4 days after re-institution of adequate caloric intake.¹⁸ During starvation, insulin levels fall and fat and protein are catabolised; once an adequate carbohydrate source is re-introduced, insulin levels rise, phosphate and potassium move into cells, and hypophosphataemia and hypokalaemia may ensue, leading to cardiac failure, hypotension, fits, coma, respiratory distress (diaphragmatic myopathy), rhabdomyolysis and leukocyte dysfunction.

Investigations – look hard for infection, as it is nearly always present, often as the precipitant that finally brought the patient to your attention. Possible exceptions might be ‘societal starvation’ – voluntary starvation, anorexia nervosa, and starvation due to being lowest on the food chain (mentally retarded individuals in very poor households). Check electrolytes and total protein, albumin, serum phosphate and magnesium, and a FBC.

Management of starvation and re-feeding syndromes

• If there is any chance of unrecognised septicaemia, treat with ceftriaxone 1 g IV daily.
• If there is likely to be intestinal overgrowth, give an oral antibiotic even if you don’t suspect sepsis, e.g. ciprofloxacin 500 mg 2x/d PO.
• Thiamine 100 mg IMI, then 100 mg orally or IM daily.
• Don’t overhydrate – normal saline is perhaps less desirable than a lower sodium fluid such as Ringers lactate or half normal saline with dextrose.
• If the serum phosphate is less than 0.5 mM, give replacement therapy – e.g. 25 mmol per day as a continuous infusion. Too rapid phosphate infusions can cause hypocalcaemia and tetany. Hypomagnesaemia is also best managed with a continuous infusion (the same dose as phosphate replacement: 25 mmol/day), as sudden boluses exceed the renal threshold and are just excreted.
• Oral or nasogastric intake should be frequent, regular (no long gaps, even at night) and in initially quite small amounts. The initial total calorie load should be limited to about 80 kJ/kg per day,¹⁹,²⁰ increasing by about 20 kJ/kg each day after the first few days.
• Protein intake need not be restricted.
• Don’t transfuse blood unless actively bleeding or air hungry because of very severe anaemia.
• Don’t give oral ferrous sulphate – it is a major gastric irritant and is usually unnecessary unless there is documented iron deficiency or at least a low MCV.
• Give lots of multivitamins – e.g. 2 or 3 tablets 3 times per day.

Specific vitamin deficiencies

(See also what may happen with over-enthusiastic vitamin prescribing: https://medeval.co.za/can-prescribing-vitamins-cause-harm/ )

Beriberi and Wernicke’s encephalopathy.

There are three distinct entities – Wernicke’s, wet beriberi and dry, or shoshin beriberi.

Wernicke’s encephalopathy is sometimes confused with cerebellar strokes – the combination of ataxia, nystagmus, 6^th nerve palsy and confusion is assumed to be due to a vascular event because the history of onset is often quite vague. Give thiamine 100 mg IM and then daily orally. There are reports of anaphylaxis after IV thiamine²¹, and very rare descriptions of progression after IM therapy has been started. On balance, however, giving IM is probably usually adequate and has the advantage that you know it is in.

Wet beriberi presents as severe cardiac failure that reverses rapidly with thiamine. An initial ECG is often normal, but one done some hours later may well show characteristic T wave changes.

Shoshin beriberi is a rare shock-like state with acidosis and preserved central pulses. Again, it resolves rapidly with therapy. If in doubt, treat for it.

Perspective – Wernicke’s encephalopathy and HIV

In HIV infected persons the classic triad of oculomotor signs, ataxia and confusion may not always be present. There are case reports of patients presenting with pathologically proven Wernicke’s but with only gait and speech changes²². If in any doubt, give some thiamine.

Pellagra

This is often missed. It is one of those ‘really obvious once you think of it’ diagnoses, although thought to be relatively uncommon in South Africa²³.

• Consider it in any frail person presenting with diarrhoea
• Consider it in any frail person presenting with confusion
• Really consider it in a frail person with diarrhoea and confusion!

Make the diagnosis clinically in an individual with confusion (‘dementia’,) diarrhoea, and a hyperpigmented rash in sun-exposed areas. The mental changes range from depression to excitement and sometimes even aggressive behaviour, although simple disorientation is probably the commonest. Occasional patients may present with rigidity and primitive reflexes (sucking, grasping), or even catatonia²⁴. Odynophagia is well described. There is an association with the use of isoniazid²⁵,²⁶ and also phenytoin.

Alcohol associated pellagra encephalopathy without an obvious skin rash is also worth considering in the right setting, and there are case reports of this worsening after giving thiamine on its own (without nicotininc acid), so if in doubt add the latter²⁷ It may even present as spinal myoclonus²⁸

Consider the diagnosis in any patient on TB treatment who presents with neurological or psychiatric symptoms, even when there are no skin changes²⁹. Consider acute nicotinic acid deficiency in the differential diagnosis of any patient presenting with stiffness and diarrhoea. There are no readily available magic tests other than a response to therapy, and the treatment is not particularly rigorous, so if in doubt, try it.

Treatment is ideally nicotinic acid 100 mg 3x/d. If this isn’t available, you may be able to get adequate amounts from high doses of vitamin B Complex (Vit B Co) – e.g. 4 or 5 tabs 3 x/d, although not all preparations contain nicotinamide.

Scurvy

Scurvy still occurs. The usual setting is either in patients with iron overload or in markedly malnourished alcoholics. It can also occur in patients with adequate energy and protein intake but an aversion to fresh fruit and vegetables. Making the diagnosis in individuals with bleeding gums and large bruises is easy, but it should also be thought about in susceptible individuals presenting with soft tissue pain, which may be due to a deep haematoma (Not a DVT!) Perifollicular haemorrhages are common in severely malnourished individuals; whether this represents pure vitamin C deficiency is unclear. Differential diagnosis includes the thrombocytopenias, Vitamin K deficiency (or warfarin poisoning), amyloidosis and even prolonged steroid use. Treatment – ascorbic acid 100 mg 8 hourly orally.

Vitamin B12 deficiency and folate deficiency.

Patients are often nutritionally disadvantaged – pregnant or breast-feeding, mental retardation, epilepsy. They are usually quite profoundly anaemic – Hb of 3 to 4 is not uncommon, as opposed to the Hb of 6 to 7 found in the anaemia of chronic disorder.

Individuals with neurological signs due to B12 deficiency may not be anaemic. Classically patients have upgoing plantars and absent ankle jerks, but a range of peripheral neuropathic and posterior column signs and symptoms have been described.

There may be features that cause confusion with infective endocarditis – fever (occurs in 40% – usually mild but can be up to 40 C on occasion)³⁰, petechiae (associated thrombocytopaenia), tachycardia, cardiac murmur (usually pulmonary flow), mild splenomegaly, and fundal haemorrhages.

The key feature on the FBC is the MCV that is greater than 100, or even 110. In mixed deficiencies (iron as well) a raised red cell distribution width (RDW) may be a clue. The diagnosis is usually fairly obvious on the next essential investigation, which is a peripheral smear (macrocytes and hypersegmented neutrophils). Bloods: serum B12 and serum folate. Local maize is fortified with folate, so folate deficiency is now rare.

Do not transfuse without discussing with someone more experienced first – it is rarely if ever necessary.

Treat with Vitamin B12 1 mg IMI daily for 5 doses and then weekly for 4 doses, and give folate 5 mg/d P.O. In genuine Vitamin B12 deficiency, it is usually advisable to continue with B12 for life (1 mg every second month).

Add potassium supplements and monitor the serum potassium, as dangerous hypokalaemia sometimes occurs in the first few days of treatment.

The issue of whether to look for pernicious anaemia only arises in patients without a clear history of dietary deficiency (i.e. nutritional B12 deficiency is now well described). Because radio-isotope assays of B12 absorption (Schilling tests) are expensive and difficult to obtain, a re-think will often allow adequate management without such testing:

• If the patient has a nutritional deficiency on history that is simply due to poor dietary habit, this can be corrected with education.
• If the patient is socio-economically unable to afford a diet, the alternatives are to direct the patient towards some means of economic support or to suggest regular folate and B12 from the nearest clinic.
• If pernicious anaemia seems a genuine consideration, the management is regular parenteral B12. The only issue is whether the patient warrants regular gastroscopies to detect cancer, as atrophic gastritis is a risk factor. The demonstration of a low pH on aspiration of fluid from a naso-gastric tube effectively excludes severe atrophic gastritis. If the pH is not low, then either the tube is past the pylorus, in the oesophagus, or the patient has genuine achlorhydria.

Perspectives – pernicious anaemia and gastric cancer risk.

Doing regular gastroscopies on individuals with atrophic gastritis associated with Vitamin B12 deficiency will not pose a major burden on most health systems, because the condition itself is relatively rare. The health benefit of targeted screening is related to both the ability to clearly identify a group at risk, and the demonstration that earlier detection of pathology improves outcome.

It is reported that the increased risk of gastric cancer in patients with pernicious anaemia and atrophic gastritis is 4% overall. A study of 21 265 Swedish patients with pernicious anaemia³¹ found that there was also, besides the risk of stomach cancer distal to the cardia, an increased risk of squamous cell carcinoma of the oesophagus. The standardised incidence ratio relative to Swedish norm for stomach cancer was 2.4 (2.1-2.7) and for oesophageal cancer was 3.3(2.4-4.4).

Perspective – clinical pernicious anaemia with a normal serum B12

In a patient with macrocytosis and a normal B12 and folate, think of haemolysis or a myelodysplastic syndrome. False negative assays are possible, as with any other test, so in the context of a suggestive clinical picture, give a trial of IM vitamin B12 and look for a reticulocyte response. A high plasma homocysteine may be another clue³².

Enteral nutrition

Ordering enteral nutrition could mean choosing a diet, but is generally considered to apply to prescribing liquid nutrition to be given through a nasogastric tube. This is a common requirement for stroke patients or other patients with impaired ability to swallow, and there are two ways to go about it.

Work out daily requirements of the main nutrients, establish the amounts of constituents in locally available enteral feeds, and then specify volumes.

Make a guess about volumes required and then work back to see if it will be more or less correct.

Both ways require some basic knowledge of nutrient requirements both in health and disease, as well as access to information on content of locally available feeds (look on the container!) Simply guessing is not advisable.

Parenteral nutrition

Some years ago parenteral nutrition was a highly desirable option for nearly all really ill patients; currently the pendulum has swung back again with the realisation that the bowel has an important immune function, and switching this off by not using the gut lumen could have deleterious consequences (more infections, longer hospital stay.)³³

Appropriate remaining indications for TPN are:

Recent major bowel surgery with severely compromised small bowel capacity.

An assessment that a patient is severely malnourished (or is likely to become so) and that enteral feeding will be unable to correct that situation.

Simply having had bowel surgery, particularly large bowel surgery, should no longer be considered a reason for TPN – one of the low residue feeds may well be tolerated, either via NGT, or if there has been upper GIT work, by feeding jejunostomy or even by a long naso-jejunal tube passed at surgery.

Food allergies

Well recognised allergies occur to nuts, eggs, shellfish and milk proteins. Food related migraine, and reactions to food additives are not usually IgE mediated, and can better be labelled as food intolerances. The clinical features of rash, swollen lips or tongue, scratchy throat and even angio-oedema are readily recognised as they usually occur within an hour or two of ingestion of the offending food. Flatulence, diarrhoea and abdominal cramps coming on later may be less easily associated with a specific food, and are more likely due to intolerance than true allergy. Lactose intolerance needs to be differentiated from allergy to milk protein – check for reducing substances in a stool sample. Cross sensitivities within groups are well described – legumes (peanuts, soya, lentils); tree nuts (hazelnut, walnut, brazil nut); milk (cow, goat, sheep); and latex (banana, kiwi, avocado).³⁴

Diagnosis is usually based on a careful history, although allergy specialists also use skin prick testing and IgE measurements. Skin prick (positive if 3 mm more in diameter than control) are reported to have sensitivities of 75-95% and modest specificities of 30-60%.

The management is avoidance.

Alpha-Gal syndrome

An interesting variant of acquired food allergy relates to apparent allergic reactions to some meat products which appears to come on later than usual, and has been labelled ‘midnight anaphylaxis’.³⁵

Alpha-gal syndrome is due to an allergy to an oligosaccharide called galactose-alpha-1,3-galactose which is found in many mammalian tissues but not in fish or poultry. Reactions can vary from severe anaphylaxis to milder skin reaction or simply gastrointestinal symptoms (abdominal pain, diarrhoea, vomiting) and happen typically 3 to 6 hours after eating red meat, but earlier reactions (less than one hour) are also possible. The reaction is inconsistent, and perhaps linked to the size and fat content of the ingested meal.

Diagnosis is based on the typical history, and the finding of specific alpha-gal IgE levels >0.35 IU/L is suggestive. Use adrenalin for treating the acute attack, if necessary, and manage by avoidance.³⁶

What makes the condition interesting is the putative association with tick bites. In the US, bites from the tick Amblyomma americanum may cause sensitisation, resulting in a new allergy to beef and pork products. Recent bites may make the condition more likely to manifest, or to be more severe. In other countries, other tick species have been implicated, although there is less clarity about which (if any) tick is involved in Africa. The condition is also possibly linked to:

• late onset milk allergy
• immunological reaction to porcine and bovine cardiac valve grafts
• reactions to equine snake antivenoms
• and perhaps even reactions to the mouse-sourced monoclonal antibody cetuximab.

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