Endgames Case Report

Seeing double: the low carb diet

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f2563 (Published 01 May 2013) Cite this as: BMJ 2013;346:f2563

This article has a correction. Please see:

  1. Louise A McKenna, academic foundation year 1 doctor1,
  2. Russell S Drummond, consultant endocrinologist1,
  3. Suzannah Drummond, consultant ophthalmologist2,
  4. Dinesh Talwar, consultant biochemist3,
  5. Michael EJ Lean, professor of human nutrition and consultant physician4
  1. 1Department of Diabetes and Endocrinology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK
  2. 2Department of Ophthalmology, Glasgow Royal Infirmary
  3. 3Department of Pathological Biochemistry, Glasgow Royal Infirmary
  4. 4Department of Human Nutrition, Glasgow Royal Infirmary
  1. Correspondence to: L A McKenna louise.mckenna{at}glasgow.ac.uk

A 38 year old white Scottish man with mild learning difficulties (able to read and write but not to maintain employment) presented with a three day history of diplopia and agitation, after seven days of presumed viral gastroenteritis.

On admission, he was agitated, mildly confused, tachycardic (115 beats/min, regular) and tachypnoeic (18 breaths/min). There were no chest signs or peripheral oedema. He had complete bilateral sixth cranial nerve palsies and horizontal nystagmus, with dilated, slowly reacting pupils. Limb movements were clumsy, with moderate cerebellar signs and dysdiadochokinesis, but no tremor. He was clinically jaundiced. Electrocardiography showed inferolateral T wave inversion. His heart size was at the upper limit of normal on chest radiography.

On specific questioning, he gave a history of lifelong avoidance of alcohol, but of 34 kg weight loss over the preceding three months. This information was corroborated by his parents and practice nurse. At an initial weight of 127 kg (body mass index 42.4), he had received “healthy eating” advice from his practice nurse, who described him as her “star patient.” His weight had rapidly fallen—from 123 kg at four weeks, to 110 kg at eight weeks, 104 kg at 11 weeks, and finally 93 kg (body mass index 31) on admission. More recently, pursuing greater weight loss, he had eliminated all bread, cereals, and fats, on a diet considered “starvation” by his parents, without nutritional supplements.

Questions

  • 1 What is the most likely diagnosis?

  • 2 What definitive investigation confirms the diagnosis?

  • 3 What treatment should you start as an emergency, without confirmatory investigation results?

  • 4 Why were the electrocardiographic and chest radiographic findings alarming?

  • 5 Why did this patient become so ill and develop jaundice, when many people follow low carbohydrate diets without evident problems?

Answers

1 What is the most likely diagnosis?

Short answer

Concurrent agitation and cerebellar signs suggest Wernicke’s encephalopathy as the most likely cause of ophthalmoplegia, with cardiac signs of vitamin B1 (thiamin) deficiency.

Long answer

Bilateral abducens (sixth) cranial nerve palsies (fig 1) are uncommon. They may indicate tumours, Rathke’s cleft cyst, diabetes, demyelination, subarachnoid haemorrhage, meningitis, increased intracranial pressure, or Wernicke’s encephalopathy.1

Figure1

Fig 1 The patient was asked to gaze to the extreme left and right. (A) Left lateral gaze; (B) right lateral gaze

The presence of agitation, cerebellar signs, and electrocardiographic abnormalities suggests Wernicke’s encephalopathy, as a result of acute thiamin deficiency, as the most likely diagnosis. Alcohol and dietary histories are vital to determining its cause, although inherited forms should be considered. Patients with learning difficulties may behave unexpectedly: our patient was praised for losing 4 kg in the first month and sought (and received) greater praise by trying harder.

Differential diagnoses seen with malnutrition include hypophosphataemia, Miller Fisher syndrome (ophthalmoplegia, ataxia, areflexia), and central pontine myelinolysis (symmetrical non-inflammatory demyelination).1

The cardiomegaly, tachycardia, and electrocardiographic abnormalities also support a diagnosis of thiamin deficiency with high output cardiac failure.

Seeing double: bilateral 6th cranial (abducent) nerve palsies, which caused complete paralysis of the lateral rectus muscles. The video shows that some recovery had already occurred 24 hours after starting thiamin replacement treatment

2 What definitive investigation confirms the diagnosis?

Short answer

Red cell thiamin diphosphate (TDP) concentration is low in patients with thiamin deficiency.

Long answer

A nutritional screen, available 10 days after admission, confirmed thiamin deficiency, and also showed low values for vitamin A, vitamin C, vitamin B6, folate, and selenium, without a marked inflammatory response (table 1).

Biochemistry, haematology, and nutritional screen results

View this table:

Thiamin is a water soluble vitamin with a nine to 18 day half life, so a regular dietary supply is important. Deficiency causes complete inhibition of carbohydrate metabolism, with accumulation of acetaldehyde mainly affecting astrocytes within cranial nerve nuclei 3, 4, 6, and 8.2 3 Magnesium is required for thiamin to bind to enzymes.4 The gold standard method to assess thiamin status is red cell concentration of TDP, the physiologically active form of thiamin. This measure reflects body thiamin stores and shows good agreement with transketolase functional testing.5

Our patient had a red cell TDP of 132 ng/g of haemoglobin, the lowest ever recorded in our laboratory, lower than values reported to cause neurological impairment.6 Thus, his strict weight loss regimen, far beyond what had been advised, eliminated most sources of thiamin, precipitating the clinical triad of Wernicke’s encephalopathy: ophthalmoplegia, ataxia, and mental confusion.7 He had no clinical features associated with other vitamin deficiencies, despite subnormal values.

3 What treatment should you start as an emergency, without confirmatory investigation results?

Short answer

Suspected thiamin deficiency, in alcoholic or other malnourished patients, demands immediate treatment with intravenous thiamin, after which ophthalmoplegia usually resolves rapidly. Without thiamin, carbohydrate administration causes Wernicke-Korsakoff syndrome and permanent anterograde amnesia.7

Long answer

Presumed or potential thiamin deficiency, regardless of its cause, requires immediate treatment with intravenous thiamin. It is commonly given with water soluble vitamins B and C as Pabrinex (thiamin 250 mg) three times daily for three days, before switching to oral thiamin 300 mg daily.8 9 Ophthalmoplegia usually resolves rapidly. Without sufficient thiamin, carbohydrate administration precipitates Wernicke-Korsakoff syndrome and permanent anterograde amnesia.7 Magnesium deficiency must also be corrected, to enable thiamin to function.4 A response to thiamin administration excludes familial syndromes, which can mimic Wernicke’s encephalopathy.

4 Why were the electrocardiographic and chest radiographic findings alarming?

Short answer

The signs of cardiomegaly and electrocardiographic abnormalities indicated cardiac involvement as “wet beri-beri,” a potentially fatal complication of starvation.

Long answer

In addition to classic neurological signs of “dry beri-beri,” our patient had electrocardiographic and chest radiographic abnormalities indicative of cardiac involvement as wet beri-beri. If left untreated, this condition progresses to high output heart failure—a cause of sudden death from starvation or anorexia nervosa.10 Outpatient echocardiography 15 days after admission confirmed enlargement of the right heart. Myocytes contain high concentrations of TDP, an essential cofactor for enzymes involved in the metabolism of glucose, high energy phosphates, and amino acids and therefore important for activating chloride channels and regulating cholinergic neurotransmission. Although thiamin deficiency is common in alcoholics, only about 10% develop Wernicke’s encephalopathy, possibly through other micronutrient imbalances or a genetic predisposition.11

5 Why did this patient become so ill and develop jaundice, when many people follow low carbohydrate diets without evident problems?

Short answer

Weight losses greater than 4 kg per week indicate extreme dieting (demanding micronutrient supplementation), marked muscle loss, or intercurrent illness. It is hard to ensure thiamin (found mainly in carbohydrate rich cereals) status, and avoid gallstones, on diets below 1000 kcal (1 kcal=4.18 kJ) per day. This patient had several small gallstones in the gallbladder, a recognised complication of consuming less than 15-30 g of fat per day.

Long answer

Severe dietary restriction potentially incurs nutritional insufficiency unless specific dietary advice is adhered to, so clinical monitoring is important. This “low carb dieter” was unusual in his extreme, prolonged dietary restriction and weight loss. Exactly what he ate during his three month diet, or his thiamin intake, is unclear. However, he reported excluding all identifiable sources of carbohydrate and for much of that time eating no solid food other than occasional rice crispies and chicken nuggets, which his parents confirmed. His pre-diet food consumption was also erratic, with high consumption of high fat, energy dense foods such as ice cream, apple pies, crisps, and of full sugar carbonated drinks.

Investigations suggested obstructive jaundice. Ultrasonography showed several small gallstones within the gallbladder. Symptomatic cholelithiasis occurs in about 6% of patients on liquid formula diets of 400-600 kcal per day, and 30% after bariatric surgery. Weight loss above 1.5 kg per week, or more than 24% of body weight, increase risks, but the inclusion of 15-30 g per day dietary fat prevents this problem.12 13 Weight loss on food based diets should not usually exceed 4 kg per month. More rapid rates of weight loss entail extreme diets (which demand micronutrient supplementation), marked muscle loss, or intercurrent illness.

Assuming mainly loss of adipose tissue, at 7000 kcal per kg,14 a 10 kg per month weight loss requires consuming 2500 kcal per day below the 24 hour metabolic rate. At 93 kg, with physical activity level equating to 1.4× basal metabolic rate, his estimated 24 hour metabolic rate was 2675 (standard error 170) kcal per day.15 16 17 Thus, his energy deficit of 2500 kcal per day implies a virtual starvation diet. An adult man requires 1.0 mg thiamin per day.17 This could be achieved by eating, for example, 400 g bread (a major source), which would provide 880 kcal per day. The addition of 20 g per day of dietary fat to avoid gallstones adds 180 kcal per day. It is therefore difficult to maintain thiamin status without supplements, and to avoid gallstones, when consuming less than 1000 kcal per day. Sudden deaths, presumed to be from cardiac causes, were reported with early semi-starvation “protein sparing modified fast” diets,18 possibly through thiamin deficiency. The cardiac abnormalities in our patient, which resolved after thiamin replacement, indicated an impending fatal outcome.19 Modern micronutrient replete formula diets seem to be safer and do not require close medical supervision except in patients taking insulin, sulfonylureas, antihypertensives, or diuretics.20 21 However, dietary advice that results in substantial weight loss should be monitored by a trained healthcare professional to prevent micronutrient intake being “forgotten.”

Patient outcome

After starting intravenous thiamin, 250 mg three times daily for three days (Pabrinex), our patient resumed normal food consumption. He had no biochemical evidence of refeeding syndrome, probably because he was still obese, with adequate mineral reserves. His neurological signs resolved within 24 hours. There is no clear evidence to inform the duration of thiamin treatment or route of administration.22 Our patient was discharged five days after admission; his liver function tests and electrocardiography had normalised, and he was taking oral thiamin 300 mg per day. At outpatient follow-up on day 50, he weighed 94 kg and no abnormal signs were noted. He had stopped taking oral thiamin and continued with a normal food based diet. Electrocardiography, chest radiography, and echocardiography were all normal and showed reductions in the previously increased heart size. His cardiac diameter had dropped from 162 mm to 142 mm and his right ventricle outflow tract diameter had dropped from 3.0 cm to 2.4 cm.

Notes

Cite this as: BMJ 2013;346:f2563

Footnotes

  • Competing interests: I/we have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None.

  • Provenance and peer review: Commissioned; not externally peer reviewed.

  • Patient consent obtained.

References