# Hyperammonemic encephalopathy after omega-loop gastric bypass for obesity: a case report and discussion

Maurine Allard, Mylène Guiho, Audrey Le Ruyet-Le Henaff, Caroline Moreau, Ronan Thibault

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Maurine Allard, Mylène Guiho, Audrey Le Ruyet-Le Henaff, Caroline Moreau, Ronan Thibault. Hyperammonemic encephalopathy after omega-loop gastric bypass for obesity: a case report and discussion. Clinical Nutrition ESPEN, 2025, 67, pp.645-651. 10.1016/j.clnesp.2025.03.165. hal-05064232

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Original article

# Hyperammonemic encephalopathy after omega-loop gastric bypass for obesity: A case report and discussion

<figure><img src="image_2.png" /></figure>

Maurine Allard<sup>a</sup>, Mylène Guiho<sup>a</sup>, Audrey Le Ruyet-Le Henaff<sup>b</sup>, Caroline Moreau<sup>c</sup>,
Ronan Thibault<sup>a, d, *</sup>

## ARTICLE INFO

**Article history:**

Received 7 January 2025

Accepted 28 March 2025

**Keywords:**

Obesity

Malnutrition

Hyperammonemic encephalopathy

Obesity surgery

## SUMMARY

**Background:** Hyperammonemic encephalopathy is a rare but potentially fatal condition, that can occur after obesity surgery.

**Case report:** A 43-year-old Caucasian woman, with history of omega-loop gastric bypass, with hydrops, dyspnoea and severe malnutrition was referred for evaluation. After admission to medical department, she experienced three episodes of coma, and biochemical investigations showed hyperammonemia, hypoalbuminemia and hyperglutaminemia. Etiological investigations were not in favour of a urea cycle disorder, but rather a nutritional catastrophe with severe malnutrition secondary to the omega-loop gastric bypass.

**Discussion:** In patients with history of obesity surgery, encephalopathy symptoms should lead to look after hyperammonemia and malnutrition.

**Conclusion:** This report demonstrates the importance of ammonemia testing in case of neurological symptoms in patients with a history of obesity surgery.

© 2025 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## 1. Case presentation

A 43-year-old Caucasian woman with a past medical history of pulmonary embolism with left popliteal thrombosis and omega-loop gastric bypass surgery in 2013, presented to the emergency department of a general hospital in Brittany, France, for oedema, hydrops and severe dyspnoea.

The patient had a previous history of grade 2 obesity (maximal weight 102 kg, height 164 cm, body mass index (BMI) 39,5 kg/m², excess weight: 21 kg due to binge eating, and treated by obesity surgery. She underwent in 2013 an omega-loop gastric bypass setting the gastrojejunal anastomosis at two meters from the

duodeno-jejunal angle. Weight nadir was reached in 2021 at 50 kg (BMI 18,6 kg/m²) after a loss of 52 kg meaning 51 % of presurgical weight, and 248 % of excess weight. There was no immediate complication of surgery. After surgery, she never took multivitamin nor trace elements supplementation. She underwent three upper gastrointestinal endoscopies since surgery, to look for a causative oncologic factor to repetitive deep vein thromboses, and they were all normal.

At hospital admission (Lorient hospital (CH Lorient), Lorient, France) on February 2021, the patient was diagnosed with severe malnutrition: her weight was 53 kg (BMI 20 kg/m²) compared to 63 kg (BMI 23,4 kg/m²) nine months ago, in favour with a severe weight loss of 16 % in nine months, defining a phenotypic criterion of severe malnutrition according to the Global Leadership Initiative on Malnutrition (GLIM) criteria [1]. Other clinical signs of malnutrition included: bilateral bucket oedema, cutaneous xosis, and brittle nails. She had significant fluid retention with voluminous oedema of the lower limbs up to mid-thigh, oedema of the lumbar region, upper limbs and neck, dyspnoea, and hydrops with bilateral

Abbreviations: CPS1, carbamoyl phosphate synthase 1; GaBHA, Gastric bypass-related hyperammonemia; MRI, magnetic resonance imagery; ONS, Oral Nutritional Supplement; OTC, ornithine transcarbamylase; RYGBP, Roux-en-Y gastric bypass; UCD, urea cycle disorders.

<footnote><sup>a</sup> Department of Endocrinology-Diabetology-Nutrition, Home Parenteral Nutrition Centre, CHU Rennes, Rennes, France</footnote>

<footnote><sup>b</sup> Department of Nutrition, CH Lorient, Lorient, France</footnote>

<footnote><sup>c</sup> Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) UMR_S 1085, F-35000 Rennes, France</footnote>

<footnote><sup>d</sup> INRAE, INSERM, Univ Rennes, NuMeCan, Nutrition Metabolisms Cancer, Rennes, France</footnote>

<footnote>* Corresponding author. Centre labellisé de nutrition parentérale au domicile - CHU Rennes 2, rue Henri Le Guilloux 35000 Rennes, France.</footnote>

<footnote>E-mail address: ronan.thibault@chu-rennes.fr (R. Thibault).</footnote>
pleural effusion, but no ascites. The patient had severe hypoalbuminemia (16 g/l, reference range ≥35 g/l) and very low serum transthyrelin (0.06 g/l, reference range ≥0.20 g/l) which can explain the severe oedema. Arterial blood gas analysis showed no acidosis. Several tests were carried out to determine the cause of hydrops: cardiac ultrasound ruled out heart failure, there was no proteinuria, no diarrhoea nor exudative enteropathy, no cirrhosis nor liver failure on biology and abdominal ultrasound, no toxic or drug-related cause. There was no vasculitis, no dysthyroid and plasma protein electrophoresis revealed only significant hypoalbuminemia.

Four days after admission (day 5), she experienced an episode of global slowdown, then confusion and coma with a Glasgow score of 11, requiring intubation and a 2-day stay in the intensive care unit (ICU) (from days 5–7). Brain computed tomography (CT)-scan found no brain damage and brain magnetic resonance imaging (MRI) found only minimal high signals of supra-tentorial white substance. Fluid depletion with furosemide was initiated, as well as intravenous (IV) infusions of hydro-soluble and fat-soluble multivitamin and albumin. Neurological status improved.

From day 7 to day 11, the evolution was initially favourable, with a loss of 10 kg, disappearance of upper limb oedema and reduction of lower limb oedema. Oral refeeding with food enrichment and oral nutritional supplements (ONS) (400 kcal per day; total daily energy and protein provided 1600 kcal and 60 g protein, respectively) was undertaken, combined with electrolytes (phosphorus, magnesium, potassium), hydro-soluble and fat-soluble multivitamin IV infusion (to prevent refeeding syndrome). This lead to improve albuminemia up to 20 g/l.

On day 11, the patient experienced again confusion with a Glasgow score of 9, requiring intubation and a 5-day ICU stay (from days 11–15). Electroencephalogram and lumbar puncture were normal. An hyperammonemia of 161 µM was found (reference range: 11–51 µM). Thus, a correlation between hyperammonemia and vigilance disorders was raised. Three hypotheses were suggested: a nutritional deficiency encephalopathy, gastric bypass-related hyperammonemia (GaBHA) or primary hyperammonemia with a urea cycle disorder (UCD). The latter was first suggested with the hypothesis of a decompensated UCD and that the hyperammonemia could result from the rapid increase of protein intake using oral nutritional supplements in the context of severe malnutrition. In the ICU, the patient received the treatment of severe decompensation of urea cycle disorders: no protein intake, drug chelation of ammonia with sodium benzoate, endogenous purification of plasma amino acids through protein anabolism with intravenous citrulline and glucose solution [2]. These therapies led to a progressive decrease in ammonemia (25 µM on day 12) and the improvement of the neurological state. Therefore, oral proteins were progressively reintroduced to stimulate the whole-body anabolism.

From days 15–30, the patient stayed in a general medicine ward, and her neurological status was fluctuant with episodes of cognitive and physical slowdown. Ammonia plasma level remained stable around 50 µM. On day 30, she experienced her third episode of confusion, just after an unexplained vomiting episode, leading to a new ICU stay. Hyperammonemia was confirmed (190 µM) and the treatment consisted of lactulose only, leading to the improvement of the neurological state.

In the context of suspicion of an UCD, specialized nutritional care was required and the patient was transferred in the Department of Endocrinology-Diabetology-Nutrition at Rennes University Hospital (CHU Rennes), 34 days after her initial hospital admission.

## 1.1. Diagnosis

The amino acid plasma profile at days 35 and 95 (Table 1) was not in favour of UCD. At day 35, it was compatible with malnutrition and a prolonged low-protein diet by showing deficits in essential amino-acids, such as leucin, methionine, phenylalanine, threonine, tryptophan and valine [3]. Hyperglutaminemia is a nonspecific stigma of hyperammonemia. At day 95, the amino acid plasma profile was globally normal, without hyperglutaminemia.

To further explore the UCD hypothesis, we realized a cycle of ammonemia on day 35, during the breakfast, lunch and dinner (Table 2). Ammonemia remained strictly normal, ranging between 19 and 34 µM. We also monitored ammonemia several times during the hospital stay, at different moments of the day, and it stayed strictly normal, between 12 and 27 µM (Table 3). The chromatography of urinary organic acids was normal without any increase of orotic acid excretion. The ratio orotic acid/creatinine was normal at 0.46 µmol/mmol (reference range <6). A markedly abnormal increase of orotic acid excretion >20 umol/mmol creatinine can correspond to an ornithine transcarbamylase deficiency, a subtype of UCD [4].

We also ruled out the differential diagnosis of hyperammonemia as liver failure, urease-producing germs as *Chlamydia* and *Mycoplasma*, portacaval shunt, spleno-renal shunt, cancers and myeloma.

A glucose breath test was performed to screen for small intestinal bacterial overgrowth (SIBO): there was no early hydrogen peak indicating the absence of SIBO. However, there was a significant elevation of hydrogen at 105 min, suggesting a colic fermentation of glucose. This fermentation can be due to an arrival of glucose in the colon because of a partial small intestine glucose malabsorption secondary to the omega-loop bypass surgery. It cannot be excluded that proteins could have the same fate, leading to a colonic fermentation of the proteins, participating to hyperammonemia. Antibiotics as rifaximin or metronidazole are useless in this case and we proposed a treatment by oral loperamide if hyperammonemia reoffends.

## 1.2. Nutritional assessment

As complications of the severe malnutrition, the patient had severe micronutrient deficiencies (Table 4) with clinical manifestations: vitamin A deficiency with diffuse retinal atrophy, temporal papillary pallor, and signs of neuropathy. We introduced an oral vitamin A supplementation (retinol palmitate): 100 000 units per week during two months. She also had a regenerative macrocytic anaemia due to multiple deficiencies in iron, vitamin B9, zinc and copper. Other deficiencies in vitamins B6, C and selenium were diagnosed and treated. The patient also presented a hepatic cytolysis without any other aetiology than severe malnutrition. Indeed, this cytolysis improved with nutritional therapy (see below paragraph).

## 1.3. Nutritional therapy

As a therapy of severe malnutrition, enteral nutrition was indicated, but the patient refused. Therefore, oral nutritional supplementation was proposed from day 45: splitting meals and ONS carefully and gradually increased to prevent the refeeding syndrome; protein intake was closely monitored to prevent recurrence of hyperammonemia. After two months of refeeding (day 60, Table 4), plasma albumin and transthyrelin improved. At the end of the hospitalization, 70 days after her initial admission, the weight was 52,9 kg (BMI 19,7 kg/m²) that we interpreted as an improvement because of the great loss of oedemas. The patient was discharged at home with ONS: three per day, one with 20 g of proteins and
<caption>**Table 1**</caption>

Plasma amino acid profile performed in the morning (7 AM) at days 35 and 95, at the fasting state. The values outside the reference range are marked in bold: L, below the reference range; H, above the reference range.

<table><caption>**Table 2**</caption><thead><tr><th>Aminoacid</th><th>Reference range</th><th>Day 35 concentrations (µM)</th><th>Day 95 concentrations (µM)</th></tr></thead><tbody><tr><td>3-methyl-histidine</td><td>&gt;6 µM</td><td>30.4</td><td>22.9</td></tr><tr><td>Alanine</td><td>182–552 µM</td><td>424</td><td>350</td></tr><tr><td>Allo-isoleucine</td><td>&lt;5 µM</td><td>2.80</td><td>1.63</td></tr><tr><td>Alpha-amino-butyrate</td><td>12–40 µM</td><td>15.8</td><td>14.5</td></tr><tr><td>Arginine</td><td>46–128 µM</td><td>51.9</td><td>55.3</td></tr><tr><td>Asparagine</td><td>35–63 µM</td><td>66.0</td><td>39.6</td></tr><tr><td>Aspartic acid</td><td>1–9 µM</td><td>10.2</td><td>3.33</td></tr><tr><td>Beta-amino-iso-butyrate</td><td>0–2 µM</td><td>3.60</td><td>3.15</td></tr><tr><td>Citrulline</td><td>25–46 µM</td><td>29.6</td><td>46.2</td></tr><tr><td>Gamma-amino-butyrate</td><td>0–2.9 µM</td><td>0.330</td><td>0.352</td></tr><tr><td>Glutamic acid</td><td>1–57 µM</td><td><strong>133 (H)</strong></td><td>52.8</td></tr><tr><td>Glutamine</td><td>435–721 µM</td><td><strong>874 (H)</strong></td><td>546</td></tr><tr><td>Glycine</td><td>123–319 µM</td><td><strong>560 (H)</strong></td><td>346</td></tr><tr><td>Histidine</td><td>67–109 µM</td><td>96.9</td><td>69.5</td></tr><tr><td>Hydroxyproline</td><td>&lt;33 µM</td><td>13.8</td><td>10.8</td></tr><tr><td>Isoleucine</td><td>34–84 µM</td><td>40.1</td><td>54.0</td></tr><tr><td>Leucine</td><td>7–160 µM</td><td><strong>50.1 (L)</strong></td><td>67.7</td></tr><tr><td>Lysine</td><td>111–248 µM</td><td>162</td><td>139</td></tr><tr><td>Methionine</td><td>12–32 µM</td><td><strong>9.56 (L)</strong></td><td>13.1</td></tr><tr><td>Ornithine</td><td>27–98 µM</td><td>44.8</td><td>43.6</td></tr><tr><td>Phenylalanine</td><td>39–74 µM</td><td><strong>23.3 (L)</strong></td><td>27.9 (L)</td></tr><tr><td>Proline</td><td>88–290 µM</td><td>238</td><td>190</td></tr><tr><td>Serine</td><td>68–160 µM</td><td>156</td><td>92.8</td></tr><tr><td>Taurine</td><td>6.0–126 µM</td><td>168 (H)</td><td>39.6</td></tr><tr><td>Threonine</td><td>102–190 µM</td><td><strong>29.8 (L)</strong></td><td>85.0</td></tr><tr><td>Tryptophane</td><td>30–95 µM</td><td><strong>4.10 (L)</strong></td><td>30.3</td></tr><tr><td>Tyrosine</td><td>35.0–84 µM</td><td><strong>9.98 (L)</strong></td><td>29.9</td></tr><tr><td>Valine</td><td>144–269 µM</td><td><strong>95.1 (L)</strong></td><td>160</td></tr></tbody></table>

Plasma ammonium measurements before and after the three meals during one day (day 35).

<table><caption>**Table 3**</caption><thead><tr><th></th><th>Before breakfast</th><th>After breakfast</th><th>Before lunch</th><th>After lunch</th><th>Before dinner</th><th>After dinner</th></tr></thead><tbody><tr><td>Plasma ammonium (µM) (reference range: 11–51 µM)</td><td>34</td><td>23</td><td>19</td><td>Not done (technical problem)</td><td>31</td><td>30</td></tr></tbody></table>

Monitoring of plasma ammonium during the hospitalization, in the morning, before and after breakfast. F, fasting; PA: post absorptive.

<table><thead><tr><th>Date</th><th>Day</th><th>Time</th><th>Timing vs oral intake</th><th>Plasma ammonium (µM) (reference range: 11–51 µM)</th></tr></thead><tbody><tr><td>2021/03/16</td><td>35</td><td>7 AM</td><td>F</td><td>34</td></tr><tr><td>2021/03/22</td><td>41</td><td>8 PM</td><td>PA</td><td>24</td></tr><tr><td>2021/03/24</td><td>43</td><td>7 PM</td><td>PA</td><td>26</td></tr><tr><td>2021/03/26</td><td>45</td><td>7 PM</td><td>PA</td><td>16</td></tr><tr><td>2021/03/27</td><td>46</td><td>7 PM</td><td>PA</td><td>27</td></tr><tr><td>2021/03/28</td><td>47</td><td>6 AM</td><td>F</td><td>13</td></tr><tr><td>2021/03/29</td><td>48</td><td>6 AM</td><td>F</td><td>14</td></tr><tr><td>2021/03/30</td><td>49</td><td>5 AM</td><td>F</td><td>12</td></tr><tr><td>2021/03/31</td><td>50</td><td>6 AM</td><td>F</td><td>16</td></tr><tr><td>2021/04/01</td><td>51</td><td>6 AM</td><td>F</td><td>23</td></tr><tr><td>2021/04/06</td><td>56</td><td>6 AM</td><td>F</td><td>14</td></tr><tr><td>2021/04/07</td><td>57</td><td>6 AM</td><td>F</td><td>20</td></tr><tr><td>2021/04/09</td><td>59</td><td>6 AM</td><td>F</td><td>19</td></tr><tr><td>2021/04/12</td><td>62</td><td>4 AM</td><td>F</td><td>20</td></tr><tr><td>2021/05/20</td><td>101</td><td>6 AM</td><td>F</td><td>18</td></tr></tbody></table>

400 kcal, and two with 18 g of proteins and 300 kcal. Table 5 showed body composition and weight evolution during CHU Rennes hospital stay and after discharge (from day 70). At day 95 (May 20, 2021), the weight was 57.3 kg (BMI 21.3 kg/m²) without any oedema. At day 215 (September 2021), the weight was 61.2 kg (BMI 22.7 kg/m²), and at day 275 (December 2021), 66.3 kg (BMI 24.7 kg/m²), without any edema, nor recurrence of encephalopathy hyperammonemia. Thanks to sufficient oral intake, ONS were stopped after six months. The oral intakes were estimated at 2015 kcal/day (34 kcal/kg/day) and 110 g of proteins (1.8 g/kg/day).

## 2. Discussion

We described here the clinical report of a 43-year-old female patient with non-hepatic hyperammonemia encephalopathy, due to nutritional catastrophe characterized by a severe malnutrition complicated with multiple micronutrient deficiencies and severe hypoalbuminemia, secondary to an omega-loop gastric bypass surgery. To our knowledge, this is the first case report of hyperammonemia encephalopathy, secondary to an omega-loop gastric bypass surgery.
<caption>**Table 4**</caption>

Albumin, transthryretin, and micronutrient plasma concentrations at Rennes University Hospital admission (day 35) and follow-up during renutrition. The values outside the reference range are marked in bold: L, below the reference range; H, above the reference range.

<table><caption>**Table 5**</caption><thead><tr><th></th><th>Reference range</th><th>Day 35</th><th>Day 65</th><th>Day 95</th><th>Day 125</th></tr></thead><tbody><tr><td>Albumin</td><td>&gt;37 g/l</td><td><strong>16 (L)</strong></td><td></td><td>30.3</td><td>35.6</td></tr><tr><td>Transthyretin</td><td>&gt;0.20 g/l</td><td><strong>0.06 (L)</strong></td><td></td><td><strong>0.16 (L)</strong></td><td>0.20</td></tr><tr><td>Vitamin A</td><td>&gt;1.05 μM</td><td><strong>0.62 (L)</strong></td><td><strong>0.50 (L)</strong></td><td></td><td>2.30</td></tr><tr><td>Vitamin B1</td><td>&gt;83 nM</td><td>222</td><td>116</td><td></td><td></td></tr><tr><td>Vitamin B2</td><td>&gt;174 nM</td><td></td><td>240</td><td></td><td></td></tr><tr><td>Vitamin B3</td><td>&gt;3 mg/l</td><td>4.80</td><td>4.60</td><td></td><td></td></tr><tr><td>Vitamin B6</td><td>&gt;20 nM</td><td><strong>12 (L)</strong></td><td></td><td></td><td>70</td></tr><tr><td>Vitamin B9</td><td>&gt;8.8 nM</td><td>36.1</td><td>&gt;90</td><td></td><td></td></tr><tr><td>Vitamin B12</td><td>&gt;216 pM</td><td><strong>141 (L)</strong></td><td>549</td><td></td><td></td></tr><tr><td>Vitamin C</td><td>&gt;26 μM</td><td><strong>4 (L)</strong></td><td>17.6</td><td></td><td></td></tr><tr><td>Vitamin D</td><td>&gt;30 ng/mL</td><td></td><td>54</td><td></td><td>46</td></tr><tr><td>Vitamin E</td><td>&gt;5 mg/l</td><td>9.10</td><td>6.30</td><td></td><td></td></tr><tr><td>Selenium</td><td>&gt;46 μg/l</td><td><strong>21 (L)</strong></td><td><strong>24.2 (L)</strong></td><td></td><td>122</td></tr><tr><td>Zinc</td><td>&gt;12.3 μM</td><td><strong>7.2 (L)</strong></td><td></td><td></td><td>10.3</td></tr><tr><td>Copper</td><td>&gt;12.5 μM</td><td><strong>8.7 (L)</strong></td><td></td><td></td><td>24.1</td></tr></tbody></table>

Body composition at Rennes University Hospital admission (day 35) and follow-up during renutrition. Body composition was assessed by monofrequency (50 kHz) bio-impedance analysis (Bodysstat 1500 MDD, Man island, UK). FFMI, fat-free mass index.

<table><thead><tr><th></th><th>Expected values for the patient</th><th>Day 35</th><th>Day 55</th><th>Day 65</th><th>Day 95</th><th>Day 215</th></tr></thead><tbody><tr><td>Fat mass</td><td>13 -17 kg</td><td>8.1 kg</td><td>9.2 kg</td><td>10.4 kg</td><td>15.0 kg</td><td>17.9 kg</td></tr><tr><td></td><td>22 - 28 %</td><td>15.1 %</td><td>17.5 %</td><td>17.5 %</td><td>26.1 %</td><td>29.3 %</td></tr><tr><td>Fat-free mass</td><td>44 -48 kg</td><td>45.8 kg</td><td>43.5 kg</td><td>43.5 kg</td><td>42.3 kg</td><td>43.3 kg</td></tr><tr><td></td><td>72 - 78 %</td><td>84.9 %</td><td>82.5 %</td><td>82.5 %</td><td>73.9 %</td><td>70.7 %</td></tr><tr><td>Dry fat-free mass</td><td></td><td>10 kg</td><td>9.5 kg</td><td>9.6 kg</td><td>10.3 kg</td><td>11.1 kg</td></tr><tr><td>Total body water</td><td>27 - 32 L</td><td>35.8 L</td><td>34 L</td><td>34 L</td><td>32 L</td><td>32.2 L</td></tr><tr><td></td><td>50 - 60 %</td><td>66.3 %</td><td>64.5 %</td><td>64.5 %</td><td>55.8 %</td><td>52.6 %</td></tr><tr><td>FFMI</td><td></td><td>17.0</td><td>16.2</td><td>16.2</td><td>15.7</td><td>16.1</td></tr><tr><td>Phase angle</td><td></td><td>2.70°</td><td>3.90°</td><td>1.20°</td><td>4.20°</td><td>5.40°</td></tr><tr><td>Total weight</td><td></td><td>53.9 kg</td><td>52.7 kg</td><td>53.3 kg</td><td>57.3 kg</td><td>61.2 kg</td></tr></tbody></table>

## 2.1. Pathophysiology

Hyperammonemia is a metabolic abnormality characterized by elevated ammonium serum levels [5]. Apart from Inherited metabolism disorders, In 90 % of the cases, it occurs in the context of decompensated cirrhosis [6], but it can also be found after obesity surgery. Hyperammonemia can lead to encephalopathy with symptoms as lethargy, confusion, coma, vomiting, seizures or nausea [5], as reported in our clinical case. Hyperammonemia can also lead to multiorgan failure. Early recognition and treatment of hyperammonemia are essential to prevent patient's deterioration and death. The pathophysiology of brain damages remains unclear but may be based on the formation of a cerebral oedema, alteration of electric potentials and disturbing synthesis of neurotransmitters [6]. When ammonia is not metabolized through the urea cycle, it is converted to glutamine in hepatocytes [7]. This hyperglutaminemia would overstimulate N-methyl D-aspartate receptors, leading to vasodilatation and increase of intracranial pressure [6].

The causes of hyperammonemic encephalopathy remain unknown, but several hypotheses have been suggested in the absence of liver disease. Increase in ammonia production and decrease in its elimination can lead to hyperammonemic encephalopathy.

Firstly, increase in ammonia production can be due to an hematologic disease, such as advanced myeloma, but the pathophysiology is unclear: the plasma cells infiltration of hepatic tissues may create a portosystemic shunt [6,8], or the plasma cells themselves may product ammonia [8]. Infections with urea-producers bacteria, such as *Proteus mirabilis*, *Escherichia coli*, *Klebsiella pneumoniae* and *Morganella morganii*, can lead to hyperammonemia [6].

An intense muscle protein catabolism as observed during starvation and trauma can release a lot of ammonium, as a result of waste nitrogen [6].

Second, hyperammonemia could be the consequence of a decrease in ammonia metabolism. In particular, inborn errors of metabolism (IEMs) are a large class of disorders leading to a blood accumulation of metabolites and toxic by-products as ammonium. Numerous EIM lead to hyperammonemia with primary hyperammonemia in urea cycle disorders and secondary hyperammonemia in certain organic aciduria. The plasmatic amino acid and urinary organic acid profiles are the main tools required for the diagnosis [9]. The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea (Fig. 1) [10]. Each of the six enzymes can be deficient, but hyperammonemia and hyperglutaminemia are common biochemical markers of the UCDs [10]. Transporters can also be deficient leading to Triple H for example. There is a very wide clinical spectrum, from neonatal death to asymptomatic adults [11]. UCDs symptoms can appear during a severe conditions such as starvation, leading to severe malnutrition, such as observed in the situation of rapid weight loss after obesity surgery, or post-partum [11,12]. Ornithine transcarbamylase (OTC) deficiency is a X-linked disorder and the most common UCD [6]. It can become symptomatic secondary to a triggering event, such as acute or chronic metabolic, inflammatory, or psychological stress. In our case report, this event was the obesity surgery, triggering a metabolic/inflammatory stress, and secondly, malnutrition [4,12].

Hyperammonemic encephalopathy can occur after obesity surgery, with an estimated prevalence of 1/1400 to 1/1300 [12].
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** - **Urea cycle.** In the situation of a deficiency in urea cycle, ammonia, that is a nitrogenic waste accumulates and leads to hyperammonemia.</figcaption></figure>

2015, Roux-en-Y gastric bypass (RYGBP) was the most common performed obesity surgery in the USA [12]. In 2019, 26 cases of hyperammonemic encephalopathy after obesity surgery have been reported in the literature after RYGBP or biliopancreatic duodenal switch [13,14], but never after omega-loop gastric bypass. Indeed, a literature search performed on PubMed in January 2024 with the terms “omega-loop gastric bypass” or “omega-loop bypass” or “omega-loop” and “encephalopathy” or “hyperammonemia” or “hyperammonemic encephalopathy” or “neurological complications” did not find any other case reports.

Neurological complications after obesity surgeries are estimated between 5 and 16 % of complications among studies [15]. There are several types of encephalopathy: Wernicke's encephalopathy, mostly linked to thiamine deficiency [15], and a few case reports described patients with hyperammonemic encephalopathy after obesity surgery, but the causes are not precisely elucidated yet.

In the literature review of Fenves et al. of 2015 [12], including a retrospective study of twenty patients (19 women) with hyperammonemic encephalopathy after a RYGBP, hyperammonemic encephalopathy occurs one month to 28 years after the surgery and the mortality was about 50 %. Mortality was quite high, but hyperammonemia was only slight to mild, from 68 to 486 uM. Symptoms were variable, from minor confusion to coma. Severe hypoalbuminemia was observed in 95 % of them, with an average of 18 g/l. The amino acid plasma profile showed hyperglutaminemia >900 uM (reference range: 435–721 uM) [12] for 6/9 patients which was a marker of altered or inhibited ureagenesis, and a lowered plasma citrulline, sign of intestinal malabsorption, for 4/6 patients. As an intense metabolic/inflammatory stress, obesity surgery can unmask a pre-existing UCD [12,16]. There was an increase of orotic acid for 5/6 patients, including one patient with a carbamoyl phosphate synthase 1 (CPS 1) deficiency. No genetic mutation in OTC gene was found in this study. None of the patients

had cirrhosis or liver failure, underlying that hypoalbuminemia was only due to malnutrition, secondary to altered protein synthesis and decreased protein intakes.

Gastric bypass-related hyperammonemia (GaBHA) has been recognized as a distinct entity which associated encephalopathy, hyperammonemia, hyperglutaminemia, hypoalbuminemia, and other nutritional deficiencies [13]. This description is confirmed by the present case report. GaBHA affects more often middle-aged women, without history of liver disease and exhibited an important weight loss after surgery, and onsets at various time intervals after surgery, from 1 month to 28 years [12,17]. After RYGBP, a few non-genetic predisposing factors have been described.

- The decrease in nutritional intakes after surgery increases catabolism and protein degradation in extra-hepatic tissues, leading to deamination and transamination of the amino-acids released by proteins, resulting in hyperammonemia [12,16];

- Reactive hypoglycaemia to malnutrition contributes to this catabolic protein state through an exaggerated glucagon-like-peptid-1 release [12,18];

- RYGBP may decrease citrulline synthesis in the intestinal mucosa, leading to depletion of urea cycle components, decrease in ureagenesis, resulting in hyperammonemia [12,19]; this hypothesis can be ruled out in our case as plasma citrulline was normal;

- RYGBP could promote SIBO resulting in microbiome alterations and dysbiosis. The latter is characterized in part by the growth in urealytic bacterial strains that may contribute to increased ammonia production, and so hyperammonemia [15,19];

- Micronutrient deficiencies as zinc deficiency can inhibit urea cycle [16];

- Some drugs can also interfere with urea cycle or the renal elimination of ammonia, such as carbamazepine, sulfadiazine, ribavirin, salicylates, glycine and valproic acid [6].
- By creating a small gastric pouch followed by gastrojejunostomy 200 cm after duodeno-jejunal angle, the omega-loop gastric bypass reinforces the risk of the complications reported above, and especially severe malnutrition due to enhanced malabsorption syndrome [20,21].

## 2.2. Diagnosis of hyperammonemic encephalopathy

There are no specific signs of hyperammonemic encephalopathy, but in front of encephalopathy signs as vomiting, confusion, ataxia, disorientation or hallucinations, hyperammonemic encephalopathy should be considered. The diagnosis should be evoked, especially when risk factors are present: nutritional deficiencies, increased protein intakes, triggering treatments as chemotherapy [22], tyrosine kinase inhibitor [23] or valproate [24], acute or chronic situations associated with metabolic/inflammatory stress, known or suspected urea cycle abnormalities [15,25]. Hyperammonemia >100 µM in adults should lead to further investigations, especially with if the liver function is normal. Acid-base status should be evaluated to eliminate organic acidemias. Serum amino acid profile, urinary organic acid profiles and dosage of orotic acid should be performed to look for an IEM disorder [6]. Brain CT-scan or MRI must be done to eliminate any brain diseases. The MRI could display some characteristics of hyperammonemic encephalopathy: cortical diffusion restriction, symmetric involvement of the cingulate gyrus and insular cortex [26].

## 2.3. Therapy

Because of the high mortality rate, it is essential to start the specific treatment as soon as the diagnosis is suspected. The mainstays of therapy are rapid lowering of the ammonemia to <200 umol/l [4], and prevention of cerebral oedema [27]. The different therapies shown to be efficient are oral lactulose, oral neomycin, oral citrulline, or zinc supplementation [12]. Exogenous protein intakes should be stopped and reverse endogenous protein catabolism can be reversed by infusing high amount of parenteral glucose [2,25].

Lactulose and rifaximin can reduce ammonia reuptake in the GI tract, but often results in modest ammonemia reduction [5,17]. Lactulose is a nonabsorbable disaccharide which decreases the production and the absorption of ammonia in the intestine: it is the first-line therapy for hepatic encephalopathy but without any impact on mortality [6]. Lactulose has also been tested and shown to be effective in hyperammonemic encephalopathy secondary to heart failure [28], tyrosine-kinase inhibitor [23], chemotherapy [22], valproate [24] or multiple myeloma [8,29]. Antibiotics, such as rifaximin and neomycin targeted against urea-producing bacteria can decrease ammonia enteric production [6].

Nitrogen scavengers drugs, such as sodium benzoate and sodium phenylbutyrate, use alternative pathways which can convert nitrogen in non-urea products, easily excreted [2,4,16,25]. Limitation of the catabolic state can be obtained with refeeding [13,19]. For refeeding, enteral, at first intent, or parenteral nutrition, when indicated, should be used. Energy intake should be made of lipids and carbohydrates covering 110 % of the energy needs. A low protein diet is indicated, the amount of proteins being variable according to the defect and the patients [25]. Attention must be paid to hidden sources of protein such as blood or plasma transfusions [25].

When hyperammonia is severe (>500 uM), hemodialysis or hemofiltration can be the last solution to rapidly decrease serum ammonia [16,25]. If a UCD is associated, arginine can replenish the

urea-cycle substrates. Liver transplantation is also an efficient treatment in UCD [6]. Surgical reversion of the gastric bypass should be considered after several hyperammonemic encephalopathy episodes, because of the risk of recurrence.

## 3. Conclusion

Hyperammonemic encephalopathy is an emergency because the severe neurological consequences could lead to death. The diagnosis of GaBHA could only be retained once other causes of hyperammonemic encephalopathy have been ruled out. Several case reports of hyperammonemic encephalopathy have been published after obesity surgery, our case report is original as, to our knowledge, this is the first to describe hyperammonemic encephalopathy after omega-loop gastric bypass. The issue was favourable but this nutritional catastrophe leading to prolonged hospitalization including three ICU stays could have been avoided if the patient had regular medical follow-up after obesity surgery. Obesity surgery represents a successful therapy of obesity, if its complications are prevented.

## Ethics

This article does not contain any results of a human research protocol or animal studies.

## Authors' contributions

Case report idea: RT and MG, data acquisition: MA, MG, ALL, CM, RT; data interpretation: MA, MG, CM, RT; writing of the first draft of the manuscript: MA and RT; supervision or mentorship: RT. All authors edited and approved the final draft. Ronan Thibault is the guarantor of this work and, as such, had full access to all the data and takes responsibility for the integrity of the data.

## Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

## Declaration of competing interest

The authors declare that they have no competing interest regarding this article. Ronan Thibault received consulting and conference fees from Aguettant, Baxter, BBraun, Fresenius-Kabi, Nestlé Health Science, Nutricia, Roche; and conference fees from Astra-Zeneca, Homeperf, Lactalis, Shire, and Theradial. Maurine Allard, Mylène Guiho, Audrey Le Ruyet-Le Henaff, and Caroline Moreau declare no competing interest.

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