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Late presentation of fatal hyperammonemic encephalopathy after Roux-en-Y gastric bypass.

Worldwide, there have been <25 reported cases of hyperammonemic encephalopathy associated with Roux-en-Y gastric bypass surgery in the absence of cirrhosis. We describe a 42-year-old woman who presented with subacute but progressive neurological decline late in her postoperative course, which deteriorated despite multiple conservative and aggressive measures, including hemodialysis, in an attempt to reduce measured plasma ammonia levels. This syndrome of hyperammonemic encephalopathy represents a serious, underrecognized, and potentially treatable complication after Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass (RYGB) surgery results in clinically important and durable cardiometabolic effects and has become an adjunctive measure in ameliorating adverse health outcomes in obese patients (1). RYGB has become the most widely employed weight loss operative procedure in the US (2). There are now numerous patients who have developed severe and symptomatic hyperammonemia at variable intervals after RYGB (3). We describe yet another patient with this relatively rare but neurologically devastating complication of hyperammonemia after successful RYGB.


A 42-year-old woman who had RYGB 11 years earlier presented with severe protein malnutrition and altered mental status. The patient had a longstanding history of elevated serum ammonia levels (of unclear etiology) being managed with lactulose and rifaximin. Several days prior to hospitalization, she developed worsening confusion and vomiting. She had a 50-pound unintentional weight loss over the preceding 6 months despite adequate oral intake. She was evaluated at an outside hospital where a plasma ammonia level was 498 [micro]mol/L (reference, 12 to 48 [micro]mol/L). Given declining mental status and refractory hyperammonemic encephalopathy, she was intubated and transferred to our intensive care unit.

On arrival at our hospital, she was ill-appearing and intubated. Her Glasgow Coma Scale score was 3 out of 15. She was afebrile, with a heart rate of 97 beats per minute and blood pressure of 135/85 mm Hg. With 16 cm [H.sub.2]O of positive end-expiratory pressure and 30% fraction of inspired oxygen, her oxygen saturation was 95%. She was unresponsive to noxious stimuli and had intact brainstem reflexes, a non-distended abdomen with prior laparoscopy scars, and diffuse anasarca.

Her serum albumin level was 1.4 g/dL; aspartate transaminase, 47 U/L; alanine transaminase, 24 U/L; alkaline phosphatase, 222 U/L; total bilirubin, 1.0 mg/dL; and international normalized ratio, 1.4. Plasma amino acids showed a citrulline level of 12 nmol/mL (reference, 17-46 nmol/mL). Serum glutamine and glutamate, as well as urine orotic acid levels, were normal. Her plasma zinc level was 0.34 mcg/mL (reference, 0.66-1.1 mcg/mL).

Noncontrast computed tomography (CT) imaging of the head disclosed bilateral cerebral edema and loss of the gray-white matter differentiation. Magnetic resonance imaging of the brain revealed diffuse T2/FLAIR hyperintensity compatible with acute hyperammonemic encephalopathy. Electroencephalography was equivocal for epileptiform activity. Abdominal ultrasound showed a macronodular liver, small volume ascites, and patent vasculature. An abdominal CT scan revealed no focal hepatic lesions, enteroenteric fistulas, or evidence of vascular shunting.

She underwent transjugular portal pressure measurement and liver biopsy. There was no portal hypertension, and core biopsies revealed marked cholestatic hepatitis but no cirrhosis. During her hospitalization, she was treated with lactulose and rifaximin. She also underwent one session of hemodialysis. Zinc repletion, intravenous thiamine, and dextrose-containing fluids resulted in normalization of serum ammonia levels. She nevertheless progressed to status epilepticus, sepsis, and multisystem organ failure and died after a prolonged hospital stay.


Gastric bypass-related hyperammonemia (GaBHA) is becoming an increasingly recognized entity (3). Shared phenotypic characteristics have emerged upon review of the 21 previously reported cases of this postoperative entity (3, 4) (Figure 1). There is a predilection for women (age range, 34 to 69 years) without established liver disease. Hyperammonemic encephalopathy manifests at varying time intervals after RYGB, ranging from early (months) to late (latest known case, 28 years postoperatively). Given the initial nonspecific signs and symptoms, there may be significant delays in management. The syndrome is often met with high case fatality and poor prognosis.

There are numerous etiologies for nonhepatic hyperammonemia (Table 1). The specific mechanisms driving the hyperammonemic state after RYGB may be multifactorial. As it has been almost exclusively observed in women, X-linked partial ornithine transcarbamylase (OTC) deficiency has been implicated (Figure 2). Previously asymptomatic heterozygous OTC-deficient women can present when faced with catabolic stressors, and biochemical profiling is consistent with impaired urea cycle function. Zinc deficiency has also been proposed to interfere with OTC function (5). Nongenetic mechanisms of increased ammoniagenesis have been considered, including portosystemic shunting, severe hepatic dysfunction, and overgrowth of intestinal flora. A profound catabolic state may also play a role, driving protein breakdown and accumulation of nitrogenous waste products.

Conservative management approaches with lactulose and rifaximin have resulted in modest reductions in measured ammonia levels. Repletion of deficient amino acids, zinc, micro nutrients, and intravenous glucose infusion may attenuate the catabolic state. Surgical reversal of the RYGB anatomy in one patient, and occlusion of a splenorenal shunt in another patient, have improved clinical trajectories (6, 7). Although the measured plasma ammonia levels were lowered in our patient after hemodialysis, she had persistent encephalopathy. The lack of success of renal replacement therapy may be related to her late presentation, irreversible hyperammonemic effects on neurons, and brain parenchymal saturation (8).

Hyperammonemic encephalopathy represents an under-recognized complication after RYGB and carries serious consequences, with mortality approaching 50%. Rigorous screening for select metabolic derangements (e.g., plasma ammonia, zinc, and serum albumin) in high-risk patients may facilitate early detection of this clinical entity. Genetic screening for OTC deficiency may also be considered, although this approach has not been fruitful in reported patients (3). Evaluating for in vivo OTC enzymatic activity in fresh liver tissue is of particular interest, but this requires a liver biopsy. A global registry of identified and confirmed cases may assist in further elucidating potential screening measures and management strategies. We welcome our colleagues to contact us regarding similar patients as we try to build on our collective experience.

(1.) Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, Aminian A, Pothier CE, Kim ES, Nissen SE, Kashyap SR, STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes-3-year outcomes. N Engl J Med 2014; 370(21):2002-2013.

(2.) Samuel I, Mason EE, Renquist KE, Huang YH, Zimmerman MB, Jamal M. Bariatric surgery trends: an 18-year report from the International Bariatric Surgery Registry. AmJ Surg 2006; 192(5):657-662.

(3.) Fenves AZ, Shchelochkov OA, Mehta A. Hyperammonemic syndrome after Roux-en-Y gastric bypass. Obesity (Silver Spring) 2015;23(4):746-749.

(4.) Acharya G, Mehra S, Patel R, Frunza-Stefan S, Kaur H. Fatal nonhepatic hyperammonemia in ICU setting: a rare but serious complication following bariatric surgery. Case Rep Crit Care 2016;2016:8531591.

(5.) Aquilio E, Spagnoli R, Riggio D, Seri S. Effects of zinc on hepatic ornithine transcarb amylase (OTC) activity. J Trace Elem Electrolytes Health Dis 1993;7(4):240-241.

(6.) Estrella J, Yee G, Wilcken B, Tchan M, Talbot M. Hyperammonemic encephalopathy complicating bariatric surgery: a case study and review of the literature. SurgObes RelatDis 2014;10(3):e35-e38.

(7.) Rogal SS, Hu A, Bandi R, Shaikh O. Novel therapy for non-cirrhotic hyperammonemia due to a spontaneous splenorenal shunt. World J Gastroenterol 2014; 20 (25) : 8288-8291.

(8.) Gupta S, Fenves AZ, Hootkins R. The role of RRT in hyperammonemic patients. Clin J Am Soc Nephrol 2016:CJN.01320216.

Amulya Nagarur, MD, and Andrew Z. Fenves, MD

From the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Corresponding author: Amulya Nagarur, MD, Department of Medicine , Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., BUL-015, Boston, MA 02114 (e-mail:

Table 1. Causes of nonhepatic hyperammonemia

* Urease-producing bacteria (Proteus, Klebsiella, Escherichia,
  and Morganella species, Helicobacter pylori)
* Drugs (valproic acid, 5-fluorouracil, carbamazepine)
* Surgery (bariatric surgery, ureterosigmoidostomy, lung and
  bone marrow transplants)
* Hyperalimentation (total parenteral nutrition)
* Anatomic (portosystemic shunts)
* Errors in metabolism (urea cycle disorder, fatty acid oxidation
  defect, organic acidemia, pyruvate metabolism disorder)

Figure 1. Shared phenotypic characteristics of hyperammonemic
encephalopathy after Roux-en-Y gastric bypass surgery. AA
indicates amino acid; N[H.sub.3], ammonia.

Clinical         * Middle-aged
  Profile        * Female-predominant
                 * No history of liver disease
Clinical         * Variable post-surgical time course
  Presentation   * Successful weight loss post-RYGB
                 * ~50% case fatality rate
Laboratory       * Elevated N[H.sub.3]
  Hallmarks      * Elevated plasma glutamate
                 * Hypoalbuminemia
                 * Nutritional and essential AA deficiencies
                 * Low zinc
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Author:Nagarur, Amulya; Fenves, Andrew Z.
Publication:Baylor University Medical Center Proceedings
Article Type:Clinical report
Date:Jan 1, 2017
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