Protein-Losing Enteropathy as a Complication of the Ketogenic Diet
The ketogenic diet (KD), is an effective treatment for intractable childhood epilepsy, such as West syndrome (WS), Lennox-Gastaut syndrome, and sometimes for refractory status epilepticus.1 The use of this treatment, however, is sometimes limited due to its complications, despite of the efficacy. While some side effects are benign and treatable, others are more problematic and rarely can interrupt the diet therapy itself.234 Protein-losing enteropathy (PLE) is a rarely recognized serious complication of the KD, and only two cases have been reported.56
We experienced one case of PLE during the KD in a 16 month old male Down syndrome baby with WS.
A 16-month-old male baby was diagnosed with Down syndrome by chromosome analysis and clinical features after birth. He presented epileptic spasms since the age of 5 months and was diagnosed with WS. He started to be treated by multiple antiepileptic drugs (AEDs), including vigabatrin, clobazam, valproic acid and oral steroids, but his epileptic seizures, developmental regression, and hypsarrhythmia on electroencephalogram persisted.
KD with 3:1 ratio of fat to non-fat was started by milk formula, and multiple AEDs (vigabatrin, clobazam, and deflazacort) were maintained at the same doses. Vomiting and diarrhea were developed after 1st week of KD. The albumin level which was 3.8 g/dL at initiation of the diet decreased to 1.8 g/dL after 16 days of KD. He was treated by intravenous albumin and intermittent parenteral nutritional support. Lipid and non-fat ratio of KD deescalated from 2:1 on the 28th days to 1.7:1 on the 30th days of the diet. Because he had not improved after 4 weeks, we changed KD to medium chain triglyceride formula on the 61st days of the diet.
Laboratory tests, abdominal ultrasonography, esophagogastroduodenoscopy (EGD), colonoscopy, and alpha-1 antitrypsin (A1AT) in stool, were done. There was no proteinuria in urine dipstick test, and blood test revealed blood urea nitrogen 9.2 mg/dL, creatinine 0.2 mg/dL, aspartate aminotransferase 16 IU/L, alanine aminotrasnferase 5 IU/L, and normal thyroid function. Echocardiography revealed normal heart function without any structural abnormalities. There were no pathogens in stool bacterial culture, but norovirus infection was detected in stool virus study. Abdominal ultrasonography revealed grossly normal liver and gallbladder, and preserved corticomedullary differentiation in both kidneys, and there was no skin lesions that could produce protein loss.
EGD revealed edematous mucosa in the duodenum, and the biopsy results revealed lymphatic ectasia in the lamina propria; thus intestinal lymphangiectasia was diagnosed (Fig. 1). A1AT of the stool was 56.60 mg/dL. These findings were concordant with interstitial lymphangiectasia as a presentation of PLE.
We discontinued the KD after 8 weeks and supported him with balanced nutrition. His general condition improved, and hypoalbuminemia, edema, and diarrhea were resolved after cessation of KD (Fig. 2).
With increasing use of KD, more early and late complications have recently been reported. Kang, et al.2 and Suo, et al.3 showed that hypoproteinemia is commonly appeared on KD with approximately 10% of the patients: 12 of 129 patients (9.3%) and 39 of 317 patients (12.3%), respectively. Gluconeogenic consumption due to restriction of carbohydrate and reduced protein intake were suspected as mechanism of hypoproteinemia. Patients with hypoproteinemia can be improved by increase of protein intake with maintenance of lipid-to-nonlipid ratio.4
Gastrointestinal (GI) disturbance, common early and late complication of KD, is related to poor tolerance of the diet and it can disturb the maintenance and efficacy of KD. The symptoms of GI disturbance were seen in 73 (56.6%) patients, reported by Kang, et al.4 Transient GI disturbances are explained by defective absorption and intolerance of high-lipid diet, there fore, adaptation periods seem to be required.
Hypoproteinemia and diarrhea as early complications of KD are expected to be controlled by well-known conservative cares. However, patients with abnormal progression, for example persistent symptoms, or who need intravenous replacement of protein continuously, have to undergo further evaluation for other causes including PLE.
In most cases, PLE can be diagnosed by history, physical examination and clinical manifestations, nevertheless, documentation of GI losses of protein by fecal A1AT levels or with functional imaging is necessary.78
There are two main mechanisms of PLE-mucosal injury or lymphatic abnormalities, sometimes both of them together.8910 Mucosal injury is caused by variety of conditions-inflammatory or ulcerative diseases, such as infections, Crohn's disease/ulcerative colitis or GI malignancies, and other non-ulcerative diseases. Intestinal lymphangiectasia is characterized by diffuse or local dilatation of the enteric lymphatics and leakage of lymphatic fluid rich in albumin and other proteins into the GI tract. Increased leakage of protein-rich fluids across damaged mucosa can cause loss of protein, and mucosal cell injury is related to secondary lymphangiectasia. Abnormality of the lymphatic drainage can be caused by either congenital defect as primary intestinal lymphangiectasia or by secondary causes as GI obstruction, congestive heart failure, lymphoma and other intestinal damage.
Norovirus infection is a major cause of GI disturbance in children. Fecal shedding of norovirus persists for up to 2 weeks, however, it can persist for up to 5 weeks in immune-compromised patient.11 Furthermore, norovirus infection is associated with exacerbation of inflammatory bowel disease.12 However, there is no definite relationship between noroviral infection and PLE. In this case, immune-compromised status due to taking steroid for long times could have made GI tract inflammation worse.
There have been two published case reports of PLE upon initiation of the KD-one case was explained by allergic gastroenteritis from a soy allergy,4 and the other case seemed to have been caused by the diet itself.5 Mucosal injury by viral infection and secondary lymphangiectasia which was aggravated by KD itself are highly suspected mechanism of PLE in our case.
PLE, a rarely experienced serious complication of the KD, can interrupt the maintenance of diet therapy. Early detection and active intervention are important in maintaining the health of such patients.
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