Herbst’s Triad as a Manifestation of Gastroesophageal Reflux Disease

Herbst triad (HT) was described in


BACKGROUND
The Herbst triad (HT) was described in 1976 by Herbst et al. (1) when detecting the association of iron deficiency anemia, hypoalbuminemia and clubbing in 3 children with hiatal hernia and severe esophagitis secondary to gastroesophageal reflux (GER). Although no chronic lung disease associated with reflux was demonstrated to justify the appearance of clubbing, these also disappeared after surgery (1). We present 2 children with HT that required surgical treatment due to lack of response to proton pump inhibitors.

CLINICAL CASES
The first case corresponds to a 4-year-old girl referred for recurrent brown vomits of one year of evolution, unrelated to the intake. Associated problems were epigastralgia, recurrent episodes of cervical hyperextension, low weight gain, and modification of the eating pattern, eating more frequent but less numerous meals. Upon examination, she had a weight of 14.6 kg (P7, −1.5 SD) and a height of 108 cm (P42, −0.2 SD), scarce adipose panniculus, skin paleness, and clubbing (Fig. 1A). Blood tests highlighted iron deficiency anemia and hypoalbuminemia with normal levels of fecal alpha-1-antitrypsin (Table 1). Esophagogastroduodenoscopy (EGD) showed a decrease in esophageal caliber and wall edema, longitudinal furrows, and discrete trachealization of the upper third of the esophagus, a cobblestone appearance in the middle third (Fig. 1C), and friable mucosa in the lower third with purulent exudate (Fig. 1D), also showing incompetence of the cardiac without hiatal hernia. All of these findings were consistent with grade B esophagitis according to the Los Angeles classification (2) . Histology revealed basal hyperplasia, fibrinopurulent material, and granulation tissue without eosinophils. The histology of stomach and duodenum were normal. Treatment with omeprazole (2 mg/kg/day), oral iron (5 mg/kg/day), and domperidone (0.75 mg/kg/day) was started. After 12 weeks of treatment, symptoms had remitted and progressive improvement of clubbing ( Fig. 1B) was observed. Blood test is shown in Table 1. However, 1 year after diagnosis, despite clinical improvement, she could not be weaned from proton pump inhibitor treatment due to recurrence of symptoms. Endoscopy at 12 months showed evidence of peptic esophagitis, a reason why she has been considered a candidate for surgical treatment.
The second case corresponds to a child of 2 years and 6 months, with a history of frequent regurgitations in the infant stage, referred for recurrent episodes of periumbilical pain of 15 months of evolution, almost daily and occasional vomiting with food content. In recent months, he was associated with intermittent eyelid edema, progressive asthenia and hyporexia. Physical examination revealed weight 11 kg (P2, −2.01 SD) and height 86.5 cm (P1, −2.26 SD), skin-mucosa pallor, palpebral edema, mild abdominal distention, and clubbing. The blood test showed iron deficiency anemia and hypoalbuminemia with normal levels of fecal alpha-1-antitrypsin (Table 1). Esophageal and gastroduodenal transit was performed, showing hiatal hernia. When the EGD was performed, in addition to the hernia, findings consistent with Los Angeles grade C esophagitis (2) were evidenced (Fig. 1E). Histology revealed intense chronic inflammation, eosinophil infiltration (1-4 eos/hpf), and foci of ulceration with areas of granulation. Treatment with omeprazole (2 mg/kg/day) and sucralfate (3 mg/kg/day) was started, but after 12 weeks, no clinical improvement was observed, persisting low levels of hemoglobin and albumin (Table 1). In the absence of response, a Nissen fundoplication was performed 16 weeks after diagnosis, presenting rapid clinical improvement, with normalization of laboratory parameters and disappearance of clubbing (Table 1). At 12 months of evolution, he was asymptomatic.

DISCUSSION
The clinical manifestations of GER are diverse, epigastralgia, heartburn, and regurgitation (3) in older children and adults, and rumination or Sandifer syndrome in infants and young children (4). To this broad spectrum, HT must be added as an unusual manifestation of GERD (5).
Regarding the pathophysiological mechanism underlying this entity, the erosion of the esophageal mucosa justifies the digestive loss of hemoglobin and albumin (1). Furthermore, plasma protein normalization after specific treatment corroborates the association between reflux esophagitis and protein-losing enteropathy (6). Despite this situation of protein-losing enteropathy, the values of fecal alpha-1-antitrypsin remains in normal range due to 2 mechanisms, intermittent losses of this protein (7) and its degradation in the acidic environment of the stomach.
The underlying mechanism of clubbing is not well defined despite its association with multiple entities and having been studied on numerous occasions (8). Three pathophysiological causes related to vascular endothelial growth factor (VEGF) are postulated: distal phalangeal hypervascularity, since platelet precursors are not fragmented in the pulmonary circulation by venoarterial shunts and are trapped in the distal circulation causing release of VEGF (9); chronic hypoxia, when there is increased expression of VEGF (10); and chronic states of inflammation, in which increased prostaglandins activate endothelial cells and VEGF (11) transcription. These arguments would explain that the cases of GER associated with microaspirations have chronic damage to the respiratory epithelium and a sustained state of inflammation that justifies the appearance of clubbing. However, in none of the described cases of HT described, chronic lung disease, hypoxemia, or venoarterial shunts that justify its presence have been found (1,6,7,12), so its pathophysiological mechanism remains enigmatic. However, due to the uniqueness of the disappearance of clubbing when treating GERD, it is reasonable to attribute its appearance to the presence of esophagitis (5,12).

Case Report
After reviewing the literature, we found 14 cases of HT published, all in children under 14 years of age, the majority under 7 (1,5-7,12-18) which suggests that this condition mainly affects children (Table 2). This could be justified by the low suspicion of GER in early childhood, given that the classic clinical picture is infrequent at these ages, causing diagnostic delay and perpetuating the pathophysiological mechanism. After diagnosis, in most cases, treatment with prokinetics, omeprazole, and/or H2 antagonists was started for a minimum of 12 weeks. Response to medical treatment was only described in 1 patient after therapy with omeprazole and domperidone for 9 months (15). However, the majority required surgical intervention.
To conclude, a high suspicion of this disease is important to make an accurate and early diagnosis due to the consequences derived from therapeutic delay, which can cause complications such as esophageal stenosis and Barret's esophagus (1,7). It is important to highlight the existence of GER in children under 8 years of age in the absence of typical symptoms, as well as the need to include esophagitis secondary to GERD in the differential diagnosis of clubbing.
Parents of the children in question aware of this Case Report and have they given their consent.