Plummer-Vinson Syndrome

Etiology

Even a century after the first reports of the cases, the etiology of Plummer-Vinson syndrome remains unknown. Proposed etiopathogenic mechanisms include nutritional and iron deficiencies, genetic predisposition, and autoimmunity.[5] The evidence for these proposed mechanisms remains weak, except for iron deficiency, which consistently plays an important role. This is partly due to studies that have reported an improvement in dysphagia with iron supplementation, whereas iron deficiency is suspected of causing mucositis leading to web formation.

As patients with Plummer-Vinson syndrome may also suffer from malnutrition, vitamin B deficiency has also been suggested as a cause, although the evidence is weak and inconclusive. Other disorders associated with Plummer-Vinson syndrome include celiac disease, Crohn disease, rheumatoid arthritis, and thyroid disease, raising the possibility that immune dysregulation may be involved in its pathogenesis, although this remains to be proven.[6][7][8] In all cases, an underlying cause of iron deficiency should be sought, such as gastrointestinal blood loss and celiac disease.[9]

Epidemiology

Epidemiological data about the incidence and prevalence of Plummer-Vinson syndrome are not widely available due to the rarity of this syndrome, as noted in the literature, with most cases focusing on case reports. Although this syndrome appeared to be more common in temperate northern countries during the previous century, improvements in nutrition and subsequent correction of iron deficiency have led to a decline in its prevalence. In addition, although webs may be identified in barium studies or esophagogastroduodenoscopy, these webs may be symptomatic in only a minority of patients, and their presence alone does not meet the criteria for diagnosing Plummer-Vinson syndrome. However, an interesting single population-based study conducted in the 1960s in South Wales reported that the prevalence of post-cricoid webs in women was between 0.3% and 1.1% and 8.4% and 22.4% in women with dysphagia. In contrast, no webs were identified in men.[10]

PVS was commoner in the earlier half of the 20th century, particularly in middle-aged Scandinavian women. The rapid decline in the prevalence of the syndrome in the second half of the 20th century is attributable to an improvement in nutritional awareness, including the widespread fortification of flour with iron.[11][12] PVS has primarily been described in the White population and is more commonly seen in women. In earlier Scandinavian studies, up to 90% of patients with PVS were reported to be women. The typical age at diagnosis is between 40 and 70 years. A limited number of cases are seen in children.[13]

Pathophysiology

The exact pathogenesis of Plummer-Vinson syndrome and the formation of the esophageal web is not well known. It has been postulated that iron deficiency induces iron-dependent enzyme dysfunction, leading to oxidative stress and deoxyribonucleic acid damage.[4] The malfunctioning of iron-dependent oxidative enzymes produces myasthenic changes in muscles responsible for swallowing, atrophy of the esophageal mucosa, and formation of webs as epithelial complications.[14] Repeated injury to epithelia due to iron deficiency leads to atrophy of mucosa and degradation of pharyngeal muscles, leading to the development of esophageal webs.[15] The esophageal web is localized below the cricopharyngeal muscle and is asymmetrically attached to the anterior esophageal wall. The esophageal web is a thin mucous membrane composed of squamous epithelia.[4] 

On biopsy, no inflammatory infiltrates are found.[16] Further, iron deficiency has been reported to cause a decrease in the contraction amplitude of esophageal muscle.[17] The role of mucosal inflammation and atrophy, especially in the post-cricoid region, has been suggested as a factor for the pathogenesis of PVS. The post-cricoid region experiences maximum trauma while swallowing the solid bolus, leading to an increased risk of web formation.[18][19] PVS has also been proposed as an autoimmune phenomenon. It has been associated with autoimmune pathologies, such as pernicious anemia, rheumatoid arthritis, celiac disease, and thyroiditis.[20] In one study, a significant proportion of PVS patients had thyroid cytoplasmic autoimmune antibodies as opposed to patients with iron deficiency without a web.[2] However, there needs to be more evidence to support this concept. A complicated inlet patch, heterotopic gastric mucosa, has also been proposed in the pathogenesis of PVS.[21][22] An ulcer in the upper esophagus may lead to stricturing (weblike formation) and hemorrhage (with subsequent iron deficiency).[23] However, many studies based on biopsy or autopsy specimens have not shown the presence of gastric metaplasia.

Histopathology

Histologically, webs in patients with Plummer-Vinson syndrome show fibrosis, epithelial atrophy, epithelial hyperplasia, hyperkeratosis, basal cell hyperplasia, and some features of chronic inflammation.[24]

History and Physical

Most patients with Plummer-Vinson syndrome are initially asymptomatic. Plummer-Vinson syndrome classically presents as a triad of iron-deficiency anemia, post-cricoid dysphagia, and upper esophageal webs.[4] Long-standing iron deficiency anemia can present as dyspnea, tachycardia, weakness, pallor, and koilonychia. Dysphagia is painless and slowly evolving, starting with solid foods and difficulty swallowing liquids after years of initial onset.[25] Dysphagia becomes symptomatic only when the luminal diameter in the region of the esophageal web becomes less than 12 mm. Dysphagia in PVS is generally divided into 2 classes, grade I (occasional dysphagia on taking solids) or grade II (able to swallow only semi-solid diet).[26] Other clinical findings can be glossitis and angular cheilitis. Interestingly, splenomegaly, enlarged nodular thyroid glands, and edentia (loss of teeth) have also been found in a few patients with PVS.[27]

Evaluation

Although Plummer-Vinson syndrome is a rare diagnosis, there should be high clinical suspicion in patients with iron-deficiency anemia, esophageal webs, and post-cricoid dysphagia. Hematological testing is done to ascertain the cause of iron deficiency and the severity of anemia. Complete blood count, peripheral smear, and iron studies (eg, serum iron, ferritin, total iron-binding capacity [TIBC], transferrin saturation) should be carried out to confirm the diagnosis of iron deficiency anemia.[28] Other tests to diagnose the underlying causes of iron deficiency should be sought.

The esophageal web is investigated by radiographic tools such as barium swallow, which is generally available easily even in remote locations and is a diagnostic tool with the advantage of reproducible documentation. Videofluoroscopy is usually more reliable for the demonstration of esophageal webs.[29] A dynamic x-ray investigation evaluates swallowing as the barium bolus moves to the esophagus from the mouth. An advantage of these newer techniques is the identification of more minor webs and the distinguishing between true and false webs. Fiberoptic endoscopy is the safest and most reliable tool for GI tract examination. Esophagoscopy, an endoscopic examination of the esophagus, can be both diagnostic and therapeutic in the same setting. During esophagoscopy, esophageal webs appear as smooth, thin, gray lesions with normal-appearing mucosa and a central or lateral lumen and are most commonly located on the anterior wall of the esophagus.

Treatment / Management

Medical management of Plummer-Vinson syndrome includes iron supplementation. Occult or overt blood loss is generally ruled out, along with any underlying malignancies or iron malabsorption. Iron replacement is essential to correct anemia and to resolve most of the features associated with iron deficiency. The need for continued iron replacement is doubtful except for anemia correction.[30] Elemental iron in the range of 150 to 200 mg is generally required to correct iron deficiency anemia. Dysphagia in many patients resolves with just iron supplementation.[4][31] However, dysphagia caused by more advanced disease is unlikely to respond to medical management alone and, thus, is managed with endoscopic dilation. Finding out the underlying cause of iron deficiency is crucial as it will require special treatment, such as celiac disease. Aside from iron replacement, dietary modification is sufficient in mildly symptomatic patients.(B3)

Those with advanced and long-standing dysphagia typically require mechanical dilation. Commonly used techniques include endoscopic balloon dilatation or Savary-Gilliard dilators.[32][33] Therapeutic endoscopy denotes rupture of the web with a small amount of fresh blood at the site of the web. The esophageal web can often be disrupted by the simple insertion of the endoscope into the esophagus. However, in some cases, a bougie is required and is quite effective. In most cases, the insertion of a single large dilator is sufficient and is often more effective than serial progressive dilation. In a prospective study, Goel et al observed that esophageal-web-related dysphagia in PVS responded well after one session of endoscopic dilation.[26] Needle-knife electro-incision has been proposed as a therapeutic alternative to dilation.[34] Patients should be advised to eat slowly and chew thoroughly. Solids should be prepared and cut into small pieces, especially meats. Surgery is rarely indicated and is reserved for those whose webs are unmanageable with dilation or associated with Zenker diverticulum.(B3)

Differential Diagnosis

Other causes of dysphagia are much more common than Plummer-Vinson syndrome; even the presence of iron deficiency anemia or an esophageal web should not lead to a diagnosis of PVS. Tracheoesophageal fistula in neonates, injuries to the esophagus like blunt trauma or penetrating injuries, gastroesophageal reflux disease, vascular rings, and diverticula are some of the conditions that can present with similar dysphagia and spectrum of symptoms. Motility disorders like scleroderma, achalasia, and diffuse esophageal spasm may present with the esophageal web and dysphagia. Benign and malignant tumors of the esophagus can have a similar presentation.

Other conditions to consider in the differentials of PVS include the following:

• Heterotopic gastric mucosa with stricture [21][22]

• Pill-induced stricture

• Hypopharyngeal bar

• Inflammatory conditions associated with webs, such as chronic graft versus host disease, blistering skin diseases

Prognosis

Patients with Plummer-Vinson syndrome have an excellent outcome, with most symptomatic patients requiring only one esophagogastroduodenoscopy with dilatation for complete relief of symptoms in conjunction with iron replacement therapy. Patients are at an increased risk of developing squamous cell carcinoma of the hypopharynx or upper esophagus, which may be related to chronic iron deficiency. This is believed to cause irreversible mucosal changes leading to malignant degeneration.[35]

Complications

The following complications may occur:

• Untreated esophageal webs can lead to dysphagia for solids, absolute dysphagia, and aspiration pneumonia.
• Iron-deficient patients may develop symptomatic anemia (fatigue, malaise, dyspnea, angina pectoris) if iron supplementation is not provided.
• Patients may develop squamous cell cancer of the proximal esophagus, although the actual risk is unknown.[36] 
• Endoscopic treatment of the esophageal web with Savary dilatations or balloon dilatations can be associated with a small risk of esophageal perforation.