Plummer-Vinson syndrome overview

# Overview
The Plummer-Vinson syndrome, also called Paterson-Brown-Kelly syndrome or sideropenic dysphagia is a disorder linked to severe, long-term iron deficiency anemia, which leads to dysphagia, glossitis and esophageal webs. The disease is named after two American physicians Henry Stanley Plummer, and Porter Paisley Vinson. It is also called "Kelly-Paterson syndrome", named after two British otolaryngologists, Adam Brown-Kelly and Donald Ross Paterson. The exact pathogenesis of Plummer-Vinson syndrome is not fully understood. It is postulated that Plummer-Vinson syndrome results from iron deficiency. Other possible factors include malnutrition, genetic predisposition and autoimmune disorders. On gross pathology, esophageal web and esophageal strictures are characteristic findings of Plummer-Vinson syndrome. On microscopic histopathological analysis, Plummer-Vinson syndrome presents with epithelial atrophy, chronic submucosal inflammation and epithelial atypia or dysplasia (in advanced cases). There are no established risk factors for Plummer-Vinson syndrome. However, chronic irritation of the esophagus may predispose to an increased risk of developing esophageal webs or strictures. Plummer-Vinson syndrome is a rare disease and the data pertaining to its incidence and prevalence is not evidently available. Overall improvement in nutritional status with better medical care has markedly reduced the number of cases of Plummer-Vinson syndrome. Common complications of Plummer-Vinson syndrome include hypopharyngeal cancer, esophageal cancer and malignant lesions of oral mucosa. Plummer-Vinson syndrome must be differentiated from other diseases that cause dysphagia such as reflux esophagitis, esophageal carcinoma, systemic sclerosis, esophageal spasm, pseudoachalasia, stroke, esophageal candidiasis, Zenker's diverticulum and Chagas disease. Physical examination of patients with Plummer-Vinson syndrome is usually remarkable for glossitis, esophageal webs or strictures, and dysphagia. Laboratory findings consistent with the diagnosis of Plummer-Vinson syndrome include presence of iron deficiency anemia. The diagnosis of Plummer-Vinson syndrome is made in the presence of iron-deficiency anemia with esophageal webs, dysphagia and glossitis. An x-ray (barium esophagogram) is the best initial imaging study in a patient suspected with Plummer-Vinson syndrome. Other imaging studies include a videofluoroscopy or an esophagogastroduodenoscopy to visualise the esophageal webs. The mainstay of treatment for Plummer-Vinson syndrome is aimed at correcting iron deficiency anemia. Effective measures for the prevention of Plummer-Vinson syndrome include good nutrition with adequate intake of iron rich foods and an upper gastrointestinal endoscopy every year to rule out malignant transformation.

# Historical Perspective
Plummer-Vinson syndrome was first discovered by Henry Plummer an American internist, in a case series of patients with long-standing iron deficiency anemia, dysphagia and spasm of the upper esophagus without anatomic stenosis in his article "Diffuse dilatation of the esophagus without anatomic stenosis." In the year 1919, Porter Paisley Vinson an American surgeon at the Mayo Clinic further described Plummer-Vinson syndrome in his article "A case of cardiospasm with dilatation and angulation of the esophagus." He reported a case of angulation of esophagus and attributed his findings to be consistent as described by Henry Plummer. In the year 1919, Donald Ross Patterson and Adam Brown Kelly, both British otolaryngologists described the characteristic clinical features of Plummer-Vinson syndrome in their article "A clinical type of dysphagia" and "Spasm at the entrance of the esophagus" respectively.

# Classification
There is no established system for the classification of Plummer-Vinson syndrome.

# Pathophysiology
Plummer-Vinson syndrome is a rare condition characterized by iron-deficiency anemia, glossitis and dysphagia. The exact pathogenesis of Plummer-Vinson syndrome is not fully understood. It is postulated that Plummer-Vinson syndrome results from iron deficiency. Other possible factors include malnutrition, genetic predisposition and autoimmune disorders. In patients with iron deficiency, the iron-dependent oxidative enzymes are unable to function at optimum level and the dependent metabolic pathways (oxidative phosphorylation) are reduced. This promotes anaerobic metabolism with increased consumption of glucose and increased production of lactic acid and may lead to myasthenic changes in muscles. These myasthenic changes are often seen in muscles involved in swallowing and may lead to atrophy of the esophageal mucosa and formation of esophageal webs. Patients who do not exhibit obstructive lesions (web or stricture) may have dysphagia resulting from muscular in-coordination. Patients with iron deficiency have low levels of myoglobin which may affect the muscles of the tongue and lead to glossitis. In Plummer-Vinson syndrome, deficiency of iron can lead to epithelial atrophy and a decrease in the regenerative capacity of the mucosa. The decrease in rate of healing allows the chronic irritants to act progressively, predisposing the oral cavity and esophagus to malignant transformation (squamous cell carcinoma). Genes involved in the pathogenesis of iron deficiency anemia associated with Plummer-Vinson syndrome include mutation in TMPRSS6 gene. The TMPRSS6 gene encodes instructions for the protein hepcidin. Increased levels of hepcidin leads to decreased release of iron from ferritin and subsequently presents as iron deficiency anemia. On gross pathology, esophageal web and esophageal strictures are characteristic findings of Plummer-Vinson syndrome. On microscopic histopathological analysis, Plummer-Vinson syndrome presents with epithelial atrophy, chronic submucosal inflammation and epithelial atypia or dysplasia (in advanced cases).

# Causes
The exact cause of Plummer-Vinson syndrome is unknown; however, iron deficiency anemia, genetic factors and nutritional deficiencies may play a role. Iron deficiency anemia is the most widely regarded cause of Plummer-Vinson syndrome and can be due to increased iron demand, decreased intake and malabsorption syndromes.

# Differentiating Plummer-Vinson syndrome overview from Other Diseases
Plummer-Vinson syndrome must be differentiated from other diseases that cause dysphagia such as reflux esophagitis, esophageal carcinoma, systemic sclerosis, esophageal spasm, pseudoachalasia, stroke, esophageal candidiasis, Zenker's diverticulum and Chagas disease.

# Epidemiology and Demographics
Plummer-Vinson syndrome is a rare disease and the data pertaining to incidence and prevalence is not evidently available. Overall improvement in nutritional status with better medical care has markedly reduced the number of cases of Plummer-Vinson syndrome. However, individuals of any age groups may develop Plummer-Vinson syndrome and it is most commonly seen in the age group of 40-70 years. Plummer-Vinson syndrome usually affects individuals of the caucasian race. Females are commonly affected than males with female to male ratio of 4:1. The majority of Plummer-Vinson syndrome cases are reported in Scandinavian countries or north European countries.

# Risk Factors
There are no established risk factors for Plummer-Vinson syndrome. However, chronic irritation of the esophagus may predispose to an increased frequency of esophageal webs or strictures. Conditions which can irritate esophagus includes thermal injury, mechanical injury, achalasia, esophageal diverticulum, chronic lye stricture, radiation therapy, injection sclerotherapy, gastric resection, celiac disease, tylosis and scleroderma.

# Screening
There is insufficient evidence to recommend routine screening for Plummer-Vinson syndrome.

# Natural History, Complications, and Prognosis
If left untreated, patients of Plummer-Vinson syndrome may progress to develop fatigue, dyspnea on exertion, esophageal strictures, and malignant lesions of the mouth and oral cavity. Common complications of Plummer-Vinson syndrome include hypopharyngeal cancer, esophageal cancer and malignant lesions of oral mucosa. Depending on the extent of Plummer-Vinson syndrome at the time of diagnosis, the prognosis may vary. Prognosis is generally good for patients who receive treatment. Iron replacement therapy and dilatation of esophageal web leads to rapid reversal of symptoms.

# Diagnosis

## Diagnostic Criteria
The diagnosis of Plummer-Vinson syndrome is made in the presence of iron-deficiency anemia with esophageal webs, dysphagia and glossitis.

## History and Symptoms
Obtaining a history gives important information in making a diagnosis of Plummer-Vinson syndrome. Complete history should be obtained regarding onset, duration, and progression of symptoms such as dysphagia (solids or liquids), weakness, fatigue, dyspnea, and history of choking spells or aspiration. The common symptoms of Plummer-Vinson syndrome are difficulty in swallowing (more for solids), burning sensation in mouth, dry tongue and pale color of the skin. Less common symptoms include cold intolerance, reduced resistance to infection and craving for for unusual items (such as ice or cold vegetables).

## Physical Examination
Physical examination of patients with Plummer-Vinson syndrome is usually remarkable for glossitis, esophageal webs or strictures, and dysphagia. Other findings on physical examination include pallor, stomatitis, atrophy of lingual papillae, splenomegaly (33%), achlorhydria and koilonychia.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of Plummer-Vinson syndrome include presence of iron deficiency anemia. Patients suspected of Plummer-Vinson syndrome should be tested with complete blood count (CBC), iron studies, peripheral smear, stool test for occult blood, blood lead levels and bone marrow biopsy for stainable iron.

## Imaging Findings
Videofluoroscopy may be helpful in the diagnosis of Plummer-Vinson syndrome. Videofluoroscopy is done in patients with normal barium esophagogram who have a high probability of Plummer-Vinson syndrome. Videofluoroscopy is superior to barium esophagogram and has the ability to detect small esophageal webs resulting from insignificant mucosal and submucosal foldings which may otherwise go undiagnosed.

## Other Diagnostic Studies
Esophagogastroduodenoscopy (EGD) may be helpful in the diagnosis of Plummer-Vinson syndrome. EGD can directly visualize the upper gastrointestinal tract and aid in diagnosing esophageal webs seen in Plummer-Vinson syndrome. Findings suggestive of esophageal webs include thin elevated mucosal membrane covered by normal squamous epithelium on the walls of esophagus.

# Treatment

## Medical Therapy
The mainstay of treatment for Plummer-Vinson syndrome is aimed at correcting iron deficiency anemia. Patients with Plummer-Vinson syndrome should receive oral iron salts (ferrous sulphate) and iron supplementation in their diet. Parenteral iron is used in patients who are unable to tolerate oral iron or with malabsorption syndromes. Another important aspect in treating Plummer-Vinson syndrome is to identify the cause of iron deficiency in order to exclude active hemorrhage, malignancy or celiac disease.

## Surgery
Surgery is not the first-line treatment option for patients with Plummer-Vinson syndrome. However, procedure such as mechanical dilatation with the use of an endoscope may be used in patients who are unresponsive to medical therapy, have multiple obstructive esophageal webs and long-standing dysphagia.

## Prevention
Effective measures for the primary prevention of Plummer-Vinson syndrome include good nutrition with adequate intake of iron rich foods. Patients of Plummer-Vinson syndrome are at a risk (10-15%) of developing malignant lesions (squamous cell carcinoma) of the oral mucosa, hypopharynx and esophagus. Effective measures for the secondary prevention of Plummer-Vinson syndrome include an upper gastrointestinal endoscopy every year to rule out malignant transformation.