Achalasia

Achalasia is a primary esophageal motility disorder that develops from the degeneration of the myenteric plexus. This condition results in impaired lower esophageal sphincter relaxation and absence of normal esophageal peristalsis. Patients typically present with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids and liquids along with regurgitation. Diagnosis is established by high-resolution manometry. To rule out malignancy as a cause of achalasia, upper endoscopy is performed. Barium swallow study helps evaluate the esophageal morphology. Management options include pneumatic balloon dilation, surgical myotomy, and botulinum toxin injection. Choice of treatment is dependent on the type of achalasia and surgical risk. Medications are available for those who fail initial intervention; however, they provide the least benefit.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

  • Primary esophageal motility disorder due to degeneration of the myenteric plexus  
  • Condition is characterized by:
    • Impaired relaxation of the lower esophageal sphincter (LES)
    • Absence of normal esophageal peristalsis

Anatomy and physiology

  • Esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus:
    • Made up of an outer longitudinal muscle layer and an inner circular muscle layer 
    • Circular muscle fibers: allow peristalsis
    • Upper ⅓ of esophagus: predominantly skeletal muscles
    • Lower ⅔ of esophagus: Smooth muscles become more dominant from the middle to the distal esophagus.
  • Myenteric plexus (Auerbach’s plexus):
    • Group of ganglia between the circular and longitudinal muscle layers
    • Part of the enteric nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System 
    • Function: controls the peristalsis of the gastrointestinal tract
  • Type of neurons or ganglion cells in the myenteric plexus:
    • Excitatory: secrete acetylcholine → muscle contraction
    • Inhibitory: secrete nitrous oxide and vasoactive peptide → muscle relaxation

Epidemiology

  • Incidence: 12 cases per 100,000 individuals
  • Prevalence: 10 cases per 100,000 individuals
  • Seen mostly in adults between 25 and 60 years of age
  • Men and women are equally affected.

Etiology

  • Primary: idiopathic
  • Secondary (also called pseudo-achalasia): 
    • Caused by diseases that lead to esophageal abnormalities, similar to primary achalasia
    • Malignancy (esophageal, gastric, or other extraesophageal cancers) by mass effect or as part of paraneoplastic syndrome
    • Chagas disease Chagas disease Chagas disease is an infection caused by the American trypanosome Trypanosoma cruzi. This parasitic protozoan is transmitted in the feces of reduviid bugs in South and Central America. Acute infection may present with inflammation at the inoculation site (chagoma), fever, and lymphadenopathy. Untreated, chronic infection can progress to severe complications. Trypanosoma cruzi/Chagas disease
      • Infection with a parasite, Trypanosoma cruzi Trypanosoma cruzi Chagas disease is an infection caused by the American trypanosome Trypanosoma cruzi. This parasitic protozoan is transmitted in the feces of reduviid bugs in South and Central America. Acute infection may present with inflammation at the inoculation site (chagoma), fever, and lymphadenopathy. Untreated, chronic infection can progress to severe complications. Trypanosoma cruzi/Chagas disease
      • Commonly found in South and Central America
    • Infiltrative disorders: amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis, sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis 
    • Genetic diseases: neurofibromatosis, multiple endocrine neoplasia Multiple endocrine neoplasia Multiple endocrine neoplasia syndromes are autosomal dominant inherited conditions characterized by 2 or more hormone-producing tumors involving the endocrine organs. There are different types of MEN, namely MEN1-4. Multiple Endocrine Neoplasia type 2B, Fabry’s disease
    • Others: eosinophilic esophagitis Esophagitis Esophagitis is the inflammation or irritation of the esophagus. The major types of esophagitis are medication-induced, infectious, eosinophilic, corrosive, and acid reflux. Patients typically present with odynophagia, dysphagia, and retrosternal chest pain. Esophagitis, juvenile Sjögren’s syndrome, chronic idiopathic intestinal pseudo-obstruction

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Pathophysiology

Pathologic process

  • Degeneration of Auerbach’s plexus, where there is selective loss of inhibitory ganglion cells in the distal esophagus 
  • Unopposed excitatory activity → failure of smooth muscle relaxation at LES → increase in LES pressure → progressive loss of peristaltic function

Proposed factors that contribute to the pathogenesis

  • Genetic predisposition
    • Achalasia is associated with genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (Allgrove’s syndrome).
    • Familial cases point to a possible inherited pattern.
  • Viral infection
    • Varicella zoster, measles Measles Measles (also known as rubeola) is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. It is highly contagious and spreads by respiratory droplets or direct-contact transmission from an infected person. Typically a disease of childhood, measles classically starts with cough, coryza, and conjunctivitis, followed by a maculopapular rash. Measles Virus, and Herpes simplex (type 1) virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins have been noted in affected patients. 
    • A causal relationship, however, has not been established.
  • Inflammation and autoimmune process
    • Autoantibodies to enteric neurons have been found in patients with achalasia.
    • In affected esophagus: Inflammatory T-cell infiltrates surround the inhibitory neurons, with relative sparing of the excitatory neurons.

Clinical Presentation and Complications

Clinical presentation

  • Insidious onset
  • Dysphagia to solids and liquids 
  • Regurgitation of bland undigested food 
  • Difficulty belching
  • Heartburn
  • Nocturnal cough
  • Hiccups
  • Weight loss

Complications

  • Aspiration pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: from regurgitation
  • Megaesophagus in 10% of cases
  • Increased risk of esophageal cancer Esophageal cancer Esophageal cancer is 1 of the most common causes of cancer-related deaths worldwide. Nearly all esophageal cancers are either adenocarcinoma (commonly affecting the distal esophagus) or squamous cell carcinoma (affecting the proximal two-thirds of the esophagus). Esophageal Cancer
Grade iv megaesophagus

Image of megaesophagus (loss of esophageal motility and diffuse esophageal dilation)
A: Posteroanterior X-ray showing widening of the superior mediastinum Mediastinum The mediastinum is the thoracic area between the 2 pleural cavities. The mediastinum contains vital structures of the circulatory, respiratory, digestive, and nervous systems including the heart and esophagus, and major thoracic vessels. Mediastinum and Great Vessels (arrows)
B: Barium swallow study demonstrating a dilated and tortuous esophagus (arrowheads)

Image: “Grade IV megaesophagus” by US National Library of Medicine. License: CC BY 4.0

Diagnosis

Diagnostic approach

  • Achalasia suspected in:
    • Dysphagia to solids and liquids
    • Heartburn unresponsive to proton pump inhibitor
  • Upper endoscopy is performed → suggestive findings or equivocal but with high suspicion → proceed with esophageal manometry:
    • If manometry is consistent with achalasia: Rule out malignancy (endoscopic ultrasound with fine needle aspiration).
    • If with equivocal manometry findings: barium swallow study
    • If with normal manometry: Achalasia is ruled out.

Esophageal manometry

  • Establishes the diagnosis of achalasia
  • High-resolution manometry (HRM) with esophageal pressure topography (EPT):
    • Gold standard test 
    • More sensors than conventional manometry
    • Pressure: represented by color (↑ intensity of color = ↑ pressure)
    • Demonstrates the following:
      • Resting pressure of the esophagogastric junction
      • Swallowing-triggered esophageal activity
    • Classifies the types of achalasia (which guide treatment):
      • Type I classic achalasia: 
        • Minimal contractility or 100% failed peristalsis in the esophageal body 
        • Due to aganglionosis
      • Type II achalasia: 
        • Intermittent periods of pressurization 
        • Magnitude of aganglionosis is lower.
      • Type III spastic achalasia: 
        • Premature or spastic distal contractions 
        • Imbalance of excitatory and inhibitory influence, mostly intact ganglion cells
  • Conventional manometry:
    • Findings:
      • Aperistalsis in lower ⅔ of esophagus 
      • Incomplete LES relaxation after swallow
      • High LES resting pressure
Achalasia types

Types of achalasia

All types exhibit impaired esophagogastric junction relaxation.
Type I: On swallow, the upper esophageal sphincter relaxed, but is followed by 100% failed contractions and no esophageal pressurization (absent peristalsis).
Type II has panesophageal pressurization in at least 20% of swallows.
Type III is defined by the presence of preserved fragments of distal peristalsis or premature contractions for at least 20% of the swallows (spastic).

Image: “Achalasia types” by US National Library of Medicine. License: CC BY 4.0, edited by Lecturio.

Other diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests

  • Esophagogastroduodenoscopy (EGD): 
    • Findings: 
      • Retained food in esophagus
      • Increased resistance to passage of the endoscope through the esophagogastric junction
    • Can have normal or equivocal results
    • Necessary to rule out malignancy as the cause of achalasia
  • Barium swallow study: 
    • Performed in equivocal manometric findings
    • Evaluates esophagogastric junction morphology
    • “Bird’s beak”: pathognomonic barium swallow finding (dilated esophagus due to lack of peristalsis, which terminates in narrowing at LES)
  • Endoscopic ultrasound:
    • Evaluates esophageal wall thickness
    • Significant and asymmetric wall thickening: suspicious for malignancy
  • EndoFLIP (functional lumen imaging probe):
    • FLIP catheter passes through esophagus and displays diameter of esophageal segments.
    • Helps assess esophageal emptying by the distensibility of the esophagogastric junction
    • Achalasia: low distensibility

Management

Approach to management

  • The loss of ganglion cells cannot be reversed.
  • Goal of intervention is to improve the passage of ingested material.
  • Among the types of achalasia:
    • Type II: has the best response to treatment options
    • Type III: the most difficult to manage

Management options

  • Pneumatic balloon dilation of LES
    • Circumferential stretching of the LES
    • Patients referred to surgery if no improvement after 3 consecutive dilations
    • Risk of esophageal perforation Esophageal perforation Esophageal rupture or perforation is a transmural defect that occurs in the esophagus, exposing the mediastinum to GI content. The most common cause of esophageal perforation is iatrogenic trauma by instrumentation or surgical procedures. Esophageal Perforation
    • For type I or type II achalasia
  • Surgical myotomy
    • Lower esophageal sphincter muscle fibers are surgically cut to relieve pressure.
    • Heller myotomy (laparoscopic option)
    • Risk of esophageal and gastric perforation
    • Risk of gastroesophageal reflux (fundoplication performed at the same time to reduce this risk)
  • Peroral endoscopic myotomy (POEM):
    • Longer myotomy
    • Procedure of choice for type III achalasia
    • Can result in severe gastroesophageal reflux
  • Botulinum toxin injection into LES
    • Botulinum toxin is injected to block the release of acetylcholine from excitatory ganglions → ↓ LES tone
    • Good short-term results; requires retreatment within 612 months
    • Reserved for poor surgical candidates
  • Pharmacologic options:
    • Least benefit
    • Considered for poor surgical candidates and for those who fail botulinum injections
    • Mechanism of medications: Reduce LES pressure.
    • Medications: nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates, calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)

Differential Diagnosis

  • Esophageal spasm: also presents with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids and liquids but is associated with sudden onset of chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain that is not exertion-related. There are 2 types of this condition: distal esophageal spasm and hypercontractile esophagus. Manometry shows characteristic esophageal contractions with normal relaxation of the esophagogastric junction. 
  • Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease): symptoms of heartburn and regurgitation caused by the reflux of stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach contents. Patients usually complain of a burning epigastric pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain radiating up the chest, with a sour or metallic taste in the mouth. Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease is due to inappropriate relaxation of the LES. Proton pump inhibitors are used to control symptoms of GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease.
  • Scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma: also called systemic sclerosis Systemic sclerosis Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma, this condition presents with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids and liquids at the onset, accompanied by findings of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin thickening and hardening (sclerosis) and specific serum autoantibodies. Lower esophageal sphincter is weak or incompetent in scleroderma, so manometry shows low or absent LES pressure.
  • Esophageal stricture: narrowing of the esophagus that is frequently a sequelae of gastroesophageal reflux. This narrowing can also result from malignancies. Esophageal stricture presents with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids, progressing to liquids. Barium swallow study shows a narrowed luminal diameter. Upper endoscopy is performed for dual purposes, as it aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS in diagnosis through visualization and biopsy and also allows dilation when necessary for treatment. 
  • Esophageal ring and web: thin structures that produce partial occlusion of the esophageal lumen. Plummer-Vinson syndrome consists of iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, and a cervical esophageal web. Presentation includes dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids. Schatzki’s ring, the most common type of esophageal ring, is also associated with intermittent dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia to solids. Diagnosis is by barium swallow study and upper endoscopy.

References

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  2. Ates, F., Vaezi, M. (2015) The Pathogenesis and Management of Achalasia: Current Status and Future Directions. Gut Liver. 9(4): 449–463. doi: 10.5009/gnl14446
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  4. Furuzawa-Carballeda, J. et al. (2016). New insights into the pathophysiology of achalasia and implications for future treatment. World J Gastroenterol. 22(35):7892-7907. doi: 10.3748/wjg.v22.i35.7892
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