Pathophysiology of Achalasia: Wai-Kit Lo and Hiroshi Mashimo
Pathophysiology of Achalasia: Wai-Kit Lo and Hiroshi Mashimo
Pathophysiology of Achalasia: Wai-Kit Lo and Hiroshi Mashimo
2
Wai-Kit Lo and Hiroshi Mashimo
Achalasia is a motility disorder of the esophagus neurons. In contrast, the smooth muscle of the
with a prevalence of 1:100,000 [1]. The most com- esophageal body lacks demonstrable tone, likely
mon primary presenting symptom is dysphagia to owing to differences in contractile proteins and
both solids and liquids, with gradual symptom pro- isoforms compared to smooth muscle of the LES
gression. Other non-specific symptoms may include [2]. Unlike contraction in the skeletal muscles
regurgitation, chest pain (predominantly in younger controlled by central sequential activation of
patients), heartburn, and halitosis. In advanced motor neurons, primary peristalsis along the
cases, patients may also report weight loss, noctur- smooth muscle portion (approximate distal two-
nal cough, and finding regurgitated food or mucous thirds) of the esophageal body is initiated by non-
on the pillow upon waking from sleep. sequential simultaneous central activation, and is
Normally, the lower esophageal sphincter believed to be propagated largely by peripheral
(LES) has myogenic tone, i.e., remains intrinsi- mechanisms to produce a deglutitive inhibition
cally contracted in the absence of neural input or followed by excitation. There is an intrinsic gra-
hormones, to prevent reflux of gastric contents. It dient of decreasing cholinergic and increasing
relaxes in response to swallowing and esophageal nitrergic innervation distally in the esophagus [3,
or gastric distention. This muscle is also under 4].
neurogenic control involving the myenteric Pathophysiology involves the selective degen-
plexus, which contain both excitatory (acetylcho- eration of inhibitory neurons in the esophagus,
line-producing) and inhibitory (nitric oxide- and which are needed for peristalsis of the smooth
vasoactive intestinal peptide-producing) motor muscle of the esophageal body, as well as relax-
ation of the tonic LES [5]. The etiology of pri-
mary achalasia remains largely unknown. Based
W.-K. Lo, MD, MPH (*) on viral antigen reactivity in some patients with
Division of Gastroenterology,
achalasia, such viruses as varicella-zoster, human
VA Boston Healthcare System,
Harvard Medical School, papilloma and herpes have been implicated in
150 South Huntington Avenue, initiating an inflammatory reaction [6, 7]. The
Boston, MA 02130, USA preference of herpes virus for squamous rather
e-mail: Wai-Kit.Lo@va.gov
than columnar epithelium could explain predom-
H. Mashimo, MD, PhD inant esophageal involvement in achalasia while
Division of Gastroenterology,
largely sparing the rest of the gastrointestinal
VA Boston Healthcare System,
Harvard Medical School, tract, and increased risk for esophageal squamous
Boston, MA USA carcinoma. However, polymerase chain reaction
amplification failed to detect such viruses in react with both small cell lung cancer cells and
myotomy specimens from achalasic patients with various nerve cells, and has been found in
[8]. Nonetheless, this negative finding does not patients with achalasia, gastroparesis, and pseu-
rule out the role of other viruses, or an earlier dobstruction, even before overt diagnosis of can-
viral assault that is cleared by the time symp- cer [20]. Allgrove’s syndrome, consisting of
toms arise. There are also known familial cases achalasia, alacrima, and adrenal insufficiency, is
of achalasia, including a case report of siblings another secondary cause of achalasia with auto-
with coexistent Hirschsprung’s disease [9]. somal recessive inheritance that has been linked
Albeit extremely rare, such cases raise the pos- to 12q13 chromosome with features also of men-
sibility of a genetic basis of the disease [10]. An tal retardation and peripheral and autonomic neu-
autoimmune etiology has been suggested, with ropathy [21].
evidence of circulating autoantibodies [11], and Whether primary or secondary, the resulting
antibodies against myenteric neurons in the esophageal aperistalsis and incomplete relaxation
serum of approximately a third of achalasic of the LES impede passage of the swallowed
patients [12], as well as association with Class food bolus into the stomach, leading to accumu-
II histocompatibility antigen [13]; however, lation of undigested material in the esophagus.
antibody detection had low specificity for the Over time, this may result in permanent dilation
disease, suggesting the likelihood of epiphe- of the body of the esophagus. In most cases, his-
nomenon rather than true causation [14]. tologic examination confirms evidence of
Neurodegeneration may be a primary etiology decreased neurons in the myenteric plexi, with
given the detection in one study of Lewy bodies, significant inflammatory infiltration including
as found in Parkinson’s disease [15], or second- lymphocytosis [22]. The nitric oxide-producing,
ary to the aforementioned viral or autoimmune inhibitory neurons are preferentially affected
processes, but no central neurologic lesion has [23], while cholinergic neurons are largely pre-
ever been implicated [16]. served [24]. As such, the acetylcholinesterase
Secondary achalasia, or pseudoachalasia, is inhibitor edrophonium choline produces
considered when achalasia arises secondary to enhanced contraction in achalasia. Specific
other known causes. For example, Chagas’ dis- targeted deletion of the neuronal nitric oxide
ease is a tropical parasitic disease found in South synthase gene in an animal model produces the
America, in which infection by the protozoan phenotype of achalasia [25]. Exceptions to this
Trypanosoma cruzi results in systemic invasion pathological finding include secondary achalasia
of internal organs, thereby disrupting normal from multiple endocrine neoplasia (MEN) type
functions of structures including the heart, brain, 2B and von Recklinghausen’s disease (neurofi-
and gastrointestinal system [17]. Malignancy is bromatosis), which are characterized not by
also an important cause of secondary achalasia, dropout, but by hyperganglionosis or dysplasia of
and must be excluded before proceeding with the myenteric plexus. A mutation in the RET
treatment for primary achalasia [18]. Invasive protooncogene, associated with Hirschsprung’s
disease, such as esophageal cancer, or extrinsic disease, was also identified in 90 % of patients
compression from lung or gastric cancer, can with MEN type2, which may explain improper
result in achalasia-like symptoms with sugges- neural crest migration and differentiation [26].
tive findings on testing modalities. Additionally, However, other hereditary forms of achalasia
several malignancies, including breast and small require further genetic characterization. Achalasia
cell lung cancer, have been associated with a is also described in patients with autoimmune
paraneoplastic phenomenon of dysmotility based polyglandular syndrome [27].
on elaboration of humoral factors, neuronal Many of the treatments applied for achalasia
degeneration, and possibly abnormal neurotrans- address and add clarity to these pathophysiologic
mission [5, 19]. Type 1 antineuronal nuclear pathways. The goal of treatment is symptom
autoantibodies (ANNA-1, also called anti-Hu) improvement by decreasing the LES resting
2 Pathophysiology of Achalasia 11
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