Pathophysiology of Achalasia: Wai-Kit Lo and Hiroshi Mashimo

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Pathophysiology of Achalasia

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

© Springer International Publishing Switzerland 2016 9


P.M. Fisichella et al. (eds.), Achalasia: Diagnosis and Treatment,
DOI 10.1007/978-3-319-13569-4_2
10 W.-K. Lo and H. Mashimo

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

pressure to enhance esophageal clearance, and to


minimize the effects of esophageal stasis leading
to progressive esophageal dilation. However, no
treatments to date have shown restoration of peri-
stalsis in the esophageal body. The non-relaxing
LES can be treated by mechanical methods
(pneumatic dilation or surgical myotomy), or
biochemical means (endoscopic botulinum toxin
injection (EBTI) and oral medications). While
mechanical methods treat the anatomic obstruc-
tion resulting from incomplete LES relaxation,
biochemical methods are targeted at specific por-
tions of the proposed pathway. In EBTI, botuli-
num neurotoxin type A is endoscopically injected Fig. 2.1 Esophagogastroduodenoscopy (EGD) is used in
into the LES. Botulinum toxin inhibits acetylcho- the assessment of dysphagia, and to evaluate for compli-
line release to reduce the unopposed excitation of cations of achalasia. Here, EGD demonstrated evidence of
white plaques in the esophagus, signifying a diagnosis of
the LES seen in achalasia, thereby allowing the esophageal candidiasis, in a patient with achalasia
LES to function as normal [28].
Oral medications such as calcium channel
blockers (nifedipine 10–30 mg SL, 30–45 min (EGD) may often reveal esophageal dilation with
before meals) [29] and nitrates (isosorbide dini- retained foodstuff, as well as complications of
trate 5 mg SL, 10–15 min before meals) [30] can esophagitis or candidiasis (Fig. 2.1). Endoscopy
also induce relaxation of the smooth muscle of is also helpful to exclude other findings such as
the LES to enhance esophageal transit in achala- esophageal or gastric malignancy that can result
sia. The efficacy of these medications, though in secondary achalasia. Barium swallow radiog-
limited, suggest that the underlying function of raphy will often reveal the characteristic finding
the LES remains preserved. More interesting, of smooth tapering or “bird-beaking” in the distal
sildenafil has also been investigated for treatment esophagus, which suggests lack of overt mucosal
of achalasia in a smaller study with some success pathology but represents poor LES relaxation
[31]. Sildenafil is a phosphodiesterase inhibitor (Fig. 2.2). Finally, esophageal manometry is key
used in functional impotence, and results in to the diagnosis of achalasia by revealing evi-
enhancement of inhibitory pathway induced by dence of aperistalsis, poor LES relaxation, and
nitric oxide. Its application in achalasic patients often an elevation in baseline LES pressure.
results in improved LES relaxation, further sup- As a result of advances in high resolution
porting the importance of the above pathophysi- esophageal manometry (HREM), the diagnosis
ologic pathway in achalasia. of achalasia can be further divided into manomet-
Complications of achalasia may include ric subtypes, with impact on treatment response
esophageal candidiasis or frank esophagitis, due [33, 34]. Although esophageal aperistalsis, poor
to retention of food matter in the esophagus. LES relaxation, and elevation in basal LES pres-
This can contribute to symptoms of dysphagia or sure are seen commonly across subtypes, distin-
odynophagia. There have also been reports of guishing manometric characteristics allows for
esophageal diverticula, developing as a result of further sub-classification. Type 1 is the classic
slowed esophageal transit with alteration in subtype, with absent esophageal pressurization
bolus flow [32]. (Fig. 2.3). Type 2 is the esophageal compression
The diagnosis of achalasia is usually made subtype, with pan-esophageal pressurization of
with a combination of three testing modalities, the esophagus in greater than 20 % of swallows
which demonstrate evidence of the pathophysio- (Fig. 2.4). Type 3 is the spastic subtype, with high
logic process. Esophagogastroduodenoscopy amplitude spastic contractions of the esophagus
12 W.-K. Lo and H. Mashimo

Fig. 2.4 A representative swallow in high resolution


esophageal manometry from a patient with Type 2 achala-
Fig. 2.2 Barium swallow radiography will often demon- sia, or the esophageal compression subtype, in which pan-
strate the classic “bird-beaking” finding in the distal esophageal pressurization is seen in greater than 20 % of
esophagus, signaling poor relaxation of the lower esopha- swallows. This subtype is most responsive to treatment
geal sphincter

Fig. 2.5 A representative swallow in high resolution


Fig. 2.3 A representative swallow in high resolution esophageal manometry from a patient with Type 3 achala-
esophageal manometry from a patient with Type 1 achala- sia, or the spastic subtype, in which high amplitude spas-
sia, or the classic subtype. Esophageal pressurization is tic contractions are seen in greater than 20 % of swallows.
absent. This subtype is moderately responsive to This subtype is least responsive to treatment
treatment
may assist in excluding etiologies of secondary
in greater than 20 % of swallows (Fig. 2.5). Distal achalasia, including lung cancer, which cannot be
esophageal peristalsis may be preserved in this identified on the aforementioned testing
subtype, but proximal peristalsis remains absent. modalities.
A normal esophageal manometric swallow is The natural disease course of patients with
included for reference (Fig. 2.6). achalasia that do not receive treatment includes
In candidates with suggestive history or risk progressive esophageal dilation and tortuosity. In
factors, chest imaging such as x-ray or CT scan late-stage achalasia, megaesophagus is irreversible
2 Pathophysiology of Achalasia 13

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