1164 Übersicht

The Elucidation of Peptic Esophagitis: from Hamperl

to Heartburn
Die Entwicklung der peptischen Ösophagitis: von der Pathologie bis Mount Sinai

Authors M. V. Malfertheiner1, S. Fill2, M. Kidd1, I. M. Modlin1

1
Affiliations Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut, USA
2
Klinik für Gynäkologie und Geburtshilfe, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany

Schlüsselwörter Zusammenfassung Abstract

●
" saurer Reflux
! !
●
" Ösophagus
Obwohl der Ösophagus in früheren Zeiten als Or- Although the esophagus was initially considered
●
" GERD
gan oft übersehen wurde, wurde ihm in der letz- as the “humble” organ, it has in recent times
●
" Hamperl

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●
" peptische Ösophagitis ten Zeit viel Aufmerksamkeit zuteil. Nachdem evoked both substantial interest and consider-
●
" peptische Ulzera die Ösophagitis sich zu einer weltweiten Pande- able controversy as esophagitis becomes a global
●
" Winkelstein mie entwickelte, schlugen die Debatten um ihre pandemic and the debate over the causes of eso-
Ursachen und das Management der Barrett-Me- phagitis and the management of Barrett's has
Key words
●
" acid reflux
taplasie hohe Wellen. Der Ösophagus war von je- escalated. The esophagus has always defied
●
" esophagus her nicht einfach zu verstehen und die Herkunft easy understanding and the origins of its name
●
" GERD seines Namens und seine Symptomatik verwir- and its symptomatology continue to confound
●
" Hamperl
ren diejenigen, welche sich mit ihm beschäfti- those who address them. Esophagitis is increas-
●
" peptic esophagitis
gen. Die Ösophagitis steigt weltweit weiter kon- ing relentlessly on a global scale and the chal-
●
" peptic ulcer
tinuierlich an und die Aufgabe, ihre Symptomatik lenge of defining its symptomatology remains
●
" Winkelstein
zu definieren, stellt heute noch ein ebenso today as great a problem as when initially iden-
großes Problem wie bei der Erstbeschreibung tified by Herwig Hamperl and Asher Winkel-
durch Herwig Hamperl und Asher Winkelstein stein. Their identification of the entity they
dar. Deren Erkenntnis der Entität, welche zuvor called “peptic esophagitis” in 1934, while initial-
meist übersehen und von ihnen dann 1934 „pep- ly for the most part overlooked, has today be-
tische Ösophagitis“ getauft wurde, ist zu einem come one of the centers of gastroenterological
Schwerpunkt der heutigen Gastroenterologie ge- focus. Although the initial symptomatology of
worden. Zunächst wurde die Symptomatik der esophagitis was limited to heartburn, it has
Ösophagitis auf Sodbrennen limitiert, mittle- more recently become apparent that a diverse
received 17.7.2007
accepted 5.8.2007 rweile hat sich jedoch herausgestellt, dass eine group of symptoms is produced by the inflam-
ganze Reihe von Symptomen durch die Entzün- mation associated with intermittent reflux of
Bibliography dung ausgelöst werden kann, welche durch gastric acid. Of interest is the nature of the origi-
DOI 10.1055/s-2007-963476
intermittierenden Reflux von Magensäure her- nal observations that led to the identification of
Z Gastroenterol 2007; 45:
vorgerufen wird. Der Ursprung der ersten Beo- the physiopathology of esophagitis and the elu-
1164 – 1168 © Georg Thieme
Verlag KG Stuttgart · New York · bachtungen, welche zur Entschlüsselung der Pa- cidation of the relationship between symptoma-
ISSN 0044-2771 thophysiologie der Esophagitis geführt haben, ist tology, acid reflux and inflammation. Although
von großem Interesse. Obwohl Asher Winkel- Asher Winkelstein of New York has long been
Correspondence
stein aus New York lange als Entdecker der Zu- considered the first to define the relationship of
Irvin M. Modlin,
MD, PhD, DSc, FRCS
sammenhänge von saurem Reflux, ösophagealen acid peptic reflux, esophageal ulceration and re-
Department of Gastroenterolo- Ulzerationen und Refluxsymptomatik galt, ist es flux symptomatology, it is of note to consider
gical Surgery, Yale University notwendig, die wegweisende Rolle des österrei- the seminal role of Herwig Hamperl, an Austrian
School of Medicine chischen Pathologen Herwig Hamperl zur Ent- pathologist in the elucidation of acid peptic eso-
333 Cedar Street schlüsselung der peptischen Ösophagitis zu er- phagitis. Indeed, a careful consideration of the
PO Box 208062 wähnen. Eine genaue Betrachtung der Beiträge relative contributions of these two pioneers sug-
New Haven
dieser beiden Pioniere zeigt, dass beiden der gests that both deserve credit for identifying a
CT 06520 – 8062
USA
Ruhm zusteht, diesen Krankheitsprozess identi- disease process that, although initially for the
Tel.: ++ 1/2 03/7 85 54 29 fiziert zu haben, welcher vor ihnen ignoriert most part ignored by clinicians, has now become
Fax: ++ 1/2 03/7 37 40 67
imodlin@optonline.net

Malfertheiner MV et al. The Elucidation of… Z Gastroenterol 2007; 45: 1164 – 1168

wurde, und heute ein fundamentales Problem für Gastroentero-
logen und Pathologen darstellt.
Background: Initial Reflections on the Concept
of Esophagitis
! It is worthy of note that a consideration of the role of acid in the
Although ancient physicians were well aware of the esophagus,
the flexible muscular tube hidden behind the sternum was not
given much attention by physicians in earlier times unless it be-
came obstructed by swallowed foreign objects or a food bolus.
Symptoms of pain or discomfort in the chest were considered
by practitioners to be either cardiac in origin or resulting from
the ingestion of bad food or to disordered digestion itself. The
esophagus itself was considered a mere conduit from the mouth
to the stomach and not worthy of consideration as a source of
disease or symptoms.
Historically, esophageal diseases have neither been readily re-
cognized nor easily understood. Galen, practicing in Rome in
the second century (A. C. E.) was the first to comment upon in-
flammation of the esophagus [1] but his description was in-
complete and he failed to differentiate between gastric acid re-
flux and pharyngitis. He also noted that the esophagus when
inflamed acted as a hindrance to swallowing due to the associ-
ated pain and provided a lucid description of dysphagia.
In 1792, J. P. Frank of Vienna was the first to provide an accurate
description of esophageal inflammation and define the concept
of esophagitis; however, his commentary failed to attract wide
attention. Almost three decades thereafter, J. T. Mondière in
1829, published a thesis describing his own personal experien-
ces with esophagitis and, in addition, collected much of the ex-
tant material on the subject. This work was to provide the source
for much of the literature pertaining to esophageal disease for
the next century such as Velpeau's The Esophagus – A Diction-
ary in Four Volumes, Follin's essay Considerations of Esophageal
Disease and Copland's Dictionary [1]. The first detailed clinical
description of esophagitis, however, was provided by the British
otolaryngologist, Morell Mackenzie in his text book Diseases of
the Nose and Throat, Vol. 2 in 1884. Despite being unaware of
its precise etiology, he defined esophagitis as an “acute idio-
pathic inflammation of the mucous membranes of the esopha-
gus giving rise to extreme odynophagia and often to aphagia”.
Early Pathological Observations
! Aware of the importance of separating post-mortem events
The fact that acid might play a role in irritating the esophagus
was first suggested by the eminent Viennese pathologist, C. Ro-
kitansky (1804 – 1878) who reported that peptic ulcer of the
lower esophagus represented the aftermath of the effect of gas-
tric juice on the esophagus [2]. H. Quincke of Kiel, in 1879, there-
after described erosions of the lower esophagus in three post-
mortem cases, as “ulcus oesophagi ex digestione”. He too pres-
ciently considered the lesions to reflect the digestive effects of
gastric juice [3]. The Yale and Harvard, pathologist Wilder Tiles-
ton further amplified Quincke's hypothesis and in 1906, repor-
ted that he could identify 44 cases in the entire English medical
literature. His review of the subject concluded that among at
least 12 other causes of esophageal ulceration the novel entity
of “peptic ulcer of the esophagus” required special considera-
tion. Tileston clearly considered that peptic esophagitis was a
unique pathological entity and raised the issue that there might
Malfertheiner MV et al. The Elucidation of… Z Gastroenterol 2007; 45: 1164 – 1168
Übersicht 1165
one of the most fundamental problems faced by both gastroen-
terologists and pathologists.
exist a relationship between a chronic gastric ulcer and an eso-
phageal ulcer [4].
process of esophageal irritation had been suggested as early as
1823 by William Prout of London, who was the first to demon-
strate that the human stomach contained free hydrochloric acid
(muriatic acid) [5].
These diverse reflections on esophageal ulcers and their nature
remained for the most part a source of minor interest for the
following three decades when once again the relationship be-
tween acid reflux and esophagitis became the subject of dis-
cussion. In 1934, in Vienna and New York, the term “peptic
esophagitis” was again raised as a source of debate by Herwig
Hamperl (1899 – 1978), an Austrian pathologist, who published
“Peptische Ösophagitis” [6] in Germany and Asher Winkelstein
(1893 – 1972), an American gastroenterologist, who presented
five cases of peptic esophagitis in the United States [7].
Reconciling the Transatlantic View of
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Peptic Esophagitis
!
In 1934, Hamperl was a young, aspiring Viennese pathologist
who noted that although erosive gastritis, duodenitis and jeju-
nitis were all well-described, nobody had addressed similar
findings in the esophagus. Hamperl considered that the influ-
ence of the acid on the esophagus was evident but had simply
not been considered at a pathological level. In this context, he
once again raised the initial descriptions of “intravital esopha-
gomalacia” or “ulcus ex digestione” that had been first pro-
posed by Quincke [3]. Hamperl was well aware of the two
main problems in his attempt to study the esophagus. Thus,
after death, gastric juice as a post-mortem event refluxed into
the esophagus and produced the well known picture of “Oeso-
phagomalazia acida”. This event obviated clear interpretation
of esophageal pathology and as a result, it was apparent to
him that only studies undertaken soon after death could pro-
vide any significant information. Hamperl also commented
upon the fact that once the first tissue damage had resolved
it was possible if the process was pre-mortem, to identify his-
tological criteria of tissue repair and evidence of new damage.
from pre-mortem acid reflux disease, Hamperl identified cases
which he had examined shortly post-mortem and who had a
history of pre-existing chronic symptoms. His meticulous eva-
luation describes a chemical burn-like morphology of changes
predominantly occurring in the lower half of the esophagus,
never involving the gastric cardia. The manuscript provides a
detailed description of the microscopic findings and emphasi-
zes that the stroma below the erosion was diffusely infiltrated
with neutrophilic leukocytes which are not evident below the
normal epithelia. Hamperl concluded that the accumulation of
neutrophilic leukocytes in the base of the erosion was indica-
tive of an infiltrative reaction. Concluding his findings, he sug-
gested that the anatomical disease pattern he had described
should be referred to as “peptic esophagitis” (● " Fig. 1) [6].
While Hamperl had chosen to approach the subject of peptic
esophagitis disease primarily from the pathological/micro-
1166 Übersicht
Fig. 1 Herwig Hamperl (1899 – 1978) (left), a great intellect in pathology
from Vienna, Austria, was the first to publish a manuscript on “peptic eso-
phagitis”. His understanding of the pathophysiology of the entity was
published in Verhandlungen der Deutschen Pathologischen Gesellschaft in
1934. Hamperl made his observations on autopsy preparations (right).
Fig. 2 Asher Winkelstein (1893 – 1972) (left), the Chief of Gastroenter-
ology at Mount Sinai Hospital (background) in New York, presented five
cases of a “new” clinical entity he referred to as “peptic esophagitis” in
June 1934, at the 85th Annual Session of the American Medical Association
in Cleveland. His manuscript detailing his views of the “novel” entity was
published March 16, 1935 in the Journal of the American Medical Associa-
tion (top). Winkelstein was an early proponent of both endoscopy and the
gastrocamera; devices that half a century later would provide indisputable
evidence of the validity of his prescient clinical observations (bottom
right).
scopic aspect, Winkelstein addressed the relationship of the
pathophysiology of acid and pepsin as it related to esophageal
inflammation and the symptomatology of gastric juice and
acid peptic reflux. In his initial presentation on June 13, 1934
at the 85th Annual Session of the American Medical Associa-
Malfertheiner MV et al. The Elucidation of… Z Gastroenterol 2007; 45: 1164 – 1168
tion at Cleveland, he described five patients who did not fit
into the previous classification of esophagitis as being either
“irritative” (mechanical, thermal, chemical), “specific” (syphi-
lis, tuberculosis, actinomycosis), or secondary to complica-
tions of cardiospasm, diverticula or neoplasm. His comments
presciently frame the originality of his thought; “The features
of these cases are so distinctive as to impress one with the
probability that they form a separate clinical entity” [7]. Win-
kelstein focusing on the clinical nature of the disease, had
performed both barium contrast radiology and rigid esopha-
goscopy in patients with severe chronic esophagitis in an ef-
fort to characterize the problem (● " Fig. 2). He clearly descri-
bed his esophagoscopic findings as “a diffuse inflammation
without a definite ulcer” in three cases with an associated
duodenal ulcer and noted “the type of substernal pain, heart-
burn, sour regurgitation and the hyperchlorhydria in all recall
the clinical features of peptic ulcer of the esophagus” [7]. Fi-
nally, he concluded “As a result of these observations, one
cannot avoid the suspicion that the disease in these five cases
is possibly a “peptic” esophagitis, i. e., an esophagitis resulting
from the irritant action on the mucosa of free hydrochloric
acid and pepsin” [7]. Indeed, in this novel assertion, the dis-
cussion section of the session records the eminent Philadel-
phian otolaryngologist and doyen of rigid endoscopy, Cheva-
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lier Jackson (1865–1958) rising from the audience to record
his similar observations and to agree with the young physi-
cian from New York [7]!
Primacy and peptic esophagitis
It is difficult to be certain to whom the kudos must be awarded
in terms of “peptic esophagitis”. There is no doubt that Asher
Winkelstein presented his “new entity” on June 13, 1934 at the
85th Annual Session of the American Medical Association and
published his manuscript the following year in the March edi-
tion of the Journal of the American Medical Association [7]. On
the other hand, the manuscript produced by Hamperl appeared
in print in the Verhandlungen der Deutschen Pathologischen
Gesellschaft on May 25, 1934 [6].
Although it seems likely that Hamperl may have slightly pre-
ceded Winkelstein, it is uncertain when each individual began
to investigate and define the disease process. There appears
some likelihood that Winkelstein, who was of German paren-
tage, spoke German and had studied and visited Germany,
may have derived the idea during his travels. As a student
he had himself spent time at the pathological institutes of
Vienna, Freiburg and Berlin in 1922 – 1923 and, as was the
custom of the times, visited Europe to learn of current medi-
cal progress. Hamperl had graduated from medical school in
Vienna in 1923, and subsequently worked in Freiburg (1928)
with Karl Aschoff (1866 – 1942), and in Berlin, where he held
the chair of pathology from 1935 – 1939.
Since both Winkelstein and Hamperl had each worked with lu-
minaries in the field such as Jacob Erdheim (1874 – 1937, Vien-
na), and Karl Aschoff (1866 – 1942, Freiburg), it is possible that
they had acquired the original concept from their teachers and
thereafter pursued it independently. There is certainly no evi-
dence indicating that they ever met in person or if there was
any connection in the time frame just prior to 1934. It seems
likely that both independently identified the area as important,
Hamperl from the pathological perspective and Winkelstein
from the clinical and physiological aspect. Thus, pathologists
became aware that peptic esophagitis was a disease process
 Übersicht 1167

related to acid peptic ulceration of the duodenum and stomach
and was not just a post-mortem event, while physicians be-
came aware that inflammation of the esophagus was a viable
clinical entity with specific symptomatology that needed to
be treated with acid-neutralizing agents in a similar fashion
to duodenal ulceration. From the perspective of history, one
may regard their contributions to have been co-equal in estab-
lishing the pathological and clinical basis of esophagitis and al-
lowing physicians to appreciate the existence of a specific dis-
ease process relevant to the esophagus itself.
The Hamperl-Winkelstein Quotient
!
A brief reflection of the men and the disease yields an interest-
ing perspective on the changes that time brings to both pa-
tients and physicians. While their individual contributions did
much to draw attention to the problem and the process, paral-
lel developments in biotechnology, pathophysiology and ther-
apy have contributed greatly to the advance in the strategies
necessary for the diagnosis and therapy of gastroesophageal re-
flux and the broader spectrum of acid peptic disease (● " Fig. 3).

Hamperl and Winkelstein
! of the population of some countries suffering from gastroeso-
Despite being from different countries and medical specialties,
both men shared the commonality of intellectual curiosity and
the ability to see beyond the conceptual horizons of their time.
Herwig Hamperl was born in Vienna, Austria, in 1899, studied
medicine at the University of Vienna, and based upon his novel
observations and breadth of vision, became one of the most im-
portant pathologists of his era. Indeed, his diverse contributions
played a part in substantiating the international status of Ger-
man pathology. During his long and lustrous career, he directed
the pathological institutes of the Universities of Berlin, Prague,
In the first decade of the 20th century, less than 200 instances
of peptic esophagitis were identifiable, yet a century later, the
disease is regarded as a global pandemic with as many as 25 %
phageal reflux (esophagitis) [9]. More recently, the proposed
sole role of acid and pepsin in “acid peptic disease” has dimin-
ished as the identification of Helicobacter pylori as a patho-
genic mechanism revolutionized the pathobiological considera-
tion of upper gastrointestinal mucosal erosion and ulceration
[10]. The diagnosis of GERD has advanced from the simplistic
concept of heartburn to endoscopic identification, electrophy-
siological delineation of mucosal damage and more recently,
complex, mathematically-weighted symptom scales capable of
identifying the protean manifestations of what may well be a

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Marburg and Bonn, thus indelibly leaving his mark on an entire disease with systemic manifestations [5]. Similarly, therapy
generation of German pathologists. In addition to his peripatetic has progressed from bland diets, antacids and milk drips, to
academic career, the research undertaken by Hamperl embraced histamine 2 receptor antagonists, antibiotics and more recent-
almost every subspecialty of general and special pathology in- ly, the proton pump inhibitor class of agents [5, 11].
cluding gynecological, bronchopulmonary, and gastrointestinal
pathology. His intellectual vigor is evident in the 216 self-au-
thored manuscripts and the additional co-authorship of more
than 600 publications with his students and assistants. Apart
from his prodigious scholarly productivity and his original de-
scription of peptic esophagitis, additional novel contributions
include the discovery of oncocysts (in the USA improperly refer-
red to as Hürthle cells), the establishment of fluorescent micro-
scopy, the first description of bronchopulmonary carcinoids and
his substantial contribution to the pathological delineation of
carcinoma in situ of the cervix. Given his diverse contributions,
Hamperl well deserves a place in the pantheon of pathology and
it is surprising that his substantial achievements are little recog-
nized even in his native country.
Asher Winkelstein was born in Syracuse, New York in 1893, and
spent his medical career at Mount Sinai Hospital, NYC where he
was a leader in the field of gastroenterology. His career bridged
the period where the discipline moved from a predominantly
clinical focus into a phase of scientific and investigative advance.
Winkelstein studied acid secretion, identified the clinical entity
of esophagitis and considered the role of nocturnal acid secre-
tion in the genesis of acid peptic disease. In addition, he devel-
oped the controversial “milk drip therapy” for neutralization of
the acid that caused both duodenal ulcer and peptic esophagitis.
Such was his perspicacity that in collaboration with the eminent
surgeon A. Berg (1872 – 1950), he became one of the early pio- Fig. 3 An acid wheel depicting the evolution of diagnostic and thera-
neers in the consideration of anterior vagotomy and gastroenter- peutic modalities for GERD. The outer ring depicts each of the major
methods for diagnosing GERD or its clinical sequelae ranging from endo-
ostomy as a viable surgical alternative for the management of
scopy (12 o'clock) through narrow band endoscopy. The spokes on the
intractable peptic ulcer disease [8].
right include the variety of etiologies ascribed to GERD ranging from ul-
ceration (top) to H. pylori (bottom). Therapies to treat GERD have evolved
from milk diets (bottom left) through antacids and PPIs to antibiotics
(top). The center represents the different components of gastroesopha-
geal reflux disease which includes a spectrum of interlinking entities from
heartburn to NERD.

Malfertheiner MV et al. The Elucidation of… Z Gastroenterol 2007; 45: 1164 – 1168
1168 Übersicht
Coda
! then and now. J Clin Gastroenterol 2004; 38: 390–402
Despite the substantial progress that has been made, the sub-
ject of GERD still remains in many ways, an enigma wrapped
in a paradox that resembles a biological riddle. Thus, there is
no clear explanation for the pandemic increase, the precise
pathogenesis is unknown and the relationship to irritable bo-
wel disease and non-erosive disease (NERD) is unclear, while
the specter of neoplastic transformation and Barrett's is utter-
ly unresolved. What is clear, however, is that as we stand at
the beginning of the 21st century, we should recognize the in-
itial contributions of Hamperl and Winkelstein who indepen-
dently, and yet synchronously, identified the disease of peptic
esophagitis and first placed it in the medical lexicon. Their
observations have not only stood the test of time, but illumi-
nated an area that has subsequently become one of global re-
levance for both patients and physicians.
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