Laser photoablation of Barrett's epithelium: Burning issues about burning tissues

June 1993

EDITORIALS

screening

tools for colorectal

malignancy.

It is neces-

sary to determine

specificities

under

conditions

than

the optimized

rather

under

actual

stances of a research study. Of great interest, ple, will be the performance of HemeSelect taking

NSAIDs

HemeSelect “field”

and eating

and

HemoccultSENSA

conditions

the positive

circumfor examin subjects

red meat. Determination

will enable

predicitivity

specificity

realistic

of each

of under

calculation

test for colorectal

The

evidence

that

HemeSelect

will be useful screening

and

tection

is less

convincing.

Should

shown

to have

appropriate

sensitivity

for reliably

detecting

adenomas,

the situation

subjects

The larger question population

above

to a worthwhile

with

could

reduction

8. be

screening

in mortality

will lead

from colorectal

be seen. colleagues

the advocates

of FOBTs

At the very least, however, have

reinvigorated

St. John

the debate

capture the attention of skeptics these issues are settled.

has yet to

and

11.

13.

until 14.

PETER LANCE, PVI.B.,F.R.C.P. GastrointestinalDivision Department of Medicine State Universit_y of New York at Buffalo Buffalo, New York

Readability and sensitivity of a new faecal occult blood test in a hospital ward environment. Med J Aust 1992; 156:420-423. Schwartz S, Dahl J, Ellefson M, Ahlquist DA. The “HemoQuant” test: a specific and quantitative determination of heme (hemoglobin) in feces and other materials. Clin Chem 1983;29:2061-

2067. 12. Ransohoff DF, Lang CA. Small adenomas detected during fecal

and his

and should

nihilists

S, Watt G, Schuman LM, Ederer F, Gilbertsen V. Sensitivity, specificity, and positive predictivity of the Hemoccult test in screening for colorectal cancers. Gastroenterology 1989;97:597-600. Morrison AS. Screening in chronic disease. New York: Oxford Unlversity, 1985. Allison JE, Feldman R, Tekawa IS. Hemoccult screening in detecting colorectal neoplasm: sensitivity, specificity, and predictive value. Ann Intern Med 1990; 1 12328-333. Ransohoff DF, Lang CA. Current concepts: screening for colorectal cancer. N Engl J Med 1991;325:37-41. Selby JV. Friedman GD, Quesenberry CP, Jr., Weiss NS. Effect of fecal occult blood testing on mortality from colorectal cancer. Ann Intern Med 1993; 1 18: l-6. St John JB, Young GP, Alexeyeff MA, Deacon MC, Cuthbertson AM, Macrae FA, Penfold JCB. Evaluation of new occult blood tests for detection of colorectal neoplasla. Gastroenterology

1993;104:1661-1668. 10. Petty MT, Deacon MC, Alexeyeff MA, St. JohnDJB, Young GP.

the entire

FOBTs

cancer is unresolved. Whether or not the introduction of HemeSelect, HemoccultSENSA, and other new tests will vindicate

9.

and specificity

large but not small

age with

6.

de-

change.

of whether

a certain

HemeSelect

5.

7.

Hemoccult-

tools for adenoma

Dis 1992;3:22-32.

4. Mandel JS, Bond JH, Bradley M, Snover DC, Church TR, Williams

of

cancer. SENSA

3. Lance P, Grossman S, Marshall JR. Screening for colorectal cancer. Sem Gastrointest

screening

1855

15.

occult blood test screening for colorectal cancer. The impact of serendipity. JAMA 1990;264:76-78. Macrae FA, St. John DJB. Relationship between patterns of bleeding and Hemoccult sensitivity In patients with colorectal cancers or adenomas. Gastroenterology. 1982;82:89 l-898. Burton RM, Landreth KS, Barrows GH, Jarrett DD. Sangster CL. Appearance, properties, and origin of altered human hemoglobin in feces. Lab Invest 1976;35: 11 I- 1 15. Young GP, St. JohnDJB. Selecting an occult blood test for use as a screening tool for large bowel cancer. In: Rozen P, Reich CB, Winawer SJ, eds. Frontiers of gastrointestinal research. Advances in large bowel cancer: policy, prevention, research and treatment. Basel, Switzerland: Karger, 199 1: 135- 156.

References 1. Levin B, Murphy GP. Revision in American Cancer Society recommendatlons for the early detectlon of colorectal cancer. CA 1992;42:296-299. 2. Simon JB. Occult blood screening for colorectal cancer: a critical review. Gastroenterology 1985;88:820-837.

Address

requests

for reprints to: Peter Lance, M.B., GI Section Administration Medical Center, 3495 Bailey AveNew York 14215. by the American Gastroenterological Association

(11 lG), Veterans nue, Buffalo, 0 1993

Laser Photoablation of Barrett’s Epithelium: Burning Issues About Burning Tissues

I

n this issue of GASTROENTEROLOGY, an exciting report by Berenson et al. on a novel treatment for Barrett’s epithelium raises important issues about the pathogenesis and management of epithelial metaplasia in the esophagus. ’ Metaplasia is the process whereby one kind of fully differentiated (adult) cell replaces another kind of fully differentiated cell.* In most cases,

metaplasia results when tissue is exposed chronically to noxious substances that injure mature cells while promoting the aberrant differentiation of immature, proliferating cells. 3 The resulting metaplastic cells often are more resistant to injury by the offending substances than are the native cells, and therefore metaplasia has been viewed teleologically as an attempt to

1856

EDITORIALS

GASTROENTEROLOGY

protect

vulnerable

ment.2

In a number

also a risk factor

tissues

from

of tissues,

for cancer

a hostile

however,

squamous

umnar sia

mucosa

epithelium.

replaces

seen

as

of columnar

tract, the uterine

cervix,

a response

glands.

mon

epithelial

pattern,

ment

however,

(Barrett’s

of damaged

thelium.4

esophagus)

squamous

mucosa

For most patients

chronic

gastroesophageal

with reflux

jures the squamous

cells and promotes

through

metaplasia.

columnar

Although

Barrett’s

epithelium

tant to reflux-induced geal squamous esophagus

it is not clear that this

nant

epi-

esophagus,

the native metaplasia

is a risk factor for malignancy.4

mucosa,

l5 Nevertheless,

of squamous

predisposition can

the

completely

complete

of

however,

esophagus, by medical

is eliminated

means. ‘~3Indeed,

recent

repair

esophageal

columnar

metaplasia

full extent

relatively

quickly,

progressing

over the years irrespective

Cancers

de-

retinoic the

acid, an agent

regression

usually

precancerous

that

develops

to its

regressing

nor

of the status of

Treatment

that has been

of certain

data suggest

neither

reflux disease.”

and rarely

Barrett’s

reflux esophagitis

the underlying

ther-

therapy

or surgical

resis-

epithe-

antireflux

even when

esophain the

an-

metaplastic

that Barrett’s with

regression

docu-

affects the malig-

apy. 16,i7These reports are unconvincing, most studies suggest that antireflux causes

well

underlying

have alleged

regress

been

epithelium

of

tissue. Some reports lium

has

in-

that

mucosal

metaplastic

overgrowth

in the

may be more

injury than mucosa, columnar

therapy.

by columnar

Barrett’s

over

tireflux

the replace-

is the factor

to grow

and after medical

chronic

metaplasia

appears

after fundoplication’3~‘4

to this com-

involves

epithelium

Partial

a superficial

residual

and the excre-

Contrary

wherein

mented

in the respiratory

the gallbladder,

of squamous

surveillance.

mucosa,

col-

metaplato

for endoscopic

of Barrett’s

No. 6

strat-

inflamed,

squamous

epithelia

tory ducts of the salivary esophagus

metaplasia,

the need

regression layer

an

‘s3 For example,

is commonly

inflammation

obviate is

development.

In most tissues that show epithelial ified

environ-

metaplasia

Vol. 104,

with 13-cis-

shown

to cause

epithelial

le-

velop in Barrett’s esophagus at the rate of approximately 1 case per 125 patient-years, a rate more than

sions (e.g., oral leukoplakia), has also failed to induce the regression of Barrett’s epithelium.*’ Furthermore,

40-fold

no treatment for Barrett’s esophagus has been shown to affect the rate of malignant transformation. Cancers

higher

than that for the general

the United States.5 Barrett’s epithelium sequence

of genetic

population

As in other tissues, cancers are thought to evolve through alterations

that activate

of in a

proto-on-

cogenes

and disable tumor-suppressor genes in the become so metaplastic cells. 6*7Before these alterations advanced as to enable the cells to invade adjacent tissues and to proliferate in unnatural locations, the DNA

abnormalities

changes recognizable dysplasia. Dysplasia neoplastic alteration

often

cause

morphological

on histological examination as in Barrett’s mucosa represents a of columnar cells and is widely

have developed

in Barrett’s

epithelium

even after an-

tireflux surgery that successfully controlled toms and signs of gastroesophageal reflux Antireflux

therapy,

no matter

ling reflux esophagitis, regular

endoscopic

how effective

all sympdisease.14 in control-

does not eliminate the need for surveillance in patients with

Barrett’s esophagus. Now, Berenson et al. describe the results of a novel therapeutic attack on Barrett’s esophagus.’ They used laser irradiation

to obliterate

the metaplastic

columnar

regarded as the precursor of invasive malignancy.* Regular endoscopic surveillance has been recommended

epithelium while administering omeprazole to inhibit gastric acid secretion. With no acid reflux to stimulate

to detect

metaplastic

dysplasia

in the columnar-lined

esophagus,

repair,

the damaged

esopha-

heal normally,

i.e., by regeneration

with the assumption that resection of the dysplastic tissue will halt the progression to malignancy.9,‘0 Al-

geal tissue

though regular endoscopic surveillance is widely accepted as the standard of care for patients with columnar metaplasia of the esophagus, there is no proof that this costly practice reduces the mortality rate caused by esophageal cancer.

men with longstanding Barrett’s esophagus. During l-8 segments of Barrett’s endoscopic examinations, epithelium with areas ranging from 0.25 cm* to 4.00 cm* were irradiated using an argon laser until the treated segments turned white. Endoscopic examinations were repeated at intervals of 2-5 weeks to assess the results of therapy and to repeat the photoablation of persistent segments of columnar epithelium. Omeprazole therapy (40 mg each day) was begun 2 weeks before the first laser treatment and was continued for the duration of the study (6-38 weeks). The success of

Metaplasia is widely regarded as a reversible process, and certain medical treatments have been shown to cause regression of squamous metaplasia in some tissues. l’,‘* Conceivably, a treatment that could effect the regression of columnar metaplasia in the esophagus might decrease the risk of cancer development and

of squamous

should

they reasoned,

mucosa.

This hypothesis

was tested in 10

EDITORIALS

June 1993

photoablation

was judged by endoscopic

and histologi-

cal criteria. In 38 of 40 laser-treated cosa completely Barrett’s had

each treated Barrett’s

epithelium

mucosa.

mous

mucosa)

only

after

multiple

by the regrowth

segments

regrowth

transient

pain

complications

of squamous in the retrosternal

by

healed In

epitheonly

Except

for

were no

shows that squamous

photoablated

segments

mucosa

of Barrett’s

can

with

Even

laser

if one

it is feasible

what

mucosa?

Presumably,

life-long

therapy

of Barrett’s

with an Nd/YAG

photoablation

of Barrett’s

finding that irradiated lium with no squamous tion

of squamous

mucosa

harbors

into squamous summary, Barrett’s tion. Despite sues must Barrett’s

esophagus.2’~22

epithelium

the

cells when

suggests

that

Barrett’s

cells that can differentiate acid reflux

this study strongly

results

be resolved

before

is controlled.

supports

is a reversible,

the exciting esophagus

Also,

segments of Barrett’s epitheborders can heal by regenera-

progenitor

esophagus

on laser

the notion

metaplastic

of this study, laser

condi-

several

photoablation

can be recommended

In that

isof

for clinical

application. First, is it feasible to obliterate all of the Barrett’s epithelium in a given patient? The investigators found that multiple laser sessions often were re-

of Barrett’s

epi-

leap

of faith

and

the metaplastic

epi-

the regrowth would

antisecretory acid

agents

reflux

to reappear.

preventing

that

The

is debated,23

of

require like

might

safety of

and the efficacy

the

recurrence

of

Barrett’s esophagus remains to be established. Brandt and Kauvar recently described the results of laser pho-

the conclusions

case reports

therapy for

in

patients

the

epithelium

treatment

of might

transformation

prevent

with potent

such protracted

with

recent

will

to eliminate

Barrett’s

when gastric acid secretion is suppressed by the chronic administration of omeprazole. This confirms of two

a substantial to obliterate

entirely,

omeprazole

devel-

proliferation

obliteration

thelium

of this

of Barrett’s

increased

Barrett’s

toablation

epithelium

takes

assumes

cause

this study has

by the laser wound

incomplete

with

area, there

the

induced

patients

of the laser treatments.

This study clearly replace

mucosa.

cells

thelium.

mucosa.

healed

Conceivably,

of col-

only

of Barrett’s

Indeed,

has any effect on the risk for cancer

metaplastic

all

leave the patient

photoablation

by squa-

borders)

borders

laser

to obliterate

might

the risk for malignant

applications,

of squamous

that had no squamous

partial

laser

epithelium

that

of the irra-

Failure

even increase

one

surrounded

re-epithelialization

epithelium

established

opment. of

squa-

islands

only

(no squamous

most cases, the irradiated lium

after

segments

epithelium

which

with

surrounded

disappeared

whereas

completely

two small

(completely

squamous

of the metaplastic not

on 1-6 occasions.

that were contiguous

1 of 9 irradiated

columnar

during

that

tissue was only partial.

still at high risk for malignancy.

patients

was best in segments

For example,

metaplasia

mu-

the photoablated

these results,

was irradiated

to laser therapy

umnar

squamous

examinations,

segment

treatment,

replaced

To achieve

endoscopic

The response mous

or partially

epithelium.

3-12

segments,

found diated

1857

longstanding

Barrett’s

scopic examination tological low-up

esophagus.*’

performed

signs of Barrett’s endoscopic

have been

epithelium.

insufficient

An

endo-

no endoscopic

or his-

However,

at 14 weeks

had returned

with omeprazole argue that this

in this patient.

man

6 weeks after treatment

examination epithelium

treatment One can

might tion

in a 43-year-old

laser revealed

that the Barrett’s going daily.

mucosa

a folshowed

despite

on-

in a dose of 20 mg dose of omeprazole

to eliminate

Nevertheless,

acid secre-

the report

suggests

that columnar metaplasia in the esophagus is both reversible and revertible. Clearly, even patients treated successfully with laser photoablation quire regular endoscopic surveillance the

metaplastic

epithelium

monitor for neoplasia. Presently, to recommend

has not laser

therapy will reto ensure that returned photoablation

and

to of

quired to ablate small segments of metaplastic mucosa. How many sessions would be necessary to treat an

Barrett’s epithelium for clinical purposes is to endorse an expensive, time-consuming, and potentially hazardous therapy that might not obliterate all of the meta-

esophagus

plastic

extensively

involved

by Barrett’s

epithe-

lium? Even for patients with limited involvement, how far distally should the laser treatment be applied? Barrett’s mucosa in the distal esophagus merges imperceptibly with the columnar lining of the stomach, and the endoscopist has no clear landmarks to delimit Barrett’s and gastric mucosae. For more than one-third of laser-treated segments, furthermore, this study

mucosa,

that has no shown

efficacy in reducing

cancer risk, that will likely require antisecretory drugs administered life-long in high doses, that might produce only temporary results, and that does not obviate the need for regular endoscopic surveillance. These considerations must temper enthusiasm for the wholesale application of this technique in clinical practice. Nevertheless, this is an exciting area for research. Care-

1858

EDITORIALS

GASTROENTEROLOGY Vol. 104, No. 6

fully controlled,

long-term

tion of Barrett’s

esophagus

the

aforementioned

shed

on these

light to burn

on laser photoabla-

considerations.

burning diseased

studies

are sorely needed issues

before

Light

to address must

shedding

be laser

tissues.

STUART JON SPECHLER, M.D. Department of Medicine Beth Israel Hospital and Harvard Medical School Boston, Massachusetts

References 1. Berenson MM, Johnson TD, Markowitz NR, Buchi KN, Samowrtz WS. Restoration of squamous mucosa after ablation of Barrett’s esophageal epithelium. Gastroenterology 1993; 104: 16861691. 2. Robbins SL, Kumar V. Basic pathology. Fourth ed. Philadelphia: Saunders, 1987:184-185. 3. Madri JA. Inflammation and healing. In: Kissane JM, ed. Anderson’s pathology. Volume 1.9th ed. St. Louis: Mosby, 1990:67110. 4. Spechler SJ, Goyal RK. Barrett’s esophagus. N Engl J Med

1986;315:362-371. 5. Spechler SJ. The frequency of esophageal cancer in patients with Barrett’s esophagus. Acta Endoscopica 1993 (in press). 6. Jankowski J, Coghill G, Hopwood D, Wormsley KG. Oncogenes and onto-suppressor gene In adenocarcinoma of the oesophagus. Gut 1992;33: 1033- 1038. 7. Blount PL, Ramei S, Raskind WH, Haggitt RC, Sanchez CA, Dean PJ, Rabinovitch PS, Reid BJ. 17p allelic deletions and p53 protein overexpression in Barrett’s adenocarcinomas. Cancer Res

1991;51:5482-5486. 8. Schmidt HG, Riddell RH, Walther B, Skinner DB, Riemann JF. Dysplasia in Barrett’s esophagus. J Cancer Res Clin Oncol

1985;110:145-152. 9. Spechler SJ. Endoscopic surveillance for patients wrth Barrett’s esophagus: does the cancer risk justify the practice? Ann Intern Med 1987; 106:902-904. 10. The role of endoscopy in the surveillance of premalignant conditions of the upper gastrointestinal tract. Guidelines for clinical application. Gastrointest Endosc 1988;34: 18S-20s. 11. Misset JL, Mathe G, Santelli G, Gouveia J, Homasson JP, Sudre MC, Gaget H. Regression of bronchial epidermoid metaplasia in heavy smokers with etretinate treatment. Cancer Detect Prev

1986;9:167-170.

Differences

C

12. Heimburger DC, Alexander B, Btrch R, Butterworth CE, Bailey WC, Krumdieck CL. Improvement in bronchial squamous metaplasia In smokers treated with folate and vitamin B,, Report of a preliminary randomized, double-blind intervention trial. JAMA 1988; 259: 1525- 1530. 13. Skinner DB, Walther BC, Riddell RH, Schmidt H, lascone C, DeMeester TR. Barrett’s esophagus. Comparison of benign and malignant cases. Ann Surg 1983; 198:554-565. 14. Williamson WA, Ellis FH Jr, Gibb SP, Shahian DM, Aretz HT. Effect of antireflux operation on Barrett’s mucosa. Ann Thorac Surg 1990;49:537-542. 15. Sampliner RE, Steinbronn K, Garewal HS, Riddell RH. Squamous mucosa overlying columnar epithelium in Barrett’s esophagus in the absence of anti-reflux surgery. Am J Gastroenterol 1988;83:5 10-5 12. 16. Brand DL, Ylvisaker JT, Gelfand M, Pope CE. Regression of columnar esophageal (Barrett’s) epithelium after anti-reflux surgery. N Engl J Med 1980;302:844-848. 17. Deviere J, Buset M, Dumonceau JM, Rickaert F, Cremer M. Regression of Barrett’s epithelium with omeprazole. N Engl J Med 1989;320: l497- 1498. 18. Sampliner RE, Garewal HS, Fennerty MB, Aickin M. Lack of rmpact of therapy on extent of Barrett’s esophagus in 67 patients. Dig Dis Sci 1990;35:93-96. 19. Cameron AJ, Lomboy CT. Barrett’s esophagus: age, prevalence, and extent of columnar epithelium. Gastroenterology 1992; 103:1241-1245. 20. Fennerty B, Sampliner R, Garewal H. Esophageal ulceration associated with 13.cis retinoic-acid therapy in patients with Barrett’s esophagus. Gastrointest Endosc 1989;35:442-443. 21. Brandt LJ, Kauvar DR. Laser-induced transient regression of Barrett’s epithelium. Gastrointest Endosc 1992;38:6 19-622. 22. Sampliner RE, Hixson l-J, Fennerty B, Garewal HS. Regression of Barrett’s esophagus by laser ablation in an anacid environment. Dig Dis Sci 1993;38:365-368. 23. Spechler SJ and the Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. N Engl J Med 1992;326:786-792.

Address requests for reprints to: Stuart Jon Spechler, M.D., Director, Treatment and Research Center for Swallowing and Motility Disorders, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215. 0 1993 by the American Gastroenterological Association

in Amino Acid Kinetics in Cirrhosis

irrhosis is considered a catabolic disease associated with protein calorie malnutrition and abnormalities in amino acid metabolism.’ The most conspicuous of these abnormalities is an altered plasma amino acid profile’ that is characterized by an increase in the levels of aromatic amino acids (phenylalanine and tyrosine), tryptophan, and methionine but a decrease in the levels of three branched-chain amino acids (BCAA: leucine, isoleucine, and valine). This

amino

acid profile

occurs pari passu with a high preva-

lence of malnutrition and abnormalities in protein metabolism,‘,3 which unfortunately remain much discussed but poorly defined areas of clinical investigation. Early interest in these associations occurred because certain studies proposed a benefit of diet in the prevention and treatment of liver disease.4,5 More recently, these associations attracted particular interest because of the false neurotransmitter hypothesis of he-