Sorbitol clearance: Shift from flow-limitation in controls to enzyme-flow dependence in cirrhosis

CORRESPONDENCE

April

1989

level

of ANF could

effective

In contrast results

be detected,

intravascular

probably

due

of Klepetko

that the plasma

ANF levels

and

coworkers.

in vascularly

our

decom-

pensated disease.

liver cirrhosis do not appear They depend upon the actual

to be characteristic of the intravascular volume and

changes

in its plasma

appear

phenomenon. Cirrhotic group

Therefore, with

this

respect:

“overflow” ments sent,

concentrations

patients in

concept

in water in their

to be a secondary

it can be both enhanced ascites

form,

the

exclusive

sodium

“underfilling”

extremes

nor

they

of a common

the

pathophysiolog-

exclusive.

Federal

Klepetko

Hungary of Pediatrics of Essen Republic

W. Miiller

rate

of Germany

Ch, Hartter

E. et al. Plasma

atria1 natri-

with ascites. Effect of peritoGastroenterology 1988;95:

764-70.

Tulassay Z, Tulassay T. Rascher W. Atria1 natriuretic peptide in the sodium retention of cirrhotic patients (abstr). Gastroen-

amount

We thank

Drs. Tulassay

and Dr. Rascher

for their

com-

rise

in ANF

of sodium

levels

after

excretion,

shunting,

we agree

irrespective

revealed

venous

First, without

blood

the any

sampling

measurements in an artery (Ci) and a constant i.v. infusion (Inf) of a substance

measure,

on the other

hand.

HC =

Q

(1

_

e

besides

requiring

t\‘,n.i\ h,,,l u,,

(11

elimination rate and K, is the halfwhere V,,,,, is the maximal saturation concentration. The term V,,,,,,:K,,, is the so-called intrinsic hepatic clearance (HC,,,,) [Equation (2)). which was also calculated by Zeeh et al. (11 according to References 2 and 3 as

that

ANF

groups

of cirrhotic

mean

patients

ANF levels

with

and

production

to be significantly

pared with normal controls. However, there impaired ANF secretion in our patients.

without higher

in

ascites when

(1) com-

was no evidence

of

CHKISTIAN MULLER. M.D. ITALTER

KLEPETKO.

ENGELBERT

Departments

M.D

HARTTER,

M.D.. Ph.D. of Gastroenterology.

Hepatology,

ln[l

- (A ~ V)/A].

Surgery.

and Medicine L’niversity of Vienna L’ienna. Austria

Hartter E. Pidlich J. Klepetko W. et al. Plasma levels of human ANF in liver cirrhosis are sensitive to volume expansion by infusion and peritoneovenous shunt. In: Brenner B, Laragh J. eds. Advances in atria1 peptide research. American Society of Hypertension Symposium Series, Volume 2. New York: Raven, 1988:422-7.

(21

where A and V are the sorbitol concentrations in peripheral blood and hepatic venous blood, respectively. The approximation of HC to Q is given by Equation (1) as HC,Q

zz

1

_

e

~~%L!,

(3)

of the

these patients is secondary to the actual vascular filling. Furthermore, an additional investigation of plasma ANF levels in different

are necessary. be measured

hepatic

misunder-

in hepatology.

1987:92:1675.

ments. In contrast to their findings, all of our cirrhotic patients with therapy-resistant ascites showed plasma ANF levels either within the normal range or above it. As all of our patients had a uniform

concepts

but requiring

from blood concentration hepatic vein (Co] during

HC,,,, = -Q. Reply.

measurements

(Q) can

concentration

To avoid

negligible extrahepatic elimination (or accounting for it] requires first-order kinetics and flow-limited elimination. Comparison of the systemic sorbitol clearance (InfiA) with the hepatic clearance [Q(A - V)/A] from Equation (1) below indicates that there may be some extrahepatic, extrarenal elimination (Inf being corrected for urinary excretion) in cirrhotic patients. More important is the question of whether the conditions for flow-limitation are fulfilled. If we assume negligible extrahepatic, extrarenal sorbitol elimination, systemic clearance = hepatic clearance (HC):

of Medicine and Pediatrics L7niversit.y Medical School

uretic factor in cirrhotic patients neovenous shunt implantation.

terology

assumptions,

flow

blood

with no extrahepatic elimination, as Q = Infi(Ci - Co]. Indocyanine green is the classic test substance in this context.

W. RASCHER

Lrniversity

on the basic

blood

venous

model-dependent,

in the use of clearance

The clearance

Departments Semmelweis

on hepatic

it is highly

comments

splanchnic model

may occur simultaneously or decompensated liver cirrhosis

T. TULASSAY

and Department

is not performed

standings some

may repre-

Z. TlILASSAY

Budapest,

Zeeh et al. (l] propose the use of systemic sorbitol clearance as a noninvasive measure of liver blood flow rate. As this clearance measurements,

for all derange-

Rather,

Dear Sir:

measure

a homogeneous

explanation

regulation.

ical process. Parts of the concepts even sequentially in patients with and may not be mutually

and depressed.

did not represent

neither

gives

and

pure

Sorbitol Clearance: Shift From Flow-Limitation in Controls to Enzyme-Flow Dependence in Cirrhosis

to an increased

volume.

to the conclusion

suggest

1227

It is seen that in order to obtain 90% approximation of HC to Q. HC,,,,IQ must be >2.3. In this case Equation (21 reduces to (3) Flow-limited

HC > 0.90

Q.

(4)

This requirement is fulfilled in the controls in Reference 1 (Table 4), with the ratio ranging from 2.3 to 5.1 (mean, 3.6). However. in the patients with liver cirrhosis. HC,,,/Q ranges from 0.10 to 0.95 (mean. 0.50). Thus, the approximation of HC to Q is poor. Cirrhosis may reduce the function of the liver cells (V,,,) so much that the liver is unable to eliminate the amount of sorbitol offered by the blood flow. Thus, the flow rate cannot be determined for the elimination rate. On the other hand, V,,, is not reduced so much that it becomes rate-limiting. To obtain a 90% approximation of HC to Q (enzyme-limited clearance), HCi,,,/Q must be
1228

patients capacity.

CORRESPONDENCE

GASTROENTEROLOGY

with liver impairment

with a smaller

cellular

elimination

SUSANNE KEIDING

Medical Department Rigshospitalet DK-2100 Copenhagen Denmark

A

Vol. 96, No. 4

Considering the complexities and variabilities of the architecture of the cirrhotic liver, many other models should also be explored. In particular, capillarization of sinusoids should be incorporated, variations in length of sinusoids, etc. Presumably, neither of these two models gives justice to the reality of the liver in cirrhosis. Nevertheless, misunderstandings derived from the use of only a single model should also be avoided. J. BIRCHER. M.D.

Zeeh J, Lange H, Bosch J, et al. Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterology 1988;95:749-59. Bass L, Winkler K. A method of determining intrinsic hepatic clearance from the first-pass effect. Clin Exp Pharmacol Physiol 1980;7:339-43. Keiding S. Hepatic clearance and liver blood flow. J Hepatol 1987;4:393-8. Winkler K, Bass L, Keiding S, Tygstrup N. Physiologic basis of clearance measurements in hepatology. Stand J Gastroenterol 1979;14:439-48. Reply. We are grateful to Susanne Keiding for clarifying in her letter some concepts that underlie noninvasive measurements of liver blood flow bv clearance techniaues. A shift from flow limitation in controls to mixed enzyme flow dependence in cirrhosis, however, is only one interpretation for our findings among several others which-at this stage-appear to be at least equally valid and worthy of consideration. The kinetic explanation offered by Susanne Keiding for our findings is implicitly based on the so-called sinusoidal model of hepatic perfusion (Bass et al., J Ther Biol 1976;61:393). It assumes that between the vascular inflow and outflow tracts of the liver there is a series of parallel tubes through which the blood flows. If a test compound is eliminated from the sinusoids by first-order kinetics, the plasma concentrations fall along the length of the sinusoids in an exponential manner. On the basis of these conditions her mathematical expressions are correct. I concur that the above concepts may satisfactorily approximate the conditions in the normal liver, but they overlook the development of intrahepatic portal-venous shunting, which is one of the well-established vascular consequences of cirrhosis. In a “dual flow” model that incorporates portal-systemic shunting, the cirrhotic liver might be viewed as an organ composed of two types of vascular channels. e.g.. relatively “normal” sinusoids within the regenerative nodules and intrahepatic portal-venous shunts between the nodules. Thus, a difference between total flow through the liver (as measured with Bradleys infusion and extraction technique] and flow through regenerative nodules-the socalled “parenchymal flow”-would be expected and could be regarded as a measure of the intrahepatic portal-venous shunt flow. Assuming this model. and accepting what we have learned about sorbitol, the nonrenal sorbitol clearance as described by Zeeh et al. most likely represents a measure of parenchymal liver plasma flow. Furthermore, parenchymal flow, as defined above, would be physiologically meaningful because all other test compounds with a similarly high hepatic extraction or intrinsic clearance would be subject to the same clearance regime by the same liver. In contrast to the concepts explained by Susanne Keiding, the dual-flow model assumes flow limitation and not a mixed type of enzyme-flow dependence. The latter is only apparent because hepatic venous blood is viewed as a mixture of blood coming from both sinusoids and shunts. The lower intrinsic clearance in these instances results from a decrease in the mass of hepatocytes and is not incompatible with the conclusion because the galactose elimination capacity or the aminopyrine breath test exhibits the corresponding reductions

Ceorg-August Universitiit Gettingen Zentrem Pharmakologie und Toxikologie Robert-Koch-Strasse 40 Federal Republic of Germany D-3400 Gdttingen.

Campylobacter pylori and Symptoms: There a Cause and Effect Relationship?

Is

Dear Sir: Citing data from three recent trials (l-3) and one uncontrolled study (4) Doctor De Wal concluded in his letter (5) that Campylobatter pylori, when present, is responsible for the symptoms of nonulcer dyspepsia (NUD). Although there appears to be little doubt that C. pylori is a major cause of chronic gastritis, the question of its role in NUD is far from clear when the literature is critically reviewed (6,7). Five double-blind placebo-controlled trials of bismuth have been reported to date (l-3,8,9). One study failed to demonstrate a statistically significant association be(8). The other four trials tween C. pylori clearance and symptoms described a statistically significant trend toward symptom improvement after clearance of the bacteria (1,3]. but two of these studies randomized only C. pylori-positive patients (12). which makes interpretation of their results difficult. It is important to note that the absolute symptom improvement in all these studies was small, there was a pronounced placebo response, and the blinding of investigators was not ideal as bismuth, unlike placebo, causes a black tongue and black stools. Even more critically. the measurement of symptoms may not have been adequate as none of the studies assessed the reliability and validity of their symptomscoring approaches. Other data indicate that C. pylori may have little role in NUD. Symptoms in C. pylori-positive and C. pyfori-negative patients with NUD appear to be little different, with the exception of heartburn (10). There is also no doubt that C. pylori-associated gastritis is very common in asymptomatic, otherwise healthy persons (11). Overall, the studies suggest that a healthy skepticism regarding the pathogenic importance of C. pylori in NUD is warranted. Moreover, even if C. pylori is a major cause of NUD, bismuth therapy alone is unlikely to be of benefit as recrudesence of infection within a month of cessation of treatment is the rule (7,121. NICHOLAS J. TALLEY. MB., B.S.. Ph.D.

Division of Gastroenterology Mayo Clinic Rochester. Minnesota 55905 Borody T. Hennessy W, Daskalopoulas G, Carrick J, Hazel1 S. Double-blind trial of De-No1 in non-ulcer dyspepsia associated with Campylobacter pyloridis gastritis (abstr). Gastroenterology 1987:92:1324. Lambert JR, Borromeo M, Korman MG. Hansky J. Role of Campylobacter pyloridis in non-ulcer dyspepsia-a randomized controlled trial (abstr). Gastroenterology 1987;92:1488. Rokkas T. Pursey C. Simmons NA, Filipe MI, Sladen GE.