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Liver Function and Hypertension

Blood Pressure and Heart Weight in Chronic Hepatitis


By FLEMMING RAASCHOU, M.D.
The purpose of the present work was to study the incidence of arterial hypertension in a series of
autopsied cases of chronic hepatitis. The frequency of patients with hypertension, examined accord-
ing to three criteria (cerebral hemorrhage, hypertrophy of the heart, and incidence of hypertension
as determined by actual measurements of blood pressure during life), is essentially lower in an
autopsy series consisting of women who died of or with subchronic hepatitis than in a control series
of autopsied female patients with the same age distribution who died of all other diseases.

HAUFFARD,7 in 1892, was the first topsied cases. During the period of this inves-
to point out that most icteric pa- tigation (January 1944, to January 1948) there
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tients have a low blood pressure. occurred in Denmark an epidemic of hepatitis


About 1900, Gilbert and Garnier1' stressed during which numerous patients died. The
low blood pressure as a characteristic feature livers of these patients showed the gross and
of cirrhosis of the liver. In 1937 Loeper'7 and microscopic characteristics of subchronic atro-
in 1949 Spatt and Rosenblatt28 made the same phy of the liver.'-4 14 With but few exceptions
observation. In 1930, Geill1'0 found strikingly the patients who died were women over 45
low blood pressure values in acute, infectious years of age. Death occurred, on the average,
hepatitis. Meakins,'s in 1932, was the first to 8.2 months after the appearance of the first
show that the blood pressure in patients with symptom4 and was the result of severe, chronic
arterial hypertension may show a pronounced hepatitis with ascites, edema, jaundice, hemor-
fall when these patients develop acute, infec- rhagic diathesis and, at last, hepatic insuffi-
tious hepatitis, and that this low blood pres- ciency with hepatic coma. In this large group
sure may persist for a prolonged period after of women, the great majority of whom had
the jaundice has subsided. In normotensive reached an age at which essential hypertension
patients, too, there seems to be a tendency to- is very frequent, the incidence of hypertension
ward a lower blood pressure when they are was amazingly low. It occurred to me, there-
attacked by acute hepatitis, a finding made fore, that in some way the severe hepatic dis-
by Selander24 in 1939 in a large series of pa- order either prevented the development of
tients with hepatitis. hypertension in patients who were to be ex-
The purpose of the present work was to pected to be hypertensive or caused an already
study the incidence of arterial hypertension developed hypertension to subside again.
in a series of autopsied cases of chronic hepa-
titis. As a result of this study the hypothesis MATERIAL
is put forward that a severely damaged liver This comprises a series of cases of hepatitis and a
function prevents the development of hyper- control series. In the course of the period mentioned
tension in man. in the preceding paragraph, 108 patients with sub-
In a previous study21 the etiologic rela- chronic atrophy of the liver were autopsied in
tionship of obstruction of the urinary tract Kommunehospitalet, Copenhagen; 102 were women.
Since so few males died of this disease, only the series
(hydronephrosis) to the development of hy- of women has been analyzed. The age incidence in
pertension was investigated in a series of au- the female patients is shown in figure 1: the curve
rises abruptly after the forty-fifth year, the summit
From Department III, Kommunehospitalet, Copen- occurring between 65 to 75 years. The control series
hagen, Chief: Senior Physician Poul Iversen, M.D. comprises 93 unselected women over 45 years of age
and from the Institute of Pathology of Kommune- who died during the same period and came to
hospitalet. Chief: Svend Petri, Prosector, M.D. necropsy. The patients of this series died of many
511 Circulation, Volume X, October, 1954
512 LIVER FUNCTION AND

-~ /y.
HYPERTENSION

cZ
I0
20
chron/c(women)
hepa[/'f//

(W/7e
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50 60 70 80 9q0 years 30 0 5O 60 70 80so qo0 ears


A B
FIG. 1. Subchronic atrophy of the liver and control material. Age distribution.
diseases, but none of them had subchronic atrophy mined by the Finding of Hypertrophy of the
of the liver; patients with hypertrophy of the heart Heart at Necropsy. Hearts weighing more than
considered to have been caused by affections other 400 Gm. were considered to be hypertrophied.
than essential hypertension (e.g., valvular heart dis-
ease, chronic glomerulonephritis, chronic cor pul- Figure 2 shows the distribution of heart
monale, pheochromocytoma) were retained in both weights in 95 female patients with subchronic
series. The age incidence in the control series corre- atrophy of the liver and in 93 women over 45
sponds fairly well with that of the series of cases of years in the control series. Five out of 95
hepatitis (fig. 1). women (5.3 per cent) with subchronic atrophy
The incidence of hypertension was examined in
the two series, and the following three criteria were of the liver had hearts which weighed more
used in determining the presence or absence of hyper- than 400 Gm.; the average weight of these
tension: (1) The frequency of cerebral hemorrhage, five hypertrophied hearts was 425 Gm. In
(2) the frequency of hypertrophy of the heart, and the control series there were 33 out of 93 women
(3) the frequency and dlegree of hypertension as (35.5 per cent) whose hearts weighed more than
shown by the recorded blood pressure determinations
in the patients. 400 Gm. the average weight being 475 Gm.
The number of cases with hypertrophy qf the
RESULTS heart was thus about seven times greater in the
control series than in the series with hepatitis,
Incidence of hypertension in patients with hepa- and the hypertrophied hearts in the control series
titis
weighed on an average 50 Gm. more than those
(1) The Occurrence of Cerebral Hemorrhage found in the case of hepatitis.
in the Two Series. None of the patients with (3) Frequency and Degree of Hypertension,
hepatitis died of cerebral hemorrhage, whereas as Determined by Actual Measurements during
11 patients in the control series (11.8 per cent) Life. This criterion is defective because not
died of this condition. all the patients had had their blood pressure
(2) Frequency of Hypertension as Deter- measured. However, since 89.2 per cent in the
FLEMMING RAASCHOU 513
control series and 83.4 per cent in the series of women who died of or with subchronic
with hepatitis had had their blood pressure hepatitis than in a control series of autopsied
measured, and as it was apparently quite acci- female patients with the same age distribution
dental that no such measurement had been who died of all other diseases. Severe, diastolic
performed in the other cases, it was considered hypertension practically does not occur in
justifiable to draw certain conclusions from patients with this disorder of the liver.
this part of the investigation. Of the three criteria, the first two (cerebral
(a) Systolic blood pressure. In the series of hemorrhage and heart weight) are presumably
patients with hepatitis 15 (or 17.7 per cent) the most important, since these could be
had pressures of 160 mm. Hg or higher, and studied in the whole series of patients. With
three (or 3.5 per cent) had systolic pressures regard to the criterion of blood pressure as
of 180 mm. Hg or higher. The corresponding measured during life, its value is diminished,
figures in the control series were: 39 patients first, as already mentioned, because one-tenth
(47 per cent) with pressures of 160 mm. Hg or to two-tenths of the patients of our series had
higher and 21 (25.3 per cent) with pressures not had their blood pressure measured, and
equal to or above 180 mm. Hg. From these second, because the number of blood pressure
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findings it can be concluded that if 160 mm. determinations in the individual patients
Hg is accepted as the lower limit of elevated varied greatly. The incidence of hypertension
systolic blood pressure, the number of hyper- found in the control series agrees fairly well
tensive patients is about three times greater with the expected incidence in an average
in the control series, than in the hepatitis population. Robinson and Brucer23 assumed
series, and if 180 mm. Hg is accepted as the that the incidence of hypertension in adults is
lower limit of systolic hypertension, the num- at least 40 per cent, and S0bye29 stated that a
ber is about seven times greater in the former hereditary predisposition to hypertension was
series than in the latter. In both instances the found in about 30 to 40 per cent of the popula-
average blood pressure of the hypertensive tion.
patients is higher in the control series than in Possible Alleviation of Hypertension after
the series with hepatitis.
(b) Diastolic blood pressure. The same con- Development of Hepatitis
clusions can be drawn from an examination If unquestionable cases of permanent hyper-
of the diastolic blood pressure. If 100 mm. Hg tension which disappeared when the patient
is fixed as the lower limit of diastolic hyper- developed chronic hepatitis can be demon-
tension, the series of cases of hepatitis contains strated, this will lend support to the hypothesis
12 patients (or 14.8 per cent) whose pressures of a causal relationship between severe hepatic
were over this value; but if 120 mm. Hg is disorders with reduced liver function and the
accepted as the beginning of diastolic hyper- low incidence of hypertension. All case records
tension, only one patient (1.2 per cent) had too in the hepatitis series have been gone through
high a diastolic pressure. In the control series
21 patients (or 26.3 per cent) had pressures tO JQ chronic AepaZf'is
above 100 mm. Hg, and nine (11.3 per cent)
had pressures over 120 mm. Hg. This analysis
of the diastolic pressure, suggests that the * ]-JLI~LlliLinW
severe cases of hypertension do not occur in confrol maer/a!
the patients with hepatitis. tO
8,
The chief conclusion of this analysis is that
the frequency of patients with hypertension,
10 Hn
examined according to the three criteria men-
tioned above (cerebral hemorrhage, heart hearft' we/Aht.
weight and incidence of hypertension), is FIG. 2. The distribution of heart weights in the
essentially lower in an autopsy series consisting hepatitis and control material.
514 LIVER FUNCTION AND HYPERTENSION

with a view to this, and only the following blood pressure, or whether it is due to non-
case could be found. It may be mentioned specific causes, such as, for instance, impair-
that, with regard to the blood pressure of ment of general health, emaciation or other
these patients with hepatitis, unfortunately factors incidental to such disease. It may be
prehepatitis details often were not available. mentioned in this connection that hyperten-
sion is seldom seen in various forms of cancer
M. E. B. was a woman 68 years of age. (Depart- presumably owing to the cachexia which de-
ment III, Kommunehospitalet, case record no. 1468/
1946, and the Institute of Pathology, case record no. velops.16
817/1946.) She gave the following history. Since 1936
(her fifty-eighth year) the patient had been suffering The Role of the Liver in Experimental, Renal
from dyspnea on exertion, restlessness and pre- Hypertension
cordial pain usually due to emotional disturbance, That the liver plays such a role is strongly
and had also had a tendency to edema of the ankles
in the evening. In 1938 hypertension (210 to 250 suggested by work such as that of Braun-
mm. Hg systolic pressure) was first recorded. In 1941 Menendez and colleagues.6 In all probability
the blood pressure ranged between 280/180 and hypertensinogen is produced in the liver'5' 19
220/140. On March 15, 1946, it was 240/150. In since the content of hypertensinogen in the
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June, 1946, the patient became ill with fatigue, blood of normal and hypertensive dogs is re-
dyspepsia and slight jaundice. She was admitted to duced or disappears completely after hepatec-
Department III of Kommunehospitalet, where she
remained from Aug. 29 to Oct. 24, 1946. The diag- tomy or injury to the liver (by carbon tetra-
nosis was chronic hepatitis. She developed ascites chloride and ethyl alcohol). Moreover Haynes
and edema of the leg, and had anemia, a positive and Dexter12' 13 found that the content of
Takata-Ara test and a positive thymol test. In the
course of the disease of the liver the following blood hypertensinogen was reduced in human plasma
pressures were measured: 170/110 on August 15, in six out of nine patients with hepatic insuffi-
160/90 on September 2, 140/90 on September 5, ciency. Renin, likewise, is generally considered
165/95 on October 18, 135/75 on October 21. An to be destroyed, in part at least, in the liver
electrocardiogram (Aug. 30, 1946) showed only left since hepatectomy will delay its removal from
axis deviation; a roentgenogram of the heart (Sept. the blood.5 Likewise hypertensinase, the hyper-
10,1946) showed the width of heart to be 14 cm. and tensin splitting enzyme, is also said to be pres-
of the thorax, 26 cm. There was slight hypertrophy
of the left ventricle. ent in liver as well as in many other parts of
On Oct. 24, 1946, about five months after the the organism; however, its concentration in
appearance of the first symptom, the patient died of the blood is said not to be changed in hepatic
hepatic insufficiency with hepatic coma. Necropsy insufficiency.'3
showed subchronic atrophy of the liver, severe
ascites, slight jaundice, enlargement of the spleen, Shorr and associates25 put forward another
and moderate pulmonary edema. The heart weight theory about the occurrence of two antagonis-
was normal (310 Gm; body weight: 61 Kg.). The tic substances: vasoexcitor material (VEM)
wall of the left ventricle measured 15 mm. and the vasodepressor material (VDM), the
Comment. This case was thus one of hyper- function of which should be to regulate the
tension of at least eight years' duration in peripheral blood flow and blood pressure.
which a high diastolic pressure had been re- Vasodepressor material is produced in the
corded. When this patient developed chronic liver, the spleen and the skeletal muscles in
hepatitis, an essentially lower blood pressure the case of tissue anoxia, and is destroyed in
was found, and at necropsy there were no the liver under aerobic conditions. These
signs of hypertrophy of the heart. authors found increased quantities of vaso-
DIscussIoN depressor material in the blood and the liver
tissue of rats with experimental cirrhosis of
The question that immediately arises is the liver; increased proportions of vaso-
whether the low incidence of hypertension depressor material are also said to be found
in this severe hepatic disorder is specific and, in the blood of patients with cirrhosis of the
therefore, attributable to special biochemical liver.27
changes in the blood which determine the low Finally, it may be mentioned that recently
FLEMMING RAASCHOU 515
Davis and co-workers8' 9 have published the the clinical experience which has been sum-
results of experiments on dogs subjected to the marized in this paper.
Goldblatt procedure which, both with regard
to the procedure and the results of experiments, SUMMARY
closely resemble the experiments on dogs, A comparison with regard to the incidence of
which have been reported by Raaschou and arterial hypertension has been made between
Trautner22 in Goldblatt dogs; Davis andj co- an autopsy series consisting of 102 women who
workers have undertaken partial clamping of had died of chronic hepatitis (subchronic yel-
the portal vein and the hepatic artery, either low atrophy of the liver) and a control series
separately or simultaneously. When the flow of autopsied patients who did not have liver
of blood through the liver had been sufficiently disease. By means of three criteria of arterial
reduced (which manifested itself, inter alia, hypertension [(1) the incidence of cerebral
by the appearance of fatty infiltration in the hemorrhage, (2) the incidence of hypertrophy
liver), they observed that the blood pressure of the heart, and (3) the incidence and degree
fell. of arterial hypertension] study of these series
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The strikingly low frequency of arterial demonstrated that the frequency of arterial
hypertension in subchronic atrophy of the hypertension is considerably lower in patients
liver, and the fact that the function of the liver with severe hepatic disease than in patients
is found to be normal in essential hypertension without liver disease.
in man,5 form the basis of the hypothesis on The hypothesis has been advanced that
which the experimental work of Raaschou and severely impaired liver function is able to
Trautner22 was based: a normal or only slightly prevent the development of arterial hyper-
damaged liver function is a necessary condi- tension, or can eliminate already existing
tion for the development of hypertension in hypertension.
man, whereas a severely damaged liver func- SUMARIO ESPANOL
tion will prevent the development of hyper-
tension or eliminate already existing hyper- Una comparaci6n con relaci6n a la inciden-
tension. The object of Raaschou and Traut- cia de la hipertensi6n arterial se ha hecho entre
ner's work was to study in dogs the effect of a una serie de autopsias consistiendo de 102 mu-
severe hepatic injury (caused by obstruction jeres que murieron de hepatitis cr6nica (atrofia
of the common bile duct) upon previously amarilla subcr6nica del higado) y una serie con-
produced experimental renal hypertension. trol de pacientes a quienes se les practice6 au-
Briefly, it can be said that six hypertensive topsia que no tenian enfermedad hepatica. Por
medio de tres criterios para la presi6n arterial
dogs (with experimental renal hypertension [(1) la incidencia de hemorragia cerebral, (2)
produced according to Goldblatt's method), la incidencia de hipertrofia del coraz6n y (3)
four with hypertension of short duration, two la incidencia y el grado de hipertensi6n arterial]
with more prolonged hypertension, displayed el estudio de estas series demostr6 que la fre-
a gradual fall in the blood pressure toward, or cuencia de hipertensi6n arterial es considerable-
to, the normal preoperative values after ob- mente mas baja en pacientes con enfermedad
struction of the common bile duct had been severa hepatica que en los pacientes sin en-
established. These falls in the blood pressure fermedad hepatica.
were observed in dogs which had been in good La hipotesis se ha propuesto que la funci6n
health and which were sufficiently fed. In hepatica severamente deteriorada es capaz de
one normotensive dog the obstruction of the evitar el desarrollo de hipertensi6n arterial o
common bile duct produced no material que puede eliminar la hipertensi6n ya existente.
changes in the blood pressure. The cause of the REFERENCES
fall of the blood pressure after obstruction of 1 ALSTED, G.: Studies on malignant hepatitis. Am.
the common bile duct could not be explained, J. M. Sc. 213: 257, 1947.
but the experimental results are in accord with 2
BJ0RNEBOE, M., AND BR0CHNER-M}ORTENSEN, K.:
516 LIVER FUNCTION AND HYPERTENSION

Om Prognosen for Hepatitis acuta. Ugesk. 17


LOEPER, MI.: Les Hepatites. Paris, MIasson et Cie,
Laeger 107: 715, 1945. 1937. P. 200.
3
-, JERSILD, M., LUNDBAEK, K., HESS-THAYSEN, 18 MEAKINS, J. C.: Jaundice and blood pressure. M.
E., AND RYSSING, E.: Incidence of chronic Clin. North America 16: 715, 1932.
hepatitis in women in Copenhagen 1944-45. 19 PAGE, I. H., 1ICSWAIN, B., KNAPP, G. M., AND
Lancet 1: 867, 1948. ANDRUS, W. D.: Origin of renin-activator. Am.
4-, AND RAASCHOU, F.: The pathology of sub- J. Physiol. 135: 214, 1941.
chronic atrophy of the liver. A comparison with 20 RAASCHOU, F.: Blodtryk og Hjaertevaegt ved
cirrhosis hepatis Laennec. Arch. Int. Med. 84: Hepatitis chronica. Spiller Leveren nogen Rolle
933, 1949. for Udviklingen af den humane, essentielle
5
BRADLEY, S. E.: Physiology of essential hyper- Hypertension? Nord. Med. 42: 1791, 1949.
tension. Am. J. Med. 4: 398, 1948. 21 -: Does urine stasis have any influence on the de-
6 BRAUN-MIENENDEZ, E., FASCIOLO, J. C., LELOIR, velopment of arterial hypertension? Acta med.
L. F., M.IuNoz, J. }I., AND TAQUINI, A. C.: scandinav. 133: 31, 1949.
Renal hypertension. Springfield, Ill1., Charles C 22 -, AND TRAUTNER, K.: Obstruction of the com-
Thomas, 1946. mon bile duct in experimental renal hyperten-
7
CHAUFFARD, MI.: in CHARCOT, BOUCHARD AND sion in dogs. Scandinav. J. Clin. & Lab. Invest.
BRISSAND: Traite de Medicine. III. Maladies du 5: 223, 1953.
23 ROBINSON, S., AND BRUCER, MI.: Range of normal
Downloaded from http://circ.ahajournals.org/ by guest on May 2, 2018

foie et des voies biliaires. Paris, 1892. P. 691.


8DAVIS, L., TANTURI, C., AND TARKINGTON, J.: The blood pressure. A statistical and clinical study
effect of reduced blood flow to the liver in renal of 11,383 persons. Arch. Int. Med. 64: 409,
hypertension. Surg., Gynec. & Obst. 89: 360, 1939.
1949. 24
SELANDER, P.: Epidemischer und sporadischer
9
-, AND -: Liver as a factor in experimental renal Ikterus. Eine statistisch-epidemiologische und
hypertension. Arch. Surg. 62: 325, 1951. klinische Untersuchung. Acta padiat. suppl. 4:
10 GEILL, T.: Studier over Icterus. I. Om Forekom- 23, 1939.
sten af Bradycardi og Hypertension. Hospi- 25 SHORR, E., ZWEIFACH, B. W., AND FURCHGOTT,
talstidende 73: 749, 761, 1930. R. F.: On the occurrence, sites and modes of
1 GILBERT, AND GARNIER: cited by LoEPER.17 origin and destruction, of principles affecting
12 HAYNES, F. W., AND DEXTER, L.: The hyper- the compensatory vascular mechanisms in
tensinogen concentration of the plasma of pa- experimental shock. Science 102: 489, 1945.
tients with various diseases. Federation Proc. 26 -, -, -, AND BAEZ, S.: Factors regulating blood
2: 20, 1943. pressure. Transactions of the first conference,
13 -, AND -: The renal humoral pressor mechanism April 24-25, 1947. Pp. 32-47. New York,
in man. III. The hypertensinase content of Josiah Macy Jr. Foundation.
plasma of control subjects and of patients with 27 -: Liver injury. Transactions of the sixth con-
hypertension and other diseases. J. Clin. In- ference, M\ay 1 and 2, 1947. New York, Josiah
vestigation 24: 75, 1945. Macy Jr. Foundation.
14 JERSILD, M.: Stigende Hyppighed af kronisk 28 SPATT, S. D., AND ROSENBLATT, P.: The incidence
Hepatitis. Ugesk. Laeger 107: 819, 1945. of hypertension in portal cirrhosis; a study of 80
15 LELOIR, L. F., MUNOZ, J. M., TAQUINI, A. C., necropsied cases of portal cirrhosis. Ann. Int.
BRAUN-MENENDEZ, E., AND FASCIOLO, J. C.: MLed. 31: 479, 1949.
La formacion del hypertensinogeno. Rev. 29 S0BYE, P.: Heredity in essential hyplertension and
argent. cardiol. 9: 269, 1942. nephrosclerosis. A genetic-clinical study of 200
16 LINDEN, L.: Blodtrycket vid cancer ventriculi. propositi suffering from nephrosclerosis. Thesis,
Nord. Med. 41:1094, 1949. Copenhagen, 1948.
Liver Function and Hypertension: Blood Pressure and Heart Weight in Chronic
Hepatitis
FLEMMING RAASCHOU

Circulation. 1954;10:511-516
doi: 10.1161/01.CIR.10.4.511
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