Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 115

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189

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June 10-14 .- The normal assimilation limit for ingested cane sugar in a 7 kilo puppy dog about 10 months of age, was estab- lished at something below 75 gms.

June 15. Operation .- A clean-cut posterior lobe removal; the anterior lobe and stalk remaining undisturbed. No complicating factors. The animal stood the procedure well and remained in good condition until sacrificed two months later.

June 15-16 .- High grade of polyuria following operation, the first 24-hour amount being 3700 cc. No spontaneous glycosuria in first specimen.

June 18-19 .- Glycosuria appeared with 50 gms. saccharose (25 gms. below the normal). Forty grams gave no reducing sub- stance. Tolerance therefore on this third day after operation had fallen 33 per cent.

June 22-23 .- Fifty grams no longer gave glycosuria, but it oc- curred with 60 gms.

June 27-July 7 .- Eighty grams were needed to give glycosuria on June 27; 100 gms. on July 1, 110 gms. on July 5, showing the rapid post-operative acquirement of this relatively high assimila- tion limit. It is presumable that there was a further rise, but no subsequent tests uncomplicated by extracts were made. (The positive reaction with only 100 gms. on August 6th was possibly associated with a prolonged action of the thyroid extract given the day before.)

July 14-August 5 .- This interval was consumed in making tests with extracts to determine their relative potency in lowering the raised assimilation limit. The results were somewhat less striking than those shown in No. 64. A coincident subcutaneous injection of .05 gm. posterior lobe extract with 50 gms. saccharose (July 19) gave glycosuria, and again with 40 gms. (July 23)-a lower- ing of the established assimilation limit therefore by considerably more than half. An equal dose of the extract given intravenously (July 26) gave glycosuria with 30 gms., lowering the established tolerance over 70 per cent.

The injection of anterior lobe extract likewise in .05 gm. dosage had a somewhat less striking effect, but nevertheless gave traces of a reducing substance with amounts of sugar as small as 60 gms. -a lowering of the tolerance about 45 per cent.

The combined action of equal parts of anterior and posterior lobe extracts in .05 gm. doses (July 30-August 3) had if anything less potency than the posterior lobe extract alone.

Double the standard dose of thyroid extract (namely, 0.1 gm.) gave glycosuria with 60 gms. but not with 50 gms. (August 4-5), being, therefore, far less active than posterior lobe extract, in this particular case.

August 8 .- The animal remains in apparently perfect health.

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Sacrificed. Autopsy: Conducted as usual, gross examination c! the organs disclosing nothing of special note.

Histological .- The tissue removed at operation (Fig. D) (c)-

TABLE XI .- TESTS OF TOLERANCE FOR INGESTED SACCHAROSE IS No. 67.

Urine.

Date.

Grams of cane sugar given.

Glandular extracts adminis- tered.

Amt.

Sp. Gr.

Fehling.

Nylander.

Fermonta-

tion.

June 10 ..

100

1030

240

1030

220

1020

+ 0

3700

1004

2150

1004

840

1020

440

1016

450

1020

470

1020

+ sl.

310

1020

420

1018

860

1020

440

1018

500

1008

100 100

1062

1020

110

840

1029

+ +

.05 gm.

180

post. lobe hypo.

slight 1.3

.05 gm.

post. lobe

hypo.

150

1065

.05 gm.

post. lobe

hypo.

110

1062

+ øl.

.05 gm.

post. lobe hypo.

1020

.05 gm.

ant. lobe hypo.

180

1020

.06 gm.

ant. lobe hypo.

140

1044

post. lobe

hypo. .05 gm.

1054

.06 gill.

150

1040

ant. lobe hypo.

.05 gm.

150

1042

atypical

ant. lobe hypo.

1048

+ susp.

+ 81.

120

1030

.05 gm.

1046

ant. lobe hypo.

100

1028

.05 gm.

ant. lobe hypo.

.05 gm . a. I.,

1050

Aug. 1

05 gm. a. I.,

180

1034

.05 gm. p. l., hypo.

.06 gm. a. 1.,

110

1034

.05 gm. p. l., hypo.

.1 gm.

1048

thyroid

.1 gm.

1052

thyroid

hypo.

440

1024

400

1024

+ +

110

340

1034

July

440

1022

susp. +

450

1012

+ sl. 0

100

1060

Hypophysectomy; removal of posterior lobe.

270

1026

sists of the intact posterior lobe with its epithelial investmec confirming the operative note. Serial sections of the iste" peduncular block removed post mortem showed the viable and : tact anterior lobe with hyperplastic pars intermedia adjoining t-

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.05 gm.

post. lobe hypo.

.06 gm. post. lobe Intraven. .05 gm.

ant. lobe hypo.

atypical atypical

.05 gm. p. l., hypo.

slight

hypo.

100

+ sl. 0

+ 01.

U uaNUCL.

Comment .- This protocol gives another example of the aracteristic temporary lowering of the assimilation limit · ingested cane sugar after posterior lobe removal and the osequent rapid rise (to 46.6 per cent) in excess of the pre- erative normal limit.

The various tests with glandular extracts, to determine their ative potency in lowering the degree of acquired tolerance, > again recorded. They show that posterior lobe extract the most efficacious, for in this instance it lowered the ac- ired high tolerance far below the original normal. Anterior Je extract was somewhat less effective, thyroid extract still s so. It is quite apparent, however, that in this animal all ree extracts showed a greater potency than usual; and to ve made the tests of actual value the extracts should have en tried out on the animal's normal tolerance before the eration.

Summary of Experimental Data.

The matter of primary interest to which we would call atten- n is the increase in the assimilation limit for sugar, whether gested or given intravenously, in experimentally produced tes of hypophyseal deficiency. This acquirement of an over- erance for carbohydrates we feel justified in attributing to a

FIG. 7 .- No. 67. Section of tissue removed at operation; ntact posterior lobe. Mag. 9 diams. Bensley; 5 ; iron æmatoxylin.

privation of posterior lobe (pars nervosa and pars inter- lia) activity.

That operative manipulations of the gland cause a marked ;urbance of the sugar storing function is shown by the quency with which transient spontaneous glycosuria occurs er operations of a certain type-namely, ones which e necessitated a certain degree of traumatism of the in- dibular stalk and its enveloping epithelium (pars inter- lia). Such operations as do not require stalk manipula- , a clean-cut posterior lobe enucleation for example, ally fail to show this immediate post-operative glycosuria, ch therefore can hardly be attributed to the anasthetic. istological studies have shown that the stalk of the hypo- sis and the floor of the third ventricle immediately ad- nt to it contain, under all circumstances, a substance- ring's " hyaline bodies "-which may be regarded as the tory product of the posterior lobe. This material appears ud its way into the infundibular cavity, and the cerebro- J fluid has been shown to contain a substance having the

fluid has an active circulation and in all probability finds its way into the blood stream. It consequently is a natural ex- planation of the phenomenon of spontaneous glycosuria that in the manipulations of the tissue holding this material an excessive amount of posterior lobe secretion, thus suddenly set free, enters the circulation and thus accounts for the glyco- suria. We have found, indeed, that, without injuring or re- moving the body of the gland, the mere crushing of the stalk by the placement on it of a silver " clip " for the purpose of pro- ducing a permanent stasis of the products of posterior lobe secretion, will usually lead to a temporary glycosuria, the procedure being in this respect equivalent to a total removal.

We assume that the spontaneous glycosuria represents a hyperglycemia from the discharge of stored glycogen which has been set free by the introduction into the circulation (by way of the cerebrospinal fluid) of the posterior lobe secretion

FIG. 8 .- Section 37 of 5 u series from interpeduncular block of No. 67. Mag. 9 diams. Bensley; 5 u; hæmatoxylin and eosin. Showing pars anterior (P A) ; hyperplasia of pars intermedia (P I) with colloid cysts; scar tissue (S) replacing posterior lobe cavity; dural envelope (D) ; optic commissure (O C).

accumulated in the infundibular tissues. We have obtained additional support for this view from some further (unpub- lished) observations concerning the effects of injections of con- centrated cerebrospinal fluids on the carbohydrate assimila- tion limit of dogs and rabbits.

Preliminary determinations of the tolerance shown by the unoperated animals gave an average assimilation limit for saccharose by mouth of about 10 gms. per kilo of body weight, and for glucose intravenously roughly about one gram per kilo. A marked augmentation-occasionally to double the normal-in the tolerance for sugars administered in either of these ways was an end result of all the hypophysectomies provided the posterior lobe was included with the glandular tissue removed.

" Cushing and Goetsch: Concerning the secretion of the in- fundibular lobe of the pituitary body and its presence in the cerebrospinal fluid. Am. J. Physiol., 1910, XXVII, p. 60.

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Though our studies on the influence of various glandular extracts in lowering the assimilation limit in these states of experimentally acquired high tolerance are rather a side issue, nevertheless the fact that posterior lobe extract proves to be an agent especially potent in bringing about a lowered degree of tolerance brings support to the assumption that we are dealing primarily with a deficiency of the posterior lobe.

It may be noted here that attention was called in the report by Crowe, Cushing and Homans to the rapid emaciation which follows repeated injections of posterior lobe extract, due, as they conjectured, to an active tissue oxidation. There was presumably a marked unloading of stored carbohydrates, and glycosuria was occasionally observed in their animals. Here, on the other hand, in these states of experimental glandular deficiency, there seems to be a lowered tissue metabolism, manifested by a tendency to subnormal temperatures and to the acquirement of adiposity. An especial rise in the weight curve often occurs coincident with the period of forced sugar feeding.

Needless to say, in order to have made these observations on the effect of glandular extracts more conclusive we should have determined their influence in each case on the normal tolerance as established before the operation.

The attempts to determine the relative efficiency of admin- istering posterior lobe extract by mouth, by subcutaneous in- jection, and intravenously, showed that about one-twentieth of a gram subcutaneously would have a definite effect on the ac- quired tolerance of the animal. To obtain the same result it required, by a rough estimate, about one-fourth of the dose when given intravenously and eight times the dose when given by mouth. These data are of some therapeutic importance in relation to the studies on the clinical cases to follow.ª

IV. THE SUGAR TOLERANCE IN CLINICAL DYSPITUITARISM.

Our experimental studies had indicated that a deficiency of posterior lobe secretion would lead to an increased tolerance for carbohydrates and that the administration of posterior lobe extract could markedly lower the acquired high assimilation limit. It was a natural conjecture that, could we demonstrate the existence of similar reactions toward the carbohydrates in the clinical cases of pituitary disease which were under our care, we might possibly have a means of determining whether there was a state of over or under glandular activity, at least so far as the posterior lobe was concerned.

Methods of estimating the tolerance .- We have unfortu- nately received but little help from earlier studies, for though it has been roughly estimated that the normal human assimi- lation for glucose by mouth is about 150 gms., and for lævu- lose about 100 gms., we have found no figures as to the average sugar tolerance for man in relation to body weight. In the canine, as will be recalled, certain approximate stand- ards for the normal were found-namely, about 10 gms. of

ingested cane sugar per kilo of body weight and about one gram per kilo for glucose administered intravenously. These proportions, of course, were not expected to hold true før man; and if they did, such enormous doses of sugar would be required as to make their administration out of the question. As it was, we experienced difficulties, even though carboby- drates are appetizing to these individuals almost without er- ception.

We began our observations with the simple administration of glucose usually given on an empty stomach about five hours after the evening meal, all subsequent specimens of urine be- ing separately saved. In many of the cases the tolerance for glucose was so great that we were never able to determine the actual assimilation limit, vomiting the sugar taking place in spite of all precautions and devices such as disguising the taste, giving divided doses and the like. We have had indi- viduals take and retain 400 gms., as the following records of sugar feeding will show, but this is exceptional, and when the assimilation limit was very high we were usually forced to de- sist from our efforts to determine it by ingestion methods.

---

A personal experience has shown us that the stomach may rebel even at the relatively small doses required to determine the assimilation limit for presumably normal states, and it takes gastric courage for patients to consume two or three times this amount.

We have done better with lævulose, and it is our impression. from one or two experiences with individuals (Cases XIII and XVI), whose stomachs tolerated the sugars well, that only about half the bulk needed with glucose is required to reach the assimilation limit with lævulose. It is of interest that, a: in the animal experiments, the excess of lævulose absorbe! from the intestine appears unconverted as lævulose in th: urine. It may be recalled that Strauss' regards the occur- rence of lævulosuria after the ingestion of amounts below liti gms. as an evidence of hepatic insufficiency. The assimilatic of three times this amount in some of our cases would seem ta indicate an extraordinary storage capacity for glycogen.

A rough estimate might place the average human assimila- tion limit for ingested glucose in a 70 kilo individual at somi- thing over 140 gms. of glucose, or about two grams per kilo of body weight, only a fifth of the canine tolerance; and for lævulose at about 100 gms. or 1.4 gms. per kilo. Though the majority of our cases of hypopituitarism with high grades ! sugar tolerance had become adipose, nevertheless the compar- ative increase in the tolerance limit per body weight was er- treme, in many running up to three and even four or five gms. of glucose per kilo.

One interesting result of the consecutive carbohydrate tesz: to which we have subjected these generously co-operating pa- tients has been the rapid increase in weight coincident wit the sugar administration. A similar effect was noted with the canine feedings. It is to be remembered, at the same time. that the observed individuals, experimental or clinical, usually

'We desire to express our obligations to Mr. F. M. Bell of Armour & Company for his generous co-operation in supplying us with the powdered preparations of posterior lobe which have been used in these experiments.

' H. Strauss: Zur Funktionsprüfung der Leber. Deutsche m. Wchnschr., 1901, XXVII, p. 757.

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"S powoLo ase av a low eDU and that the stored glycogen is transformed into fat. In the brief abstracts which we have given of the experiments we could not go with ny detail into the histological studies of the other ductless glands, though it may be said in passing that the general features of the changes throughout the whole body consist n a striking deposition of fat within the cells.

The experimental subcutaneous administration of posterior obe extract in repeated doses appears to bring about the re- 'erse picture-namely, excessive emaciation-and, as we have een, small individual doses serve to lower either the normal ugar tolerance or the high tolerance succeeding posterior obe removal. This suggests, of course, a ready means of de- ermining the tolerance for ingested sugars in clinical cases. Thus, coincident with the administration by mouth of an mount of sugar which would represent the presumed normal olerance according to the body weight, the dosage of the extract necessary to produce a transient glycosuria can be de- ermined (cf. Case XIII). This, however, requires further nvestigation and better methods of administration, for the ubcutaneous or intermuscular injection even of one-twentieth of a gram of the boiled extract suspended in 2 cc. of fluid is upt to produce an uncomfortable point of tenderness, and in ne patient caused a local amicrobic abscess.

Tolerance in Acromegaly and Gigantism .- It has been rnown for a number of years that a spontaneous glycosuria is not uncommon accompaniment of acromegaly, a malady in which hypophyseal overactivity has been assumed by many. indeed, attention has been called to the fact that a lowered assimilation limit may be associated with pituitary lesions in he absence of any clinical manifestations of acromegaly. An nteresting illustration of this had been given in one of our wn cases observed before we began these experimental studies n sugar tolerance. The patient, who exhibited certain ob- cure cerebral symptoms thought to be of vascular origin, was egarded at first as the subject of diabetes mellitus, and sub- equently, as the glycosuria disappeared and marked polyuria ersisted, as a case of diabetes insipidus. At autopsy a year r two later a gumma of the anterior lobe was disclosed. Our resent interpretation of the case would be that the lesion had imulated the pars nervosa into an abnormal activity.

Other examples of spontaneous glycosuria which we are in- ined to attribute to a pituitary body lesion rather than to the psetting of a cerebral " sugar-center " might be given. We 'e inclined to the view that the fleeting glycosurias which :company certain bursting fractures of the cranial base are : this nature, for the line of fracture usually seeks out the iddle cranial fossa and may readily traumatize the pituitary dy itself.

However, in none of the twenty cases of acromegaly or gantism which have occurred in our personal series, has ere been a coincident spontaneous glycosuria. The reason r this doubtless lies in the fact that the cases have been en late in the progress of the disease. In all probability had e urine been examined at a sufficiently early stage, glyco-

tected. In one instance, indeed, the patient had failed to pass a life insurance examination some years before, as he was sup- posed to be suffering from diabetes, though at the time of his admission to our care an abnormally high assimilation limit was present.

It is presumable that the syndromes of acromegaly and gigantism primarily represent states of hypophyseal, and as we believe of anterior lobe overactivity, it being a natural conjecture that the posterior lobe meanwhile is functionally stimulated. As the disease progresses and the pituitary struma forms (whether it be a simple hyperplasia, a cyst or " malignant adenoma ") a condition of glandular insufficiency results and states comparable to those seen in the animals with experimentally defective glands are superimposed. In other words, there appears to be, at least for such outspoken states of hyperpituitarism as we have up to this time come to recog- nize clinically (represented by acromegaly and gigantism), an inevitable tendency for them to be transformed ultimately into states of hypopituitarism.

The case reports will be given in the greatest brevity, for all that we wish to show is the high degree of carbohydrate toler- ance acquired by these patients. In a few instances sufficient doses of posterior lobe extract have been given to produce gly- cosuria with amounts of sugar below the established assimila- tion limit.

We have subdivided the acromegalies into separate groups according to the duration of the symptoms. In only one of these patients (Case I) was the condition recent and acute, possibly of not more than a year's duration. A subnormal tolerance was present, namely 1.4 gms. of glucose per kilo of body weight.

CASE I .- No. 25827. April 25, 1910. D. (Acromegaly.)-Male, aged 33, weight 72 kilos (160 lbs.). Urine, high specific gravity; no sugar.

May 1 .- Glucose 100 gms. Glycosuria on first three specimens. May 5, 6, 7 .- Glucose in 25, 50 and 75 gm. doses respectively gave no reducing body.

May 8 .- Glucose 100 gms. gave glycosuria on first specimen.

In the following case the symptoms were of about four years' duration and were not particularly outspoken. The patient was not fat. The tolerance was about normal, approx- imately 150 gms. or 2 gms. of glucose per kilo of body weight.

CASE II .- No. 27247. January 10, 1911. (Acromegaly.) Male, aged 40, weight 73 kilos (162 lbs.).

January 15 and 17 .- Glucose 100 gms. gave an atypical, and 150 gms. a strong reduction to Fehling's.

January 22 and 23 .- Lævulose 100 gms. gave an atypical, and 150 gms. a strong reduction to Fehling's.

January 25 .- Lævulose 100 gms. with 0.4 gm. post. lobe ext. gave a strong reduction.

The disease in the two succeeding patients, both females, was of about five and eight years' duration respectively, judg- ing from the onset of the amenorrhoea. They were tested only with lævulose, for which they showed a fairly high tolerance, 1.7 gm. per kilo in the first and 2.4 gms. per kilo in the second case. There were no posterior lobe injections.

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CASE III .- No. 27256. January 23, 1911. (Acromegaly.) Female, aged 37, weight 84 kilos (188 lbs.).

January 24 .- Lævulose 100 gms. gave an atypical reduction.

January 25 .- Lævulose 150 gms. gave a positive reduction in a single specimen nine hours after ingestion.

CASE IV .- No. 27290. February 1, 1911. (Acromegaly.)

Fe- male, aged 35, weight 66 kilos (148 lbs.).

February 4 .- Lævulose 150 gms. gave an atypical reduction in first two specimens.

February 5 .- Lævulose 175 gms. gave a positive glycosuria in first two voidings seven and nine hours later.

The three following cases were of longer duration. The first had progressed rapidly during a period of about four years and showed pronounced neighborhood symptoms due to a " malignant adenoma " of the pars intermedia (?). The assimilation limit for ingested glucose was never fully deter- mined, but it was over 5 gms. per kilo of body weight.

The second was a slowly progressive case of 13 years' dura- tion, with a small gland and no neighborhood pressure symp- toms. The sugar tolerance for glucose was 3 gms. per kilo of body weight.

The third was a case of about six years' duration, associated with an intrathoracic goitre. This had caused disturbing pressure symptoms, and the patient in the past few months had lost the 50 pounds in excess of his previous normal weight which he had put on since the onset of the disease. His tol- erance for glucose could not be established, but it was enor- mous and possibly over 5 gms. per kilo of body weight.

CASE V .- No. 25971. May 1, 1910. (Acromegaly.) Female, aged 28, weight 64 kilos (142 lbs.).

May 6 .- Glucose 300 gms. in divided doses gave an atypical re- duction.

May 14 .- Glucose 250 gms. with 0.1 gm. post. lobe ext. subcu- taneously gave a positive reduction (1.5 per cent dext. rotatory). May 16 .- Lævulose 100 gms. gave no reduction.

May 19, 22 and 24 .- Glucose in 100, 200 and 300 gm. doses re- spectively gave no glycosuria. Larger doses were not retained.

CASE VI .- No. 26210. July 6, 1910. (Acromegaly.) Male, aged 40, weight 85 kilos (191 lbs.).

July 6 and 7 .- Glucose 100 gms. and 200 gms. respectively was negative.

July 8 .- Glucose 300 gms. heavy reduction.

July 9 .- Glucose 250 gms. slight reduction with first voided specimen.

CASE VII .- No. 25977. May 21, 1910. (Acromegaly.) Male, aged 59, weight 70 kilos (156 lbs.).

July 2 .- Glucose 200 gms. 10 a. m., and 200 more 10 p. m., gave no reduction.

July 4 .- Glucose 300 gms. in one dose gave no reduction.

July 6 and 7 .- Glucose in 400 gm. amounts vomited on each trial.

The three following cases belong in the group of acrome- galic giants or actual gigantism. The increase in height was not marked in the first patient who in many respects was a typical example of acromegaly, beginning in about the 22d year of life. There were no neighborhood symptoms. The second patient was a huge acromegalic giant with an enor- mous gland, causing blindness: and the third was a typical giant, with a huge sella turcica, the symptoms dating from

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Twentieth Century History of Findlay and Hancock County, Ohio, and Representative Citizens, Part 115

Author: Jacob Anthony Kimmell Publication date: 1910 Publisher: Number of Pages: 1189

Author: Jacob Anthony Kimmell
Publication date: 1910
Publisher:
Number of Pages: 1189