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Hereditary Diabetes Insipidus: Unusual Urinary Tract Changes
THE JOURNAL OF UROLOGY
Vol. 64, No. 5, November 1950
Printed in U.S.A.
HEREDITARY DIABETES INSIPIDUS: UNUSUAL URINARY TRACT CHANGES CHARLES G. WELLER, WILLIAM ELLIOTT,
AND
A. RODRIGUEZ GUSMAN
Diabetes insipidus is a symptom complex consisting of polyuria with resultant polydipsia, and caused by pathological changes in the supraoptico-hypothalamic tract. Although not strictly a urologic condition, it is of interest to the urologist 1) because individuals suffering from this disease are inclined to seek his advice, 2) because the disease frequently demands his consideration in the differential diagnosis of common urologic conditions, and 3) because changes secondary to or associated with diabetes insipidus are occasionally discovered in the urinary tract. It is not our purpose to review the literature in this paper, but a brief resume of the salient points previously reported is essential to an understanding of the subject. The symptom complex was first recognized by Willis in 1674 as differing from diabetes mellitus. The earliest observation of familial involvement was reported by La Combe in 1841 (Fontan and Verger). A voluminous literature has accumulated, mainly dealing with experimental studies and etiologic data. The conclusions most important to an understanding of the subject are here summarized: 1) The supraoptic nucleii send fibers through the hypothalamus to the posterior lobe (pars nervosa) of the pituitary gland. Any bilateral interference with the continuity of this tract will initiate the symptoms of diabetes insipidus. 2) Polyuria is induced by suppression of the production of antidiuretic hormone by the posterior lobe, thereby allowing the diuretic hormone of the anterior lobe to act unopposed. The effect of this secretion is probably synergistic with the thyroid and adrenal hormones but does not ,vork exclusively through them. The resulting diuresis is due to decreased water absorption in the renal tubules, not to glomerular or circulatory effects. The polyuria is primary; the polydipsia, secondary. 3) Etiologic factors are divided into symptomatic and idiopathic. The average age of onset in the symptomatic group is 21 years, but in the familial cases polyuria is usually well established before the seventh year of life. The incidence of the two categories is reported to be about equal and is divided as follows: A. Symptomatic. a. Neoplasm of the pituitary or hypothalamus. b. Xanthomatosis (Hand-Schuler-Christian disease). c. Chronic encephalitis. d. Syphilis. e. Traumatic injury to the head. f. Pituitary infarction. g. Oerebrovascular accident. 716
HEREDITARY DIABETES INSIPIDUS
717
h. Subarachnoid hemorrhage. i. Hypothalamic damage. B. Idiopathic. j. Heredity. k. Undetermined. The familial form is probably less rare than the literature suggests. In 1945, Fontan and Verger collected 26 reported families and added one. Most of these cases have been reported in the German, French, and Spanish literature. Available information concerning the hereditary type has been well summarized by Warkany and Mitchell as follows: "In Adolph Weil's classic description, he gave a detailed account of four generations in a family consisting of 91 persons, 23 of whom suffered from diabetes insipidus. Weil's son, Alfred, continued these studies over a fifth generation of this family and found among 220 members a total of 35 in whom diabetes insipidus developed. Hereditary transmission from parent to offspring was direct in all but one instance. Of all of the children of affected parents, more than one half of the boys and one third of the girls suffered from the disease. Polyuria and polydipsia, while probably present at birth in these cases, were noticed definitely during the second year. The thirst increased as the age advanced and usually reached its height between the twentieth and thirtieth year. A slow improvement took place after the age of 50 years, but the affected persons :retained their abnormality for life. A few days before death the symptoms ceased. It was repeatedly observed that during periods of fever the symptoms disappeared and the specific gravity of the urine was a high as 1.018. By adding 12 gm. sodium chloride to the diet of one of these patients it could be shown that the kidneys had not lost their ability to concentrate. The abnormal water metabolism did not affect the general health and the patients carried on their usual occupations without much difficulty. There were no complaints of headache or vertigo. The family was free from mental disorders, neuroses, and alcoholism. The digestion was normal. Although in many cases the diet consisted mainly of bread and potatoes, a satisfactory nutritional state was maintained. The circulatory system showed no abnormalities, the heart was not hypertrophied, and arteriosclerosis did not develop in the older members of the family. The sexual functions were normal, and the fecundity of the family was above average. No difficulties were encountered by the affected women during pregnancy and delivery. There was no special predisposition to any particular disease. The course of contagious diseases in the children did not differ from that in normal children. Three members of this family had syphilis; this was certainly not etiologically related to the diabetes insipidus. Physical development was normal. The only development defect in this family was polydactylism in one child, but he did not suffer from diabetes insipidus. Some of the affected people lived to such ages as 83, 87, and 93 years. In addition to the family just described, there have been others in which diabetes insipidus appeared to be hereditary. Bulloch in 1909 published the pedigrees of 13 affected families, and a more recent critical review of this subject
718
CHARLES G. WELLER AND WILLIAM ELLIOTT
in 1935 by de Lange included 21 families. There can be no doubt that the hereditary form is more frequent than Lange's report indicated because to this can be added the reports, of Mensi, Peterman, Sugimoto, and Levit and Pessikova. In the family described by the W eils, the ratio of the affected to healthy siblings was such that diabetes insipidus could be considered a dominant character (Just). No generalizations, however, can be made. Levit and Pessikova examined 16 cases of "idiopathic" diabetes insipidus and found only 3 cases in which it was familial. In 2 of the families concerned only 2 members had the disease. It is evident, therefor, that idiopathic diabetes insipidus cannot always be a dominant hereditary character. The observation has been made that in several families, members of one generation may escape the condition. Both males and females are affected, although as previously stated, a greater number of males with the hereditary form have been reported. Transmission may
•
8/l~lll>lif ... lff>/Qf!J
~
,01.w,..,.f/'P,J111JtI-fJ.IV!m1NJJl'lt>v1)
0
IIQS)#l'TOMt,.H-
D/Afj£f£J /NSIPIPI/S roll/I GCNf/1.ATIONS
~ Jt/4
Frn. 1. Incidence of diabetes insipidus in family R
take place through either the paternal or maternal side. Consanguinity was present in only two families. The nature of hereditary diabetes insipidus can only be speculated on. No reliable reports of necropsies are available, and therefor the pathologic changes underlying this form of the disease are unknown. Adolph Weil suggested that there are hereditary morphologic abnormalities of certain parts of the nervous system. According to the present understanding of the pathogenesis of diabetes insipidus, these hereditary abnormalities should involve the diencephalo-pituitary region." Of the family in which our cases occurred, we personally studied 3 members and have obtained reports concerning one through another physician. Except for these 4, we assume that members of the family group whose fluid intake regularly exceeded 2 gallons daily suffered from diabetes insipidus. The earliest available record of this symptom complex in the family concerns 2 brothers whom we have designated generation one (fig. I). One of them is reported to have been an extremely heavy water drinker, whereas the other was normal in this respect, as were also his descendants. All of the affected brother's 3 children (generation two) showed symptoms of diabetes in-
HEREDITARY DIABETES INSIPIDUS
719
sipidus. In the third and fourth generations, 10 developed the disease, 9 did not, and of 21 (all belonging to generation four) no record is available. Among those whose records can be analyzed, there were 14 probable cases of diabetes insipidus in 4 generations whereas 9 were not affected. Of 14 men, 10 showed involvement; of 9 women, 4 were affected. Of the 4 patients given careful study, including urinary concentration tests, and proven to have the disease, 2 adults, brothers in generation three (T. R., aged 44 years, and V. R., deceased, aged 50) showed identical changes in the urinary tract and are of special interest to us as urologists. The vesical detrussor muscle was greatly hypertrophied as was also the internal sphincter. The bladder capacity was increased retaining 500 to 700 cc without discomfort. Both urters and renal pelves were enormously dilated (fig. 2). The arterial pressure and
Fm. 2. Pyelograms made before and after bilateral ureterotomy and transuriothra electroresection.
the blood nitrogen were elevated. In the case of T. R., a blood nonprotein nitrogen of 66, urea nitrogen 28.4, and creatinine of 2.15 dropped following resection of a muscular contracture of the internal urethral orifice and bilateral ureteral meatotomy. His blood pressure also dropped from 220/140 to 136/90. One child, aged 10 years (fig. 3) had definite early dilatation of both ureters, and her brother, aged 6, showed no change (generation four). One of the adults (V. R.) died of cerebral hemorrhage proven at autopsy. This is presumed to have been due to arterial hypertension secondary to renal damage from his advance:i hydro-ureteronephrosis. The other has arterial hypertension which was greatly benefited by improvement in renal function. Two adult members of the second generation died of cerebral hemorrhage. This suggests that they too may have suffered obstructive changes in the urinary tract. We suggest the following mechanism to explain the changes noted in these
720
CHARLES G. WELLER AND WILLIAM ELLIOTT
individuals. The enormously increased urinary output initiates a corresponding increase in physiologic activity of the bladder, eventually resulting in increased vesical capacity and compensatory hypertrophy of the detrussor and internal sphincter. The intramural portion of the ureters is progressively obstructed by this greatly hypertrophied bladder wall, leading to bilateral hydro-ureteronephrosis, renal insufficiency, and compensatory arterial hypertension. Referring to the literature, we were unable to find any mention of renal or ureteral pathological changes associated with diabetes insipidus except a statement appearing in the first and every succeeding edition of Osler's Principles and Practise of Medicine (Appleton 1892) as follows: "The kidneys have been
Fm. 3 Excretory urogram showing early hydro-ureteronephrosis
found enlarged and congested. The bladder has been found hypertrophied. Dilatation of the ureters and pelves of the kidneys has been present." One is immediately impressed with the lack of urologic study of the patients reported. Generally, the reports have been made either by internists, pediatricians, or by physicians in general practice. We have found no mention of pyelography, either excretory or retrograde. Since excretory urography is apt to be unsatisfactory due to dilution of the dye because of the intense polyuria, we would urge complete urologic study of these patients in order to evaluate the presence and extent of renal damage and of ureteral and vesical neck obstruction. We, as urologists, should emphasize to our confreres in other fields of medical practice the importance of transurethral resection and ureteral meatotomy in the correction of such obstructive changes.
HEREDITARY DIABETES INSIPIDUS
721
The diagnosis of diabetes insipidus is based on the increased intake and output of fluids, urinary specific gravity constantly below 1.010, and aglycosuria. The individual with diabetes insipidus is unable to concentrate the urine above 1.010 either by withholding fluids or by the administration of 2.5 per cent saline solution (0.25 cc per kg. per minute intravenously) unless posterior pituitary substance is administered (as pitressin 0.1 unit intravenously). In certain symptomatic cases, specific therapy may be instituted, such as anti-syphilitic management, irradiation therapy for neoplasms, inflammations, or Hand-Schuler-Christian disease. In cases not amenable to specific therapy, the symptom complex can be controlled by administration of posterior pituitary substance. This may be supplied as pitressin 2 to 3 cc daily or pitressin tannate 1.0 cc every 2 or 3 days intramuscularly, or by intranasal insuffiation of the desiccated gland as powder or jelly. Dosage must be adjusted to the requirements of each patient. For a more complete review of the subject of diabetes insipidus, including a generous bibliography, the reader is referred to articles in English by Jones, Fisher, Ingram and Ranson, Winer, and by Warkany and Mitchell. In summation, diabetes insipidus is a symptom complex of varied etiology and responds well to replacement therapy when the underlying cause cannot be treated directly. Fourteen cases occurring in four generations of the same family are here reported. Several of these individuals have shown definite pathologic changes in the urinary tract which are believed to have resulted from increased physiologic activity initiated by the extreme polyuria. We urge more frequent urologic study of individuals affected with this disease to the end that such urinary tract changes may be recognized and corrected.
12 Fox St., Aurora, Ill.
Vol. 64, No. 5, November 1950
Printed in U.S.A.
HEREDITARY DIABETES INSIPIDUS: UNUSUAL URINARY TRACT CHANGES CHARLES G. WELLER, WILLIAM ELLIOTT,
AND
A. RODRIGUEZ GUSMAN
Diabetes insipidus is a symptom complex consisting of polyuria with resultant polydipsia, and caused by pathological changes in the supraoptico-hypothalamic tract. Although not strictly a urologic condition, it is of interest to the urologist 1) because individuals suffering from this disease are inclined to seek his advice, 2) because the disease frequently demands his consideration in the differential diagnosis of common urologic conditions, and 3) because changes secondary to or associated with diabetes insipidus are occasionally discovered in the urinary tract. It is not our purpose to review the literature in this paper, but a brief resume of the salient points previously reported is essential to an understanding of the subject. The symptom complex was first recognized by Willis in 1674 as differing from diabetes mellitus. The earliest observation of familial involvement was reported by La Combe in 1841 (Fontan and Verger). A voluminous literature has accumulated, mainly dealing with experimental studies and etiologic data. The conclusions most important to an understanding of the subject are here summarized: 1) The supraoptic nucleii send fibers through the hypothalamus to the posterior lobe (pars nervosa) of the pituitary gland. Any bilateral interference with the continuity of this tract will initiate the symptoms of diabetes insipidus. 2) Polyuria is induced by suppression of the production of antidiuretic hormone by the posterior lobe, thereby allowing the diuretic hormone of the anterior lobe to act unopposed. The effect of this secretion is probably synergistic with the thyroid and adrenal hormones but does not ,vork exclusively through them. The resulting diuresis is due to decreased water absorption in the renal tubules, not to glomerular or circulatory effects. The polyuria is primary; the polydipsia, secondary. 3) Etiologic factors are divided into symptomatic and idiopathic. The average age of onset in the symptomatic group is 21 years, but in the familial cases polyuria is usually well established before the seventh year of life. The incidence of the two categories is reported to be about equal and is divided as follows: A. Symptomatic. a. Neoplasm of the pituitary or hypothalamus. b. Xanthomatosis (Hand-Schuler-Christian disease). c. Chronic encephalitis. d. Syphilis. e. Traumatic injury to the head. f. Pituitary infarction. g. Oerebrovascular accident. 716
HEREDITARY DIABETES INSIPIDUS
717
h. Subarachnoid hemorrhage. i. Hypothalamic damage. B. Idiopathic. j. Heredity. k. Undetermined. The familial form is probably less rare than the literature suggests. In 1945, Fontan and Verger collected 26 reported families and added one. Most of these cases have been reported in the German, French, and Spanish literature. Available information concerning the hereditary type has been well summarized by Warkany and Mitchell as follows: "In Adolph Weil's classic description, he gave a detailed account of four generations in a family consisting of 91 persons, 23 of whom suffered from diabetes insipidus. Weil's son, Alfred, continued these studies over a fifth generation of this family and found among 220 members a total of 35 in whom diabetes insipidus developed. Hereditary transmission from parent to offspring was direct in all but one instance. Of all of the children of affected parents, more than one half of the boys and one third of the girls suffered from the disease. Polyuria and polydipsia, while probably present at birth in these cases, were noticed definitely during the second year. The thirst increased as the age advanced and usually reached its height between the twentieth and thirtieth year. A slow improvement took place after the age of 50 years, but the affected persons :retained their abnormality for life. A few days before death the symptoms ceased. It was repeatedly observed that during periods of fever the symptoms disappeared and the specific gravity of the urine was a high as 1.018. By adding 12 gm. sodium chloride to the diet of one of these patients it could be shown that the kidneys had not lost their ability to concentrate. The abnormal water metabolism did not affect the general health and the patients carried on their usual occupations without much difficulty. There were no complaints of headache or vertigo. The family was free from mental disorders, neuroses, and alcoholism. The digestion was normal. Although in many cases the diet consisted mainly of bread and potatoes, a satisfactory nutritional state was maintained. The circulatory system showed no abnormalities, the heart was not hypertrophied, and arteriosclerosis did not develop in the older members of the family. The sexual functions were normal, and the fecundity of the family was above average. No difficulties were encountered by the affected women during pregnancy and delivery. There was no special predisposition to any particular disease. The course of contagious diseases in the children did not differ from that in normal children. Three members of this family had syphilis; this was certainly not etiologically related to the diabetes insipidus. Physical development was normal. The only development defect in this family was polydactylism in one child, but he did not suffer from diabetes insipidus. Some of the affected people lived to such ages as 83, 87, and 93 years. In addition to the family just described, there have been others in which diabetes insipidus appeared to be hereditary. Bulloch in 1909 published the pedigrees of 13 affected families, and a more recent critical review of this subject
718
CHARLES G. WELLER AND WILLIAM ELLIOTT
in 1935 by de Lange included 21 families. There can be no doubt that the hereditary form is more frequent than Lange's report indicated because to this can be added the reports, of Mensi, Peterman, Sugimoto, and Levit and Pessikova. In the family described by the W eils, the ratio of the affected to healthy siblings was such that diabetes insipidus could be considered a dominant character (Just). No generalizations, however, can be made. Levit and Pessikova examined 16 cases of "idiopathic" diabetes insipidus and found only 3 cases in which it was familial. In 2 of the families concerned only 2 members had the disease. It is evident, therefor, that idiopathic diabetes insipidus cannot always be a dominant hereditary character. The observation has been made that in several families, members of one generation may escape the condition. Both males and females are affected, although as previously stated, a greater number of males with the hereditary form have been reported. Transmission may
•
8/l~lll>lif ... lff>/Qf!J
~
,01.w,..,.f/'P,J111JtI-fJ.IV!m1NJJl'lt>v1)
0
IIQS)#l'TOMt,.H-
D/Afj£f£J /NSIPIPI/S roll/I GCNf/1.ATIONS
~ Jt/4
Frn. 1. Incidence of diabetes insipidus in family R
take place through either the paternal or maternal side. Consanguinity was present in only two families. The nature of hereditary diabetes insipidus can only be speculated on. No reliable reports of necropsies are available, and therefor the pathologic changes underlying this form of the disease are unknown. Adolph Weil suggested that there are hereditary morphologic abnormalities of certain parts of the nervous system. According to the present understanding of the pathogenesis of diabetes insipidus, these hereditary abnormalities should involve the diencephalo-pituitary region." Of the family in which our cases occurred, we personally studied 3 members and have obtained reports concerning one through another physician. Except for these 4, we assume that members of the family group whose fluid intake regularly exceeded 2 gallons daily suffered from diabetes insipidus. The earliest available record of this symptom complex in the family concerns 2 brothers whom we have designated generation one (fig. I). One of them is reported to have been an extremely heavy water drinker, whereas the other was normal in this respect, as were also his descendants. All of the affected brother's 3 children (generation two) showed symptoms of diabetes in-
HEREDITARY DIABETES INSIPIDUS
719
sipidus. In the third and fourth generations, 10 developed the disease, 9 did not, and of 21 (all belonging to generation four) no record is available. Among those whose records can be analyzed, there were 14 probable cases of diabetes insipidus in 4 generations whereas 9 were not affected. Of 14 men, 10 showed involvement; of 9 women, 4 were affected. Of the 4 patients given careful study, including urinary concentration tests, and proven to have the disease, 2 adults, brothers in generation three (T. R., aged 44 years, and V. R., deceased, aged 50) showed identical changes in the urinary tract and are of special interest to us as urologists. The vesical detrussor muscle was greatly hypertrophied as was also the internal sphincter. The bladder capacity was increased retaining 500 to 700 cc without discomfort. Both urters and renal pelves were enormously dilated (fig. 2). The arterial pressure and
Fm. 2. Pyelograms made before and after bilateral ureterotomy and transuriothra electroresection.
the blood nitrogen were elevated. In the case of T. R., a blood nonprotein nitrogen of 66, urea nitrogen 28.4, and creatinine of 2.15 dropped following resection of a muscular contracture of the internal urethral orifice and bilateral ureteral meatotomy. His blood pressure also dropped from 220/140 to 136/90. One child, aged 10 years (fig. 3) had definite early dilatation of both ureters, and her brother, aged 6, showed no change (generation four). One of the adults (V. R.) died of cerebral hemorrhage proven at autopsy. This is presumed to have been due to arterial hypertension secondary to renal damage from his advance:i hydro-ureteronephrosis. The other has arterial hypertension which was greatly benefited by improvement in renal function. Two adult members of the second generation died of cerebral hemorrhage. This suggests that they too may have suffered obstructive changes in the urinary tract. We suggest the following mechanism to explain the changes noted in these
720
CHARLES G. WELLER AND WILLIAM ELLIOTT
individuals. The enormously increased urinary output initiates a corresponding increase in physiologic activity of the bladder, eventually resulting in increased vesical capacity and compensatory hypertrophy of the detrussor and internal sphincter. The intramural portion of the ureters is progressively obstructed by this greatly hypertrophied bladder wall, leading to bilateral hydro-ureteronephrosis, renal insufficiency, and compensatory arterial hypertension. Referring to the literature, we were unable to find any mention of renal or ureteral pathological changes associated with diabetes insipidus except a statement appearing in the first and every succeeding edition of Osler's Principles and Practise of Medicine (Appleton 1892) as follows: "The kidneys have been
Fm. 3 Excretory urogram showing early hydro-ureteronephrosis
found enlarged and congested. The bladder has been found hypertrophied. Dilatation of the ureters and pelves of the kidneys has been present." One is immediately impressed with the lack of urologic study of the patients reported. Generally, the reports have been made either by internists, pediatricians, or by physicians in general practice. We have found no mention of pyelography, either excretory or retrograde. Since excretory urography is apt to be unsatisfactory due to dilution of the dye because of the intense polyuria, we would urge complete urologic study of these patients in order to evaluate the presence and extent of renal damage and of ureteral and vesical neck obstruction. We, as urologists, should emphasize to our confreres in other fields of medical practice the importance of transurethral resection and ureteral meatotomy in the correction of such obstructive changes.
HEREDITARY DIABETES INSIPIDUS
721
The diagnosis of diabetes insipidus is based on the increased intake and output of fluids, urinary specific gravity constantly below 1.010, and aglycosuria. The individual with diabetes insipidus is unable to concentrate the urine above 1.010 either by withholding fluids or by the administration of 2.5 per cent saline solution (0.25 cc per kg. per minute intravenously) unless posterior pituitary substance is administered (as pitressin 0.1 unit intravenously). In certain symptomatic cases, specific therapy may be instituted, such as anti-syphilitic management, irradiation therapy for neoplasms, inflammations, or Hand-Schuler-Christian disease. In cases not amenable to specific therapy, the symptom complex can be controlled by administration of posterior pituitary substance. This may be supplied as pitressin 2 to 3 cc daily or pitressin tannate 1.0 cc every 2 or 3 days intramuscularly, or by intranasal insuffiation of the desiccated gland as powder or jelly. Dosage must be adjusted to the requirements of each patient. For a more complete review of the subject of diabetes insipidus, including a generous bibliography, the reader is referred to articles in English by Jones, Fisher, Ingram and Ranson, Winer, and by Warkany and Mitchell. In summation, diabetes insipidus is a symptom complex of varied etiology and responds well to replacement therapy when the underlying cause cannot be treated directly. Fourteen cases occurring in four generations of the same family are here reported. Several of these individuals have shown definite pathologic changes in the urinary tract which are believed to have resulted from increased physiologic activity initiated by the extreme polyuria. We urge more frequent urologic study of individuals affected with this disease to the end that such urinary tract changes may be recognized and corrected.
12 Fox St., Aurora, Ill.