Diabetes insipidus

Japanese: 尿崩症

Definition/Concept Vasopressin (AVP), an antidiuretic hormone, is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus, transported to the posterior pituitary gland by axonal transport, and then secreted into the bloodstream, promoting water reabsorption in the kidney. Diabetes insipidus is a disease characterized by polyuria, thirst, and polydipsia due to impaired synthesis, secretion, and action of AVP.
Classification Diabetes insipidus is broadly divided into central diabetes insipidus, which is caused by disorders of AVP synthesis and secretion, and nephrogenic diabetes insipidus, which is caused by disorders of AVP action. Central diabetes insipidus is classified into idiopathic, in which no organic abnormality is found in the hypothalamus-posterior pituitary system, secondary, in which organic abnormality is found in the hypothalamus-posterior pituitary system, and familial, which generally shows an autosomal dominant inheritance pattern. Central diabetes insipidus can also be classified into complete and partial types depending on the degree of AVP secretion disorder (Figure 12-3-5). Meanwhile, nephrogenic diabetes insipidus is classified into congenital, which occurs from birth, and acquired, which is caused by electrolyte abnormalities.
Causes and Etiology Although autoimmunity has been suggested to be involved in idiopathic central diabetes insipidus, the mechanism of onset has not yet been fully elucidated. In secondary central diabetes insipidus, AVP neurons are damaged by tumors, inflammation, surgery, etc., resulting in impaired synthesis and secretion of AVP. In familial central diabetes insipidus, mutations are found in the AVP gene locus, which impairs the folding of the mutated AVP precursor. There are three types of AVP receptors: _V1a , _V1b , and _V2 . AVP promotes water reabsorption via the _V2 receptor expressed in the collecting duct of the kidney, but congenital nephrogenic diabetes insipidus is caused by genetic mutations in the _V2 receptor or the water channel aquaporin-2. Acquired nephrogenic diabetes insipidus is caused by electrolyte abnormalities such as hypercalcemia and hypokalemia, or by drugs such as lithium.
Epidemiology According to an epidemiological survey conducted by the Ministry of Health, Labor and Welfare in 1999, the number of patients with central diabetes insipidus is estimated to be approximately 4,700. The ratio of idiopathic central diabetes insipidus to secondary central diabetes insipidus varies depending on the report, but the ratio of secondary central diabetes insipidus is increasing with the advancement of imaging diagnosis. Familial central diabetes insipidus accounts for approximately 1% of central diabetes insipidus, and most cases show an autosomal dominant inheritance pattern, with most gene mutations found in the region of neurophysin, the carrier protein of AVP (Babey et al., 2011). In congenital nephrogenic diabetes insipidus, 90% of cases are caused by mutations in the _V2 receptor of AVP, and the remaining 10% are caused by gene mutations in aquaporin-2. Nephrogenic diabetes insipidus caused by mutations in the _V2 receptor for AVP is inherited in an X-linked recessive manner, whereas nephrogenic diabetes insipidus caused by mutations in the aquaporin-2 gene is inherited in either an autosomal recessive or autosomal dominant manner (Babey et al., 2011).
Pathologically, germ cell tumors and craniopharyngiomas are tumors that frequently cause secondary central diabetes insipidus. In cases of lymphocytic posterior infundibulitis, an inflammatory disease, pituitary or pituitary stalk biopsies show cellular infiltration, mainly lymphocytes. In recent years, central diabetes insipidus associated with IgG4-related disease has also been reported, and in these cases, pituitary or pituitary stalk biopsies show infiltration of IgG4-positive plasma cells.
Pathophysiology In central diabetes insipidus, impaired synthesis and secretion of AVP, and in nephrogenic diabetes insipidus, impaired AVP action impairs reabsorption of water in the kidneys, causing large amounts of hypotonic urine and dehydration. When serum sodium concentration rises to around 145 mEq/L, thirst occurs and the patient consumes fluids until the thirst is quenched, but in diabetes insipidus, large amounts of hypotonic urine persist, so even with polydrinking, patients tend to become dehydrated. In addition, because the thirst center is located in the hypothalamus, just like AVP neurons, if damage caused by a tumor or other condition extends not only to AVP neurons but also to the thirst center, thirst impairment will occur, and patients may develop severe hypernatremia because thirst does not occur despite dehydration.
Clinical manifestations
1) Symptoms:
Patients experience frequent dry mouth and the need to urinate, waking several times during the night to drink fluids and urinate. Patients may also complain of dry mouth and decreased sweating due to dehydration, and loss of appetite due to the large amount of fluid they are drinking.
2) Objective symptoms:
Diabetes insipidus causes dehydration, resulting in weight loss and dry oral mucosa.
Test results
1) Urine test:
Generally, polyuria is defined as a daily urinary volume exceeding 3 L, but in diabetes insipidus, it is not uncommon for the daily urinary volume to exceed 10 L. Urine specific gravity and urinary osmolality are low, reflecting a disorder of urinary concentration.
2) Blood test:
Serum sodium concentration and plasma osmolality are slightly higher than the upper limit of normal. In central diabetes insipidus, plasma AVP concentration is relatively low compared to serum sodium concentration and plasma osmolality. On the other hand, in nephrogenic diabetes insipidus, there is no decrease in plasma AVP concentration.
DiagnosisIf thirst, polydipsia, and polyuria are present and blood and urine tests suggest diabetes insipidus, the following tests should be performed (Guide to the diagnosis and treatment of reduced vasopressin secretion (central diabetes insipidus), 2010).
1) Hypertonic saline challenge test:
5% hypertonic saline is administered intravenously at a rate of 0.05 mL/kg/min for 120 minutes to raise the serum sodium concentration by approximately 10 mEq/L and examine the AVP response. In healthy individuals, plasma AVP concentration increases in proportion to an increase in serum sodium concentration, but in central diabetes insipidus, there is a decreased AVP increase response (Figure 12-3-5). There are two types of central diabetes insipidus: one in which no increase in AVP response is observed (complete type) and one in which there is a slight increase (partial type).
2) Water deprivation test:
Fasting is continued for 6 hours or until 3% of body weight is lost, and changes in urine osmolality are examined. In healthy individuals, urine osmolality increases over time, but in diabetes insipidus, urine osmolality remains low. After water restriction is completed, water-soluble pitresin is injected subcutaneously. In central diabetes insipidus, urine osmolality increases to 300 mOsm/kg or more, but in nephrogenic diabetes insipidus, no increase in urine osmolality is observed.
3) Imaging tests:
The hypothalamus-posterior pituitary system is evaluated using MRI. In healthy individuals, high signals are seen in the posterior pituitary gland on T1 _- weighted images, but in patients with central diabetes insipidus, this high signal disappears (Figure 12-3-6). This is thought to be because the high signal in the posterior pituitary gland on T1 _- weighted images reflects AVP that has accumulated in the pituitary gland. Furthermore, in patients with secondary central diabetes insipidus, findings suggestive of tumors or inflammation are seen in the hypothalamus-posterior pituitary system.
Differential diagnosis: Diabetes mellitus is the most common disease that presents with polyuria. Therefore, in the differential diagnosis of polyuria, it is first necessary to determine whether or not osmotic diuresis is occurring due to increased glucose excretion in the urine. If diabetes-related polyuria is ruled out, the differential diagnosis then moves on to diabetes insipidus and psychogenic polydipsia. Psychogenic polydipsia is a condition in which polyuria occurs due to increased thirst and excessive water intake. Like diabetes insipidus, urine specific gravity and urine osmolality are low, but serum sodium concentration and plasma osmolality are at or below the lower limit of normal. In addition, psychogenic polydipsia can be differentiated from diabetes insipidus because an increased AVP response is observed in the hypertonic saline load test, and an increase in urine osmolality is observed in the water deprivation test.
If complications are left untreated for a long period of time, megacystis and hydronephrosis may occur. It should also be noted that if left untreated, dehydration (hypernatremia) may occur, and after starting treatment with desmopressin, an AVP analog, water intoxication (hyponatremia) may occur. Furthermore, if central diabetes insipidus is complicated by adrenal insufficiency, polyuria may not be apparent (masked diabetes insipidus), but polyuria becomes apparent when steroid hormone supplementation is started.
Course and prognosis Regardless of the type of disease, once central diabetes insipidus develops , recovery is rare. However, if thirst is maintained and drinking is possible, the prognosis is good, and in some cases the disease is not diagnosed until 10 years have passed since onset. On the other hand, if thirst is impaired or drinking is restricted for some reason, the patient may develop severe dehydration and may progress to a serious condition. The prognosis of secondary central diabetes insipidus also depends on the underlying disease. In cases of nephrogenic diabetes insipidus caused by electrolyte abnormalities, diabetes insipidus improves with improvement of electrolyte balance, and in cases of nephrogenic diabetes insipidus caused by drugs, diabetes insipidus improves by discontinuing the causative drug.
Treatment
1) Central diabetes insipidus:
Treatment is with desmopressin nasal drops, nasal spray, or tablets. In order to avoid water intoxication, treatment with desmopressin is generally started with a small dose (2.5 μg per dose for nasal drops or spray, 60 μg per dose for tablets), and the dosage is adjusted while monitoring urine volume, serum sodium concentration, etc.
2) Nephrogenic diabetes insipidus:
There is no fundamental treatment for congenital nephrogenic diabetes insipidus, and it is recommended that salt intake be restricted from infancy. Although the effect is insufficient, thiazide diuretics or large doses of desmopressin may be administered. [Hiroshi Arima]
■ References
Babey M, Kopp P, et al: Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol, 7: 701-714, 2011.
Diagnosis and treatment guide for vasopressin hyposecretion (central diabetes insipidus). Research on diencephalo-pituitary dysfunction, funded by the Ministry of Health, Labor and Welfare Science Research Grant, Research on overcoming intractable diseases, FY2010, General and co-research report, pp155-157, Ministry of Health, Labor and Welfare, Tokyo, 2010.

Figure 12-3-5
Relationship between serum sodium concentration and plasma AVP concentration ">

Figure 12-3-5

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　抗利尿ホルモンであるバソプレシン（arginine vasopressin：AVP）は視床下部視索上核および室傍核で合成され，軸索輸送により下垂体後葉に運ばれた後に血中に分泌され，腎臓において水の再吸収を促進する．尿崩症はAVPの合成・分泌・作用障害により多尿および口渇，多飲を呈する疾患である．
分類
　尿崩症は，AVPの合成・分泌の障害に起因する中枢性尿崩症（central diabetes insipidus）と，AVPの作用障害による腎性尿崩症（nephrogenic diabetes insipidus）に大別される．中枢性尿崩症は器質的異常を視床下部-下垂体後葉系に認めない特発性，器質的異常を視床下部-下垂体後葉系に認める続発性，原則として常染色体優性遺伝形式を呈する家族性に分類される．また，中枢性尿崩症はAVPの分泌障害の程度から完全型と部分型に分類されることもある（図12-3-5）．一方，腎性尿崩症は出生時から発症する先天性と電解質異常などによる後天性に分類される．
原因・病因
　特発性中枢性尿崩症に関しては自己免疫の関与が示唆されているが，発症機序に関してはいまだ十分には解明されていない．続発性中枢性尿崩症では腫瘍や炎症，手術などによりAVPニューロンが傷害を受けてAVPの合成および分泌の障害が生じる．家族性中枢性尿崩症はAVP遺伝子座に変異を認め，変異したAVP前駆体の折りたたみなどが障害される．AVPの受容体にはV_1a， V_1b， V₂の3種類が存在し，AVPは腎臓の集合管に発現するV₂受容体を介して水の再吸収を促すが，先天性腎性尿崩症はV₂受容体もしくは水チャネルであるアクアポリン-2の遺伝子変異により発症する．後天性腎性尿崩症は高カルシウム血症，低カリウム血症などの電解質異常やリチウムなどの薬剤により生じる．
疫学
　1999年度に行われた厚生省の疫学調査によれば中枢性尿崩症の患者数は約4700人と推計される．特発性中枢性尿崩症と続発性中枢性尿崩症の割合は報告により異なるが，画像診断の進歩に伴い続発性中枢性尿崩症の割合が増加している．家族性中枢性尿崩症は中枢性尿崩症の約1％を占め，ほとんどは常染色体優性遺伝形式を示し，遺伝子変異の多くはAVPのキャリアプロテインであるニューロフィジンの領域に認められる（Babeyら，2011）．先天性腎性尿崩症はAVPのV₂受容体の変異が90％で残りの10％がアクアポリン-2の遺伝子変異である．AVPのV₂受容体の変異による腎性尿崩症はX連鎖劣性遺伝形式を示すが，アクアポリン-2の遺伝子変異による腎性尿崩症は常染色体劣性遺伝のものと常染色体優性遺伝のものがある（Babeyら，2011）．
病理
　続発性中枢性尿崩症をきたす腫瘍としては胚細胞腫瘍と頭蓋咽頭腫の頻度が高い．炎症性疾患であるリンパ球性漏斗下垂体後葉炎では下垂体または下垂体茎生検でリンパ球を中心とした細胞浸潤を認める．近年，IgG4関連疾患に伴う中枢性尿崩症も報告されており，こうした症例では下垂体または下垂体茎生検でIgG4陽性形質細胞の浸潤を認める．
病態生理
　中枢性尿崩症ではAVPの合成および分泌の障害により，また腎性尿崩症ではAVPの作用障害により腎臓における水の再吸収が損なわれ，大量の低張尿が生じ脱水となる．血清ナトリウム濃度がおよそ145 mEq/L前後まで上昇すると口渇が生じ，患者は口渇が癒えるまで水分を摂取するが，尿崩症では大量の低張尿が持続するため多飲をもってしても脱水傾向となる．また，渇中枢はAVPニューロンと同様に視床下部に存在するため，腫瘍などにより障害がAVPニューロンのみでなく渇中枢まで及ぶと渇感障害を呈し，脱水にもかかわらず口渇が生じないため患者は著しい高ナトリウム血症を呈することがある．
臨床症状
1）自覚症状：
口渇および尿意が頻回に生じ，夜間も何度か覚醒して水分を摂取するとともに排尿をする．脱水のため口腔内の乾燥や発汗低下を，また大量の水分を摂取するため食欲低下を訴える場合もある．
2）他覚症状：
尿崩症では脱水のため体重減少や口腔粘膜の乾燥などを認める．
検査成績
1）尿検査：
一般的に1日尿量が3 Lをこえる場合を多尿と定義するが，尿崩症では1日尿量が10 Lをこえることもまれではない．尿の濃縮障害を反映して尿比重および尿浸透圧は低値を示す．
2）血液検査：
血清ナトリウム濃度および血漿浸透圧は正常上限から軽度高値を示す．中枢性尿崩症において血漿AVP濃度は血清ナトリウム濃度および血漿浸透圧に対して相対的に低値を示す．一方，腎性尿崩症では血漿AVP濃度の低下を認めない．
診断
　口渇，多飲，多尿を認め，血液・尿検査から尿崩症が疑われる場合には以下の検査を行う（バゾプレシン分泌低下症（中枢性尿崩症）の診断と治療の手引き，2010）．
1）高張食塩水負荷試験：
5％高張食塩水を0.05 mL/kg/分の速さで120分間点滴投与し，血清ナトリウム濃度を約10 mEq/L上昇させてAVPの反応を検討する．健常人では血清ナトリウム濃度の上昇に比例して血漿AVP濃度も上昇するが，中枢性尿崩症ではAVPの増加反応の低下を認める（図12-3-5）．中枢性尿崩症ではAVPの増加反応をまったく認めないもの（完全型）と，軽度増加を認めるもの（部分型）がある．
2）水制限試験：
絶飲食を6時間あるいは体重が3％減少するまで継続し，尿浸透圧の変化を検討する．健常人では尿浸透圧が継時的に上昇するが，尿崩症では尿浸透圧は低値のままである．水制限終了後に水溶性ピトレシンを皮下注射する．中枢性尿崩症では尿浸透圧が300 mOsm/kg以上に上昇するが，腎性尿崩症では尿浸透圧の上昇を認めない．
3）画像検査：
MRIにて視床下部-下垂体後葉系の評価を行う．健常人ではT₁強調画像で下垂体後葉に高信号を認めるが，中枢性尿崩症の患者では高信号が消失する（図12-3-6）．これはT₁強調画像の下垂体後葉高信号が下垂体に蓄積されているAVPを反映しているためと考えられている．また，続発性中枢性尿崩症では視床下部-下垂体後葉系に腫瘍や炎症を示唆する所見を認める．
鑑別診断
　多尿を呈する疾患として最も頻度が高いのは糖尿病である．したがって，多尿の鑑別診断においては尿中への糖排泄増加に伴い浸透圧利尿を呈しているか否かをまず判断する必要がある．　糖尿病による多尿が否定された場合には尿崩症と心因性多飲症との鑑別に移る．心因性多飲症は口渇が亢進して水分を過剰に摂取するために多尿となる病態である．尿比重および尿浸透圧が低値であることは尿崩症と同様であるが，血清ナトリウム濃度および血漿浸透圧は正常下限から低値を示す．また，心因性多飲症では高張食塩水負荷試験においてAVPの増加反応を認め，水制限試験では尿浸透圧の上昇を認めることから尿崩症と鑑別できる．
合併症
　未治療の期間が長い場合には巨大膀胱や水腎症を呈することがある．また未治療の場合には脱水（高ナトリウム血症）を，AVPアナログであるデスモプレシンによる治療開始後には水中毒（低ナトリウム血症）を呈する可能性があることに留意する必要がある．なお，中枢性尿崩症に副腎不全を合併すると多尿が不顕在化する（仮面尿崩症）が，ステロイドホルモンの補充を開始すると多尿が顕在化する．
経過・予後
　中枢性尿崩症は病型にかかわらず，いったん発症すると回復することはまれであるが，渇感が保たれ，飲水が可能な状態であれば生命予後は良好であり，発症後10年以上経過してはじめて診断される場合もある．一方，渇感が障害されている場合や何らかの原因で飲水が制限される場合には著明な脱水を呈し，重篤な転機をたどる場合もある．また，続発性中枢性尿崩症の予後は原疾患に依存する側面もある．電解質異常による腎性尿崩症では電解質バランスの改善とともに，また薬剤による腎性尿崩症では原因となる薬剤を中止することで尿崩症は改善する．
治療
1）中枢性尿崩症：
デスモプレシン点鼻液，点鼻スプレーあるいは錠剤を用いて治療する．水中毒を避ける目的で原則としてデスモプレシンによる治療は少量（点鼻液あるいはスプレーの場合は2.5 μg/回，錠剤の場合は60 μg/回）から開始し，尿量，血清ナトリウム濃度などをみながら投与量を調整する．
2）腎性尿崩症：
先天性腎性尿崩症には根本的な治療法は存在せず，幼少期から塩分制限を行うことが推奨されている．効果は不十分であるが，サイアザイド利尿薬や大量のデスモプレシンを投与することもある．［有馬　寛］
■文献
Babey M， Kopp P, et al: Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol, 7: 701-714， 2011.
バゾプレシン分泌低下症（中枢性尿崩症）の診断と治療の手引き．厚生労働科学研究費補助金難治性疾患克服研究事業間脳下垂体機能障害に関する調査研究平成22年度総括・分担研究報告書， pp155-157，厚生労働省，東京， 2010.

図12-3-5
血清ナトリウム濃度と血漿AVP濃度の関係">

図12-3-5

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