低鉀血癥診斷策略

1、低鉀血癥診斷策略,成都軍區(qū)總醫(yī)院內(nèi)分泌科 游志清,主要內(nèi)容,鉀平衡低血鉀常見(jiàn)原因低鉀血癥的診斷流程,主要內(nèi)容,鉀平衡低血鉀常見(jiàn)原因低鉀血癥的診斷流程,人體鉀的數(shù)據(jù),正常血鉀濃度3.5—5.5mmol/L體內(nèi)鉀總量。男性50—55mmol/Kg，女性40—50mmol/Kg鉀的分布:細(xì)胞內(nèi)98%，細(xì)胞外2%鉀的生理需要量:0.4mmol/Kg,3—4g（75—100mmol）鉀的排泄:腎85%，糞10%，汗5%無(wú)鉀攝

2、入，腎排鉀40—50mmol/日,鉀平衡,在細(xì)胞內(nèi)液（ICF）中K +中的濃度比細(xì)胞外液（ECF）中的高 30--50倍，每日攝入K +量大約與ECF K +相當(dāng)。維護(hù)正常的血清K+濃度需要在ECF 和ICF之間精細(xì)調(diào)節(jié)K+的分布（內(nèi)部K+平衡）和腎排泄K+ （外部K+平衡）。無(wú)論是在內(nèi)部（ECF 和ICF）之間平衡紊亂（例如 K+的轉(zhuǎn)移）或外部平衡（如K+的消耗），均可導(dǎo)致低鉀血癥。,轉(zhuǎn)運(yùn)K+的主要途徑—維持細(xì)胞內(nèi)高鉀,Ele

3、ctrolyte Blood Press 8:38-50, 2010,（Na+/H+ exchanger）,Metabolic alkalosis,Θ,,Cortical collecting duct,,ROMK,,,（Renal outer medullary K+ Channel）,,,,,,,,阿米洛利：作用于腎臟遠(yuǎn)端小管，阻斷Na+-K+交換機(jī)制，促使鈉、氯排泄而減少鉀和氫離子分泌,氫氯噻嗪主要抑制遠(yuǎn)端小管前段和近

4、端小管(作用較輕)對(duì)氯化鈉的重吸收，從而增加遠(yuǎn)端小管和集合管的Na+-K+交換，K+分泌增多。,氨苯喋啶：直接抑制腎臟遠(yuǎn)端小管和集合管的Na+-K+交換，從而使Na+、C1-、水排泄增多，而K+排泄減少,,,呋噻米本類藥物主要通過(guò)抑制腎小管髓袢厚壁段對(duì)氯化鈉的主動(dòng)重吸收（抑制基底膜外側(cè)存在與Na+-K+-ATP酶有關(guān)的Na+、Cl-配對(duì)轉(zhuǎn)運(yùn)系統(tǒng)），遠(yuǎn)端小管Na+濃度升高，促進(jìn)Na+-K+和Na+-H+交換增加，K

5、+和H+排出增多。通過(guò)抑制亨氏袢對(duì)Ca2+、Mg2+的重吸收而增加Ca2+、Mg2+排泄。尚可能抑制近端小管和遠(yuǎn)端小管對(duì)Na+、Cl-的重吸收，促進(jìn)遠(yuǎn)端小管分泌K+。,,,,,呋噻米：本類藥物主要通過(guò)抑制腎小管髓袢厚壁段對(duì)氯化鈉的主動(dòng)重吸收，結(jié)果管腔液Na+、C1-濃度升高，而髓質(zhì)間液Na+、Cl-濃度降低，使?jié)B透壓梯度差降低，腎小管濃縮功能下降，從而導(dǎo)致水、Na+、Cl-排泄增多。由于Na+重吸收減少，遠(yuǎn)端小管Na+濃度升高，促

6、進(jìn)Na+-K+和Na+-H+交換增加，K+和H+排出增多。至于呋塞米抑制腎小管髓袢升支厚壁段重吸收Cl-的機(jī)制，過(guò)去曾認(rèn)為該部位存在氯泵，目前研究表明該部位基底膜外側(cè)存在與Na+-K+-ATP酶有關(guān)的Na+、Cl-配對(duì)轉(zhuǎn)運(yùn)系統(tǒng)，呋塞米通過(guò)抑制該系統(tǒng)功能而減少Na+、C1-的重吸收。另外，呋塞米可能尚能抑制近端小管和遠(yuǎn)端小管對(duì)Na+、Cl-的重吸收，促進(jìn)遠(yuǎn)端小管分泌K+。呋塞米通過(guò)抑制亨氏袢對(duì)Ca2+、Mg2+的重吸收而增加Ca2+、Mg

7、2+排泄,腎對(duì)的K+調(diào)控,經(jīng)腎小球?yàn)V過(guò)的K+大部分被近曲小管和亨利氏袢重吸收終尿中的K+最終主要是由遠(yuǎn)曲小管（DCT）遠(yuǎn)端，連接小管和皮層集合管（CCD）控制。有兩個(gè)因素影響K+的排泄：CCD終端流速=尿滲透壓×容積/血漿滲透壓 或尿滲透壓/肌酐 CCD主細(xì)胞凈分泌K+( [K+]CCD)=（尿/血漿[K+])/(尿/血漿滲透壓）,腎對(duì)的K+調(diào)控,Q J Med 2005;

8、98:305–316,ENaC,epithelial Na+ channels,腎對(duì)的K+調(diào)控,Q J Med 2005; 98:305–316,腎對(duì)的K+調(diào)控,Electrolyte Blood Press 8:38-50, 2010,CCD,cortical collecting ductENaC,epithelial Na+ channels.,Aldosterone,,+,HCO3¯,plasma [K+]<3

9、.5mmol/L, TTKG ≥3indicates fast Na+ or slow Cl¯ disorders,K+：ROMK,,+,,-,ENaC,epithelial Na+ channels,主要內(nèi)容,鉀平衡低血鉀常見(jiàn)原因低鉀血癥的診斷流程,低血鉀原因,缺鉀性 攝入不足，＜3克/日，2周 排出過(guò)多 腎，胃腸，其他轉(zhuǎn)移性：代堿，大量糖（+胰島素），周癱，應(yīng)急，棉子油，氯化鋇，葉

10、酸，維生素B12稀釋性：水過(guò)多，水中毒,主要內(nèi)容,鉀平衡低血鉀常見(jiàn)原因低鉀血癥的診斷流程病史腎排鉀評(píng)估血壓血?dú)夥治鲅?、尿電解質(zhì)，RASS，皮質(zhì)醇及ACTH,病史,起病急緩伴隨癥狀過(guò)去史藥物史家族史,評(píng)判腎排鉀的指標(biāo)，尤其是低鉀麻痹時(shí),常用的4個(gè)指標(biāo)，均為隨意尿fractional excretion of K+, K+ 排泄分?jǐn)?shù)TTKG,transtubular K+ gradient，跨小管 K+ 梯度u

11、rine K+/creatinine ratio，尿 K+/肌酐比值urine osmolality/creatinine，尿滲透壓/肌酐比值主要目的：是否為腎排鉀增多,Arch Intern Med. 2004;164:1561-1566,A spot urine sample,Hypokalemic periodic paralysis (n = 30),Non–hypokalemic periodic paralysis (n

12、 = 13),a plasma K+≤ 3 mmol/L,TTKG,transtubular K+ gradient,=[(urine/plasma [K+])/(urine/plasma osmolality)].,,,RVH,renal vascular hypertension CAH,congenital adrenal Hyperplasia RTA,renal tubular acidosisCOA,coarctati

13、on of the aorta DKA,diabetic ketoacidosisRST,renin-secreting tumorsAME,apparent mineralocorticoid excess.,P,potassiumC,creatinine,GI,gastrointestinal,PP,periodic paralysis,PRA,plasma renin activityPAC,plasma aldost

14、erone concentration,IJKD 2008;2:115-22,Andersen-Tawil syndrome,：CLD,CLD： Congenital chloride-losing diarrhea,,Patients with a potassium excretion rate of 10 mmol/d to 15 mmol/d and a creatinine excretion rate of 10

15、mmol/d to 15 mmol/d will have a urine K/C ratio less than 1.5. ---J Clin Invest 1959; 38:1149–65,Cystic fibrosis,Andersen-Tawil syndrome,It is an autosmal-do

16、minant channelopathy resulting in episodic attacks of muscle weakness (mainly acute hypokalemia, but can be normo- or hyperkalemia), cardiac arrhythmia (ventricular arrhythmias and QT prolongation) and distinctive phys

17、ical features.These features often include a very small lower jaw (小頜畸形), dental abnormalities, low-set ears, widely spaced eyes, and unusual curving of the fingers or toes (clinodactyly). Some affected people also hav

18、e short stature and an abnormal curvature of the spine (脊柱側(cè)彎).,Andersen-Tawil syndrome,Two types of Andersen-Tawil syndrome are distinguished by their genetic causes. Type 1, which accounts for about 60 percent of all ca

19、ses of the disorder, is caused by mutations in the KCNJ2 gene. The remaining 40 percent of cases are designated as type 2; the cause of these cases is unknownMutations in the gene KCNJ2 encoding a pore-forming subunit

20、of the inward rectifier K channel protein, Kir2.1, which is expressed in skeletal muscles and heart, lead to this syndrome,Congenital chloride-losing diarrhea (CLD),Congenital chloride-losing diarrhea (CLD) is a rare au

21、tosomal recessive disorder characterized by watery diarrhea, hypokalemia and hypochloremic metabolic alkalosis with high fecal content of Cl¯ (>90 mEq/L),Cystic fibrosis,Cystic fibrosis (CF) is an exocrine diseas

22、e affecting multiple organ systems. The defect in the cystic fibrosis transmembrane regulator (CFTR), acting primarily as a Cl¯ channel, is associated with CF,. Hypokalemia is not uncommon in patients with CF, espec

23、ially in tropical or subtropical areas. Defective chloride reabsorption by the dysfunctional CFTR in the sweat ducts of CF patients is responsible for excessive Cl¯ and Na+ loss in sweat. ECF volume depletion with s

24、econdary hyperaldosteronism not only causes Na+ reabsorption and K+ secretion in the CCD, but may also augment K+ secretion in sweat ducts and thereby contribute to the hypokalemia.,Electrolyte Blood Press 8:38-50, 2010,

25、ECF,extracellular fluid BP, blood pressure,ECF, BP,RVH:right ventricular hypertrophy,AME:Apparent mineralocorticoid excess,DOC:11-deoxycorticosterone,Electrolyte Blood Press 8:38-50, 2010,ECF,extracellular fluid BP, bl

26、ood pressure,,,Liddle’s syndrome,其原因是. ENaC的β或γ單位突變，導(dǎo)致其胞漿內(nèi)C末端丟失或結(jié)構(gòu)變化。突變后的 ENaC 保持被激活形式。 not internalized (clathrin-coated pits pathway) or degraded (Nedd4 pathway)突變后的 ENaC對(duì)阿米洛利和氨苯喋啶敏感,Apparent mineralocorticoid excess

27、 (AME),AME ,caused by mutations in the gene (HSD11B2) encoding renal-specific 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). is a rare but potentially fatal autosomal recessive form of hypertension and hypokalemic m

28、etabolic alkalosis associated with hyporeninemia and hypoaldosteronemia and an abnormal ratio of urinary metabolites of cortisol with a high tetrahydrocortisol:tetrahydrocortisone (THF:THE) ratio,,,11β-HSD2,,Cortisol,cor

29、tisone,MR,+,,The principal cells of distal tubules,lycyrrhetinic acid,,Θ,Electrolyte Blood Press 8:38-50, 2010,ECF, BP,,,RTA,renal tubular acidosisGS,Gitelman’s syndromeBS,Bartter’s syndrome,Bartter’s syndrome (BS) a

30、nd Gitelman’s syndrome (GS),BS results from defective reabsorption of NaCl in the LOH whereas GS is secondary to defective reabsorption of NaCl in the DCT.High urine Ca2+ and Mg2+ excretion is universally present in les

31、ions of the loop of Henle (LOH) whereas low urine Ca2+ and high Mg2+ excretion is invariably found in lesions of the distal convoluted tubule(DCT),CTAL, cortical thick ascending limb,Bartter’s syndrome (BS) and Gitelman

32、’s syndrome (GS),The five subtypes of BS arise from inactivation mutations in genes encoding the Na+/K+/2Cl¯ cotransporter (NKCC2), K+ channel (ROMK), kidney-specific Cl¯ channel (CLCNKB), barttin (BSND) and ca

33、lcium-sensing receptors (CaSR),Fig. Transport proteins in the thick ascending limb (TAL) of loop of Henle (LOH) (left panel) and distal convoluted tubule (DCT) (right panel) affected by gene mutations.,Electrol

34、yte Blood Press 8:38-50, 2010,,,,,,,Bartter’s syndrome (BS) and Gitelman’s syndrome (GS),At the molecular level, GS is mostly due to inactivating mutations in the SLC12A3 gene, which encodes the thiazide-sensitive Na+/Cl

35、¯ cotransporter (NCC) on the apical membrane of the DCT,Fig. Mechanisms for persistent hypokalemia in Gitelman's syndrome (GS),ROMK, renal outer medullary K+ channel CNT, cortical connecting tubulesNCC,

36、thiazide-sensitive Na+/Cl¯ cotransporter,Electrolyte Blood Press 8:38-50, 2010,Bartter’s syndrome (BS) and Gitelman’s syndrome (GS),A maternal history of polyhydramnios, age of onset, neurologic symptoms, deafness,

37、presence of nephrocalcinosis or renal stones, and serum divalent concentration with their urine excretion rates help distinguish among the subtypes of BS and GS. Because Cl- channels are expressed in both the basolatera

38、l membrane of LOH and DCT, some patients with classical BS may have clinical profiles similar to that of GS.,Bartter’s syndrome (BS) and Gitelman’s syndrome (GS),Unlike BS, non-steroid anti-inflammatory drugs (NSAIDs) ar

39、e usually not effective in patients with GS due to the relatively normal urinary prostaglandin E2 excretion.,Characteristic of Bartter’s syndrome (BS) and Gitelman’s syndrome (GS),AR, autosomal recessive,SeSAME, seizures

40、, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance,PHYSIOLOGICAL REVIEWS Vol. 80, No. 1, January 2000,Orphanet Journal of Rare Diseases 2008, 3:22,DCT-1 (top) and DCT-2 (bottom) cells in norm

41、al (left) and Gitelman’s (right) individuals are shown.,PHYSIOLOGICAL REVIEWS Vol. 80, No. 1, January 2000,,,,17α-羥化酶缺乏，最多見(jiàn)于女性患者，有些到成年表現(xiàn)為皮質(zhì)醇低水平，ACTH代償性增高。原發(fā)性閉經(jīng)，性幼稚，很少有男性假兩性畸形。鹽類皮質(zhì)激素分泌過(guò)多引起高血壓，以11-脫氧皮質(zhì)酮增高為主。部分聯(lián)合缺乏17,20裂解

42、酶，不缺乏皮質(zhì)醇，無(wú)腎上腺皮質(zhì)增生。,,,,11β-羥化酶缺乏使皮質(zhì)醇和皮質(zhì)酮的形成受阻，ACTH釋放過(guò)高，致深度黑色素沉著，由于11-去氧皮質(zhì)酮分泌過(guò)量而引起高血壓，無(wú)明顯性征異常。,21-羥化酶的不足或缺乏使17-羧孕酮不能轉(zhuǎn)化為皮質(zhì)醇，多見(jiàn)的不足有二種形式：（1）多種多樣的丟鈉，醛固酮低或缺乏；（1）更常見(jiàn)的是非丟鈉型，多毛，男性化，低血壓和色素沉著常見(jiàn)。,Hyperchloremic metabolic acidosis--re

43、nal tubular acidosis (RTA),Hyperchloremic metabolic acidosis involving both K+ depletion and direct or indirect loss of HCO3¯An indirect estimate of NH4+ can be obtained from the urine anion gap (Na++K+–Cl¯) o

44、r osmolal gap (measured-calculated urine osmolality)/2.Positive urine net charge and osmolal gap less than 100 mOsm/kg H2O are indicative of low urine NH4+ excretion, pointing to the diagnosis of RTA.Intravenous NaHCO3