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Cirrhosis: new research provides a basis for rational andtargeted treatments

Citation for published version:Iredale, JP 2003, 'Cirrhosis: new research provides a basis for rational and targeted treatments' BMJ, vol327, no. 7407, pp. 143-7., 10.1136/bmj.327.7407.143

Digital Object Identifier (DOI):10.1136/bmj.327.7407.143

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Clinical review

Science, medicine, and the futureCirrhosis: new research provides a basis for rational andtargeted treatmentsJohn P Iredale

Liver transplantation and antiviral treatments for hepatitis have improved the outlook for manypatients with liver disease. For patients with cirrhosis, new developments herald targeted treatments

It is an exciting time to be working in hepatology. Thesuccess of liver transplantation and the advances in theradiological and endoscopic management of portalhypertension have improved the longevity and qualityof life of patients with liver cirrhosis. Additionally, thedevelopment of effective antiviral treatments meansthat disease can be cured in many patients infectedwith hepatitis B and hepatitis C. However, theseinterventions also serve to highlight our current impo-tence in altering the underlying fibrotic process inmany patients with liver disease. This rather depressingperspective may soon change: data from clinical andlaboratory based research are showing that cirrhosismay be reversible. By highlighting the attributesrequired of an effective antifibrotic, a new dynamicmodel is likely to lead to the development of targetedtreatment for liver cirrhosis.

MethodsThis article is based on knowledge accrued over 13years of work investigating the mechanisms of fibrosisand aspects of hepatic stellate cell biology and onregular Medline searches of the peer reviewedscientific literature during that time. The field hasbenefited from the recognition that certain mecha-nisms are common to hepatic, renal, and pulmonaryfibrosis, and I have reviewed models of these pro-cesses while preparing this article. My examples high-light how laboratory based studies of the biologyof hepatic fibrosis may inform the design of futuretreatments.

Clinical impact of cirrhosisLiver fibrosis and its end stage, cirrhosis, representenormous worldwide healthcare problems. In theUnited Kingdom, more than two thirds of the 4000people who died of cirrhosis in 1999 were under 65,and the incidence of cirrhosis related death is increas-ing.1 Worldwide, the common causes of liver fibrosisand cirrhosis include hepatitis B and hepatitis C andalcohol. Other causes include immune mediated dam-age, genetic abnormalities, and non-alcoholic steato-

hepatitis, which is associated with diabetes and themetabolic syndrome.2 Changing patterns of alcoholconsumption in the West and the increasing rates ofobesity and diabetes mean that advances in preventingand treating viral hepatitis may be offset by an increas-ing burden of fibrosis and cirrhosis related to alcoholand non-alcoholic steatohepatitis.13

Current treatments for cirrhosis are limited toremoving the underlying injurious stimulus (wherepossible); eradicating viruses using interferon, riba-virin, and lamivudine in viral hepatitis; and liver trans-plantation. Transplantation is a highly successfultreatment for end stage cirrhosis, with a 75% five yearsurvival rate. But limited availability of organs, growinglists of patients needing a transplant, issues of compat-ibility, and comorbid factors mean that not everyone iseligible for transplantation. As a result, effective anti-fibrotic treatments are needed urgently.

Summary points

Fibrosis, the livers wound healing response, isbi-directional and potentially reversible

Antiviral treatments provide increasing evidencefor reversibility of fibrosis and cirrhosis

Excess fibrillar (scar) matrix can be degraded evenin advanced cirrhosis but is held in check byprotease inhibitors termed TIMPs

Antifibrotic treatments are likely to bedeveloped in the next decade, on the basis of abetter understanding of the pathogenesis offibrosis

Hepatic stellate cells have been shown tocontribute to portal hypertension by dynamiccontractile activity; this could lead to thedesign of specific agents to reduce portalhypertension

Division ofInfection,Inflammation andRepair, Universityof Southampton,SouthamptonGeneral Hospital,SouthamptonSO16 6YDJohn P Iredaleprofessor

jpi@soton.ac.uk

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Inflammation and repairLiver fibrosis and cirrhosis represent a continuous dis-ease spectrum characterised by an increase in totalliver collagen and other matrix proteins which disruptthe architecture of the liver and impair liver function.4 5

Fibrosis results from sustained wound healing in theliver in response to chronic or iterative injury. Thewound healing response is an integral part of the over-all process of inflammation and repair: it is dynamicand has the potential to resolve without scarring (fig 1).

Pathogenesis of fibrosisHigh quality experimental evidence supports thehypothesis that the final common pathway of fibrosis ismediated by the hepatic stellate cells.47 Hepatic stellatecells in normal liver store retinoids and reside in thespaces of Disse (fig 2). In injured areas of the liver,hepatic stellate cells undergo a remarkable transforma-tion: they resemble myofibroblasts and expresscontractile proteins. In this activated phenotype,hepatic stellate cells proliferate and are known to bethe major source of the fibrillar collagens that charac-terise fibrosis and cirrhosis (fig 2). The mechanismsmediating activation of hepatic stellate cells are a majorsubject of research.

In injured areas, soluble factors (cytokines) arereleased by the incoming inflammatory cells, the dam-aged and regenerating hepatocytes, and other livercells that target the hepatic stellate cells, activatingthem so they become the central mediators of woundhealing.5 Because of the key role of inflammation,removing the causative agent and treating the patientwith immunosuppressive drugs are effective interven-tions for some diseases (box). Greater understanding ofthe specific cytokine and chemokine messengers thatmediate the inflammatory process in liver disease isinforming the design of future treatments. This isexemplified by the identification of interleukin-10 as adownregulator of the inflammatory response andtumour necrosis factor as a pro-inflammatorymediator.8 9 Studies using interleukin-10 knockoutmice have identified this cytokine as a majoranti-inflammatory effector in fibrotic liver injury. Apilot study suggested that interleukin-10 may bevaluable clinically in the context of hepatitis C virusinfection,10 but definitive evidence of efficacy has yet tobe produced in a large scale clinical trial. Antagonisingtumour necrosis factor would also be expected todownregulate hepatic inflammation. Reagents toneutralise tumour necrosis factor are available forclinical use, and this approach is likely to beinvestigated further in the clinic.11

Another approach to chronic liver fibrosis is toblock the signals which promote transition of hepaticstellate cells from a quiescent to an activatedphenotype and promote collagen secretion. Foremostamong the soluble mediators promoting the fibro-genic response from hepatic stellate cells is transform-ing growth factor -1 (box). This cytokine also has arole in the development of fibrosis in other organs,including the lung and kidney.12 13 The activatedhepatic stellate cells respond to it by increasingproduction of collagen and decreasing its breakdown(see below). Models in other internal organs suggestthat modifying the secretion or activity of transforminggrowth factor -1 can attenuate fibrosis, whichindicates that this is a possible antifibrotic target in theliver.14 Recent studies of experimental liver fibrosishave shown the potential of this approach.15

Matrix synthesis and turnover in fibrosisand cirrhosisActivated stellate cells proliferate, with the result thatincreases in numbers of hepatic stellate cells, inaddition to increases in secretion of the fibrillar (or

Normal liver Inflamed Fibrotic liver Cirrhotic liver

Resolution Remodelling of cirrhosis

?

a c

ef

b d

Fig 1 Liver cirrhosis as wound healing: damage to the normal liver (a) results ininflammation (b) and activation of hepatic stellate cells (brown) to secrete collagen,culminating in the development of fibrosis (c) and ultimately in cirrhosis (d). Withdrawal ofthe injurious agent may allow remodelling of the fibrillar matrix, leaving an attenuatedcirrhosis (e). Spontaneous resolution of fibrosis after removal of injury results in a return tonear normal architecture (f). Whether complete resolution of cirrhosis can occur iscurrently unknown

Hepaticstellate cell

Activated hepatic stellate cell

Endothelium

Fenestration

Hepatocytes

Matrix

Microvilli

Fig 2 Normal liver (top) and liver injury (bottom). After livery injury, hepatic stellate cellsbecome activated and secrete a collagen rich matrix. Through associated changes incell-matrix interactions, hepatocytes lose their microvillii and sinusoidal endothelial cells losetheir fenestrations. Reproduced with permission26

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scarring) collagens, result in the deposition of excessfibrotic matrix. Collagen synthesis is therefore clearly atarget for therapeutic intervention.16 Because fibrosis isadvanced when most patients present, understandingthe processes regulating matrix degradation is likely tobe pivotal to the development of effective anti-fibrotictreatments. Effective treatment will require breakdownof the pre-existing matrix.

Stellate cells and other cells involved in the fibroticprocess, including macrophages and Kupffer cells,secrete a repertoire of matrix degrading metallo-proteinase enzymes (MMPs).17 These enzymes degradecollagen and other matrix molecules, and theirpresence in the fibrotic liver highlights the potentialdynamic nature of scarring within the liver. Molecularstudies of the expression of mRNA for these enzymes(including those with collagenolytic activity) haveshown that they are expressed in the liver even incirrhosis, but their activity is held in check by powerfulinhibitors, the tissue inhibitors of metalloproteinases(TIMPs) 1 and 2.18 The potential for matrix degra-dation is present, even in advanced cirrhosisbut it isheld in check by concurrently secreted TIMPs (fig 3). Itshould be possible to unharness the latent matrixdegrading capacity of a fibrotic or cirrhotic liver and tofacilitate matrix degradation, resulting in a return tonormal or near normal architecture.19

Models of resolution of liver fibrosisStudies that used pathological specimens and pairedbiopsies from trials of antiviral treatments in chronichepatitis have shown that matrix degradation occurs inadvanced human cirrhosis. In parallel, rodent modelsin which spontaneous recovery from liver fibrosis andcirrhosis occurs have allowed the frequent samplingthat is needed to identify the critical features of theprocess.1921 In recovery, expression of TIMPs 1 and 2decreases rapidly while matrix degrading metallo-proteinases continue to be expressed, resulting inincreased collagenase activity and consequent matrixdegradation within the liver (see fig 1).

Together with these changes, apoptosis of thehepatic stellate cells occurs. Apoptosis, in effect the sui-cide of a cell, fulfils a function in mammalian tissue,removing unwanted cells when they become toonumerous or redundant. During progressive liver

injury, when stellate cells are activated in the normalwound healing response, stellate cell apoptosis is fore-stalled, probably through signals from soluble factorsand changes in the matrix. When the injuriousstimulus is withdrawn and remodelling of matrix isrequired, the loss of these survival factors causes theactivated stellate cell to default into apoptosis, whichfacilitates the remodelling process by removing themajor cellular source of collagen and TIMPs. Logically,therefore, manipulating matrix degradation orenhancing hepatic stellate cell apoptosis might beexpected to reduce fibrosis and promote a return tonormal liver architecture. Studies in this area arecurrently limited to experimental models but showpromise that liver fibrosis can be attenuated bymanipulating the TIMP-MMP balance or enhancinghepatic stellate cell apoptosis.22 23

Stellate cells as mediators of portalhypertensionA major and life threatening consequence of cirrhosisis the development of portal hypertension. Studies ofisolated hepatic stellate cells have revolutionised our

Possible therapeutic interventions in liver fibrosis

In progressive or established fibrosisInflammation Removal of injurious agent Interleukin-10anti-inflammatory effect Tumour necrosis factor inhibitorsanti-inflammatory effect Antioxidantssuppress fibrotic response to oxidative damage

Stellate cell activation Interferon gamma (or interferon alfa)inhibits activation of hepaticstellate cells Hepatocyte growth factorinhibits activation of hepatic stellate cells Peroxisome proliferator-activated receptor ligandreduces activation ofhepatic stellate cells

Perpetuation of stellate cell activation Transforming growth factor -1 antagonistsreduce matrix synthesis andenhance matrix degradation Platelet derived growth factor antagonistsreduce proliferation of hepaticstellate cells Nitric oxideinhibits proliferation of hepatic stellate cells Angiotensin-converting-enzyme inhibitorsinhibit proliferation ofhepatic stellate cells

Stellate cell secretion of collagen rich matrix Angiotensin converting enzyme inhibitorsreduce fibrosis Polyhydroxylase inhibitorsreduce experimental fibrosis Interferon gammareduces fibrosis Endothelin receptor antagonistsreduce fibrosis and portal hypertension

To enhance or initiate resolution of fibrosisStellate cell apoptosis Gilotoxincauses apoptosis of hepatic stellate cells Nerve growth factorcauses apoptosis of hepatic stellate cells

Degradation of collagen rich matrix Metalloproteinasesenhance activity of metalloproteinases Tissue inhibitor of matrix (TIMP) antagonistsenhance activity ofmetalloproteinases Transforming growth factor -1 antagonistsdownregulate TIMPs andincreases activity of metalloproteinases Relaxindownregulates TIMPs and increases activity of metalloproteinases

Hepatic stellatecell (HSC)

TIMP

Collagen rich matrix

Matrix degrading metalloproteinase (MMP)from HSC, Kupffer cell, or other inflammatory cell

MMP activityinhibited; no matrixdegredation occurs

Activated hepatic stellatecell (HSC) synthesises collagens I and IIIand TIMPs 1 and 2

Fig 3 Tissue inhibitors of metalloproteinases (TIMPs) secreted byactivated hepatic stellate cells prevent matrix degradation byinhibiting the enzymatic activity of matrix degradingmetalloproteinases (MMPs)

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view of the mechanisms underlying portal hyper-tension and point to a role for these cells. Activation ofhepatic stellate cells is associated with the expression ofcontractile intracellular proteins such as smoothmuscle actin, and activated cells become sensitive tothe potent vasoactive substance endothelin. Endothe-lin concentrations increase after fibrotic liver injury,promoting contraction of hepatic stellate cells. Inparallel, injury results in a reduction in nitric oxidederived from hepatic endothelial cells, which antago-nises the effect of endothelin (fig 4). The net result ofthis imbalance is that stellate cell contraction is stimu-lated, and the consequent increases in intrahepatic

sinusoidal resistance contribute to portal hyper-tension. The observation that this process is dynamicand might be manipulated has led to the exciting con-cept that effective endothelin antagonism mightreduce portal hypertension in cirrhosis.24

Serum markers of fibrosisAt present, the clinical assessment of antifibrotic inter-ventions relies on serial liver biopsies. Liver biopsyremains associated with a (small) morbidity andmortality, and even though effective fibrosis scoringsystems have been introduced, liver biopsy is prone tosampling error. It may not be an appropriate way ofmonitoring in a dynamic situation such as a clinicaltrial of an antifibrotic agent. A further likelydevelopment is the identification of a panel of serumfibrosis markers which can be used to predict the stageof fibrosis and monitor disease progression orresolution without recourse to repeated liver biopsies.25

The futureIn future, patients with cirrhosis are likely to be treatedsimultaneously with a targeted anti-inflammatoryagent, an agent to lower portal pressure, and an anti-fibrotic or fibrolytic agent, and the effectiveness of thetreatment may well be monitored by using a panel ofserum markers. The development of effective targetedtreatments and the tools to monitor their effectivenessnon-invasively will change the way we view and treatcirrhosis.

I gratefully acknowledge the support of the MRC(UK), the Well-come Trust, the British Liver Trust, the Childrens Liver DiseaseFoundation, and the Wessex Medical Trust and thankChristothea Constandinou, Catriona J Gunn, and ChrisShepherd for their help in compiling the manuscript.Competing interests: JPI has received research grant fundingfrom Bayer AG.

1 Annual report of the chief medical officer 2001. Liver cirrhosisstartingto strike at younger ages. www.doh.gov.uk/cmo/annual report2001/livercirrhosis.htm (accessed 1 Jul 2003).

2 Day CP. Non-alcoholic steatohepatitis (NASH): where are we now andwhere are we going? Gut 2002;50:585-8.

3 National Center for Chronic Disease Prevention and Health Promotion.US Obesity Trends 1985 to 2000. www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm (accessed 1 Jul 2003).

4 Friedman SL. The cellular basis of hepatic fibrosis: mechanisms andtreatment strategies. N Engl J Med 1993;328:1828-35.

5 Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cel-lular response to tissue injury. J Biol Chem 2000;275:2247-50.

6 Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: the princi-pal collagen-producing cells of normal rat liver. Proc Natl Acad Sci USA1985;82:8681-5.

7 Maher JJ, McGuire RF. Extracellular matrix gene expression increasespreferentially in rat lipocytes and sinusoidal endothelial cells duringhepatic fibrosis in vivo. J Clin Invest 1990;86:1641-8.

8 Wang SC, Ohata M, Schrum L, Rippe RA, Tsukamoto H. Expression ofinterleukin-10 by in vitro and in vivo activated hepatic stellate cells. J BiolChem 1998;273:302-8.

9 Thompson KC, Maltby J, Fallowfield J, McAulay M, Millward-Sadler GH,Sheron N. Interleukin-10 expression and function in experimentalmurine liver inflammation. Hepatology 1998;28:1597-606.

10 Nelson DR, Lauwers GY, Lau JY, Davis GL. Interleukin 10 treatmentreduces fibrosis in patients with chronic hepatitis C: a pilot trial of inter-feron nonresponders. Gastroenterology 2000;118:655-60.

11 Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SJ, et al.Anti-tumour necrosis factor-alpha monoclonal antibody therapy insevere alcoholic hepatitis. J Hepatol 2003;38:419-25.

12 Border WA,Noble NA. Transforming growth factor beta in tissue fibrosis.N Engl J Med 1994;10:1286-92.

13 Border WA, Ruoslahti E. Transforming growth factor beta in disease: thedark side of tissue repair. J Clin Invest 1992;90:1-7.

14 Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y,Pierschbacher MD, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature1992;360:361-4.

15 George J, Roulot D, Koteliansky VE, Bissell DM. In vivo inhibition of ratstellate cell activation by soluble transforming growth factor beta type II

Educational resources

The August 2001 edition of Seminars in Liver Diseasesis devoted to the hepatic stellate cell and reviews ofhepatic stellate cell biology. Chapters of particularinterest are:

Rockey DC. Hepatic blood flow regulation by stellatecells in normal and injured liver. (pp 337-50)Schuppan D, Ruehl M, Somasundaram R, Hahn EG.Matrix as a modulator of hepatic fibrogenesis. (pp351-72)Benyon RC. Arthur MJP. Extracellular matrixdegradation and the role of hepatic stellate cells. (pp373-84)Pinzani M, Marra, F. Cytokine receptors and signallingin hepatic stellate cells. (pp 397-416)Maher JJ. Interactions between hepatic stellate cellsand the immune system. (pp 417-26)Iredale JP. Hepatic stellate cell behaviour duringresolution of liver injury. (pp 427-37)

Design of anti-fibrotic treatments:

Bataller R, Brenner DA. Hepatic stellate cells as atarget for the treatment of liver fibrosis. Seminars inLiver Disease 2001;21:437-51.Murphy F, Arthur M, Iredale J. Developing strategiesfor liver fibrosis treatment. Expert Opin Investig Drugs2002;11:1575-85.Friedman SL. Liver fibrosisfrom bench to bedside. JHepatol 2003;38(suppl):S38-53.

For information on the incidence and epidemiology ofliver disease, the addresses of patient support groups,and information for patients:

British Liver Trust (www.britishlivertrust.org.uk)Childrens Liver Disease Foundation(http://childliverdisease.org)

Nitric oxide

Collagen richmatrix

Sinusoidal

Lumen ofsinusoid

endotheliumEndothelin

Endothelin

Fig 4 Endothelin-nitric oxide imbalance results in contraction ofhepatic stellate cells, with consequent sinusoidal constriction(indicated by yellow arrows), contributing to portal hypertension

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receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad SciUSA 1999;96:12719-24.

16 Bataller R, Brenner D. Hepatic stellate cells as a target for the treatmentof liver fibrosis. Seminars in Liver Disease 2001;21:437-51.

17 Benyon RC, Arthur MJP. Extracellular matrix degradation and the role ofhepatic stellate cells. Seminars in Liver Disease 2001;21:373-84.

18 Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJP. Expressionof tissue inhibitor of metalloproteinases-1 and -2 is increased in fibrotichuman liver. Gastroenterology 1996;110:821-31.

19 Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, etal. Mechanisms of spontaneous resolution of rat liver fibrosis: hepaticstellate cell apoptosis and reduced hepatic expression of metallo-proteinase inhibitors. J Clin Invest 1998;102:538-49.

20 Kweon YO, Goodman ZD, Dienstag JL, Schiff ER, Brown NA, BurkhardtE, et al. Decreasing fibrogenesis: an immunohistochemical study ofpaired liver biopsies following lamivudine therapy for chronic hepatitis B.J Hepatol 2001;35:749-55.

21 Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et

al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis inpatients with chronic hepatitis C. Gastroenterology 2002;122:1303-13.

22 Wright MC, Issa R, Smart DE, Trim N, Murray GI, Primrose JN, et al.Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cellsand enhances the resolution of liver fibrosis in rats. Gastroenterology2001;121:685-98.

23 Imuro Y, Nishio T, Morimoto T, Nitta T, Stefanovic B, Choi SK, et al Deliv-ery of matrix metalloproteinase-1 attenuates established liver fibrosis inthe rat. Gastroenterology 2003;124:445-58.

24 Rockey DC. Hepatic blood flow regulation by stellate cells in normal andinjured liver. Seminars in Liver Disease 2002;21:337-49.

25 Rosenberg W, Burt A, Becka M,Voelker M,Arthur MJP. Automated assaysof serum markers of liver fibrosis predict histological hepatic fibrosis.Hepatology 2000;32:183A.

26 Friedman SL, Arthur MJP. Reversing hepatic fibrosis. Sci Med2002;8:194-205.

(Accepted 18 June 2003)

Lesson of the weekInteraction of spironolactone with ACE inhibitors orangiotensin receptor blockers: analysis of 44 casesEike Wrenger, Regina Mller, Michael Moesenthin, Tobias Welte, Jrgen C Frlich,Klaus H Neumann

The randomised aldactone evaluation study (RALES)proved a substantial (30%) reduction in risk ofmortality in patients with severe congestive heartfailure by treatment with low dose spironolactone(25-50 mg a day) in addition to standard treatment.1

Exclusion criteria for treatment in the study were aplasma potassium concentration > 5.0 mmol/l andserum creatinine concentration > 221 mol/l. A pilotstudy had previously shown that the higher the dosageof spironolactone (up to 24% with 75 mg a day) thehigher the risk of hyperkalaemia.2 Standard treatmentfor patients with heart failure categorised as New YorkHeart Association class II to IV includes angiotensinconverting enzyme (ACE) inhibitors or angiotensin IIAT1 receptor antagonists (AT1 receptor blockers).

3 Bothspironolactone and ACE inhibitors or AT1 receptorblockers reduce the renal elimination of potassium.4 InRALES, the increase in potassium was judged not to beimportant as serious hyperkalaemia ( > 6 mmol/l)occurred in only 10 (1%) of 841 patients takingplacebo and in 14 (2%) of 822 patients taking spironol-actone, with no significant difference between thegroups. Discontinuation of the treatment was neces-sary in only one patient taking placebo and threepatients taking spironolactone.1

We present a larger case series of life threateninghyperkalaemia in patients who were receivingspironolactone plus ACE inhibitors or AT1 receptorblockers. We identify clinical circumstances associatedwith this medical emergency and suggest recommen-dations for prevention.

Case seriesFrom January 1999 until December 2002 we observed44 patients (17 men) with congestive heart failure whowere taking spironolactone and ACE inhibitors or AT1receptor blockers and were admitted to our nephrol-ogy unit (serving a population of about 250 000) fortreatment of life threatening hyperkalaemia. Their

mean age was 76 (standard deviation 11) years. Themean dosage of spironolactone was 88 (SD 45, range25-200) mg daily. All patients also received ACEinhibitors or AT1 receptor blockers (table). Fourteenpatients were treated with receptor blockers and 40with loop diuretics.

Thirty five of the 44 patients had diabetes mellitustype 2. Symptoms on admission were vomiting (19),diarrhoea (8), bradyarrhythmia (14), muscle weaknessand paralysis (27), and severe dehydration (28). Meanplasma potassium concentration on admission was 7.7(SD 0.9, range 6.04-9.65) mmol/l and mean serum cre-atinine concentration was 294 (SD 175, range 88-940mol/l. Nineteen of the 44 patients had a serum creati-nine concentration < 221 mol/l. Creatinine clear-ance estimated by the formula of Cockroft and Gault5

was 0.38 (SD 0.22) ml/s and below the lower limit ofnormal in all patients. Five patients had to beresuscitated on admission. The figure shows electro-cardiograms for patient 39, who on admission had aserum potassium concentration of 9.65 mmol/l and,after dialysis, had a lowered value of 4.65 mmol/l.

Haemodialysis was immediately started in 37patients. Seven patients received conventional potas-sium lowering treatment consisting of intravenoussodium bicarbonate, intravenous furosemide (fruse-mide), and intravenous glucose and insulin. The meannumber of dialysis treatments per patient was 2.5 (SD1.2). However, in six patients renal function did notrecover, and they had to be kept on chronic dialysistreatment. Two patients developed fatal complicationsduring their stay in the intensive care unit: a 75 year oldman died of gastrointestinal bleeding and an 88 yearold woman died of sepsis. Renal function recovered in34 patients after closely monitored volume administra-tion as dehydration was a common problem. Atdischarge, creatinine clearance in the patients whowere not receiving dialysis was 0.65 (0.27) ml/s, withserum creatinine values between 79 (SD 0.9) mol/l

Clinical review

Beware severehyperkalaemiain patientstakingspironolactoneplus ACEinhibitors orAT1 receptorblockers

Division ofNephrology,Department ofInternal Medicine,Otto-von-Guericke-University, LeipzigerStrasse 44, D-39120Magdeburg,GermanyEike WrengernephrologistRegina MllerinternistMichael MoesenthinnephrologistKlaus H Neumannprofessor of nephrology

Division ofCardiology,Pulmonology, andAngiology,Department ofInternal Medicine,Otto-von-Guericke-UniversityTobias Welteintensive carephysician

continued over

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