Aquaporin1 and aquaporin-2 urinary excretion in cirrhosis: Relationship with ascites and hepatorenal syndrome

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Several experimental models of cirrhosis have shown dysregulation of renal aquaporins in different phases of liver disease. We investigated the urinary excretion of both aquaporin-1 and aquaporin-2 in patients with cirrhosis at different stages of
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  PBC—Susceptibility to Toxin Exposure Over the years therehave been various re-ports of environmentalinfluences on the inci-denceofprimarybiliary cirrhosis (PBC). Ini-tially,thesecenteredonatemperateclimate,thenlocalreservoirsuppliesofdrinkingwater,and more recently on the use of nail varnish and proximity tolandfill sites for noxious waste. Support for the concept that sus-ceptibilitytoPBCisconferredatleastinpartbyinabilitytoexcretechemicals of endogenous and exogenous srcin in a biotrans-formedstateismountingirresistibly.Adherentstosuchanhypoth-esis would argue that immunological features constitute a secondary phenomenon and thus a consequence, rather than thecause of the disease. In their report, Zein et al. demonstrated a significantassociationoftobaccoconsumptionwithadvancedhe-paticfibrosis,definedasLudwigstage2andstage3inPBC.Smok-ers (a lifetime consumption of more than 100 cigarettes) were atgreater risk of advanced fibrosis (27/38, 71% versus 13/39, 33%. P   .0001). A smoking history of more than 10 pack years wassimilarly associated with greater risk of advanced fibrosis (27/38,71% versus 7/37, 19%.  P   .0001). The risk was confirmed in a second cohort of 175 patients with PBC. (See Fig.) Promotion of fibrosis may, like production of mitochondrial antibodies, be re-garded as a reaction to disease, rather than the specific injury-generatingdiseaseitselfinPBC;nevertheless,theresultsencouragethe search for defective hepatic biotransformation mechanisms asthe foundation of susceptibility to PBC. (See H EPATOLOGY   2006;44:1564-1571.) Portopulmonary Hypertension Pulmonary hypertension, when due to increased pulmonary vascular resistance (PVR) and the result of liver disease, isknown as portopulmonary hypertension and may be reversedby liver transplantation . Patients with the most severely ele-vated mean pulmonary arterial pressure (MPAP) tend to farepoorly with liver transplantation and run a high risk of intra-operativedeathfromrightheartfailure.Krowkaetal.reportona 10-year experience of assessing 1235 liver transplant candi-dates according to a protocol in which echocardiography wasused to screen for portopulmonary hypertension. In 101 pa-tients, a right ventricular systolic pressure (RVSP) was esti-matedas  50mmHgpromptedfurtherwork-upbyrightheartcatheterization. The key element of portopulmonary hyperten-sion is increased PVR, which cannot be readily reversed. Insomepatients,highpressureoccurseventhoughPVRisnormalor low when it is the consequence of the high cardiac outputseen cirrhosis, or even an elevated left atrial filling pressure(measured as pulmonary artery occlusion pressure). Using guideline criteria of MPAP    25 mm Hg and PVR     240dyness  cm  5 ,portopulmonaryhypertensionwasdocumentedin 66 of the 101 patients. Adherence to this protocol is com-mended by the fact that all patients with MPAP  35 mm Hg  were identified by echocardiography so that no patient had a transplant operation canceled at the last minute due to an un-expectedfindingofseverepulmonaryhypertension.(SeeH EPA  - TOLOGY   2006;44:1502-1510.)  Adrenal Support for the Sick Patient WithCirrhosis Recent reports haveshown suboptimal re-sponsiveness of theadrenal cortex tostress from sepsis inpatientswithcirrhosisin an intensive caresetting. Administra-tion of exogenous hy-drocortisone has been shown to have numerous advantages,includingrestorationofresponsivenesstothepressoractionsoftherenin-angiotensin system and infused norepinephrine; however,nosurvivalbenefithadbeenshown.Fernandezetal.performedtheshort corticotropin test on 25 successive patients admitted to theintensive care unit with cirrhosis and septic shock. A baselineplasmacortisolconcentration  15  g/dLorariseof   9  g/dLinpatientswithabaselinecortisolconcentration  35  g/dLfollow-ingsynacthenstimulation,wasdeemeddiagnosticofrelativeadre-nal insufficiency. These features were detected in 17 patients(68%)whowereconsequentlytreatedwithintravenoushydrocor-tisone(50mg/6hours).Theoutcomeinthisgroupwascomparedto that of the previous consecutive series of 50 patients admitted withcirrhosisandsepticshockinwhomnocorticotropinstimula-tiontesthadbeenperformedandnohydrocortisoneadministered.Thehydrocortisone-treatedgrouphadbetterratesofresolutionof shock,intensivecareunitsurvival,andhospitalsurvival(64%ver- Copyright © 2006 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience ( 10.1002/hep.21469 Potential conflict of interest: Nothing to report. HEPATOLOGY HIGHLIGHTS  Elwyn Elias, Liver Failure and Liver Disease Editor 1374  sus32%, P   .003)whencomparedwiththeretrospectivecohort.(See Fig.) (See H EPATOLOGY   2006;44:1288-1295.) Screening for Cholangiocarcinoma in PSC Lack of a reliable screening tool for detection of cholangiocar-cinoma(CC)inprimarysclerosingcholangitis(PSC)isofgreatconcern.ImagingwithCT,MRI,andultrasoundandmeasure-ment of various tumor markers in blood have been of no avail.The impact is massive, as by the time CC is diagnosable by any ofthesemethods,thetumorhasalreadyprogressedtothepoint where liver transplantation cannot be justified given the highrecurrence and poor survival rates. The lifetime risk of CC inPSC is of the order of 15%-30% but prophylactic transplantcannot be justified merely to avert this risk. Positron emissiontomography (PET) is the latest technique to promise some ad-vance in detection of early tumors. Prytz et al. report on theresults of screening with dynamic PET using 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) in 24 consecutive patients with PSC within 2 weeks of being listed for transplantation. PET cor-rectly identified all 3 patients with CC as well as giving a falsepositiveresultinonepatientwithepithelioidcellgranulomasinthe explanted liver. A single patient with high-grade dysplasia had a negative result. One patient did not undergo transplan-tationbecauseofadiagnosisofdisseminatedCCmadewhileonthe transplant waiting list. One patient died of CC 7 monthsafter transplant and another died due to stricturing the duode-num by CC, although none had been detected within the ex-planted liver. The series therefore offers evidence of increasedsensitivity for the diagnosis of CC in patients with PSC during evaluation for liver transplantation but, allowing for smallnumbers, does not encourage optimism that early detection of CC by PET would greatly improve the prospects of its cure.(See H EPATOLOGY   2006;44:1572-1580.) Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome In a previous H EPATOLOGY   report highlighted in the Hepatol-ogy Highlights, it was shown that the hepatorenal reflex couldbe attenuated by blockade of afferent adenosine signaling fromthe space of Mall, a small fluid space surrounding the terminalbranches of the hepatic arterioles, portal venules, and hepaticnerves. It is thought that adenosine is secreted at a constant rateintothisspaceandthatitswashoutbybloodflowisthekeystepin feedback regulation of the reciprocity of portal venous andhepatic arterial blood flow as well as stimulation of hepatorenalreflexes that influence fluid retention by the kidneys. Hepaticthirstforincreasedperfusionproducesasignalforsaltandwaterconservation, resulting in renal afferent vasoconstriction andultimately the potential for developing hepatorenal syndrome.Inmodelsofcirrhosis,reflexrenalvasoconstrictionandoliguria could be prevented by intraportal infusion of the nonselectiveadenosine receptor antagonist 8-phenyl theophylline. Ming etal. extended these observations to the rat model of thioacet-amide-induced acute liver failure. They showed that renal saltand water retention could be blocked by intraportal infusion of 8-cyclopentyl-1,3-dipropylxanthine an adenosine A1 receptorantagonist, but not by specific blockade of the A2 receptor. Adenosine A1 receptor blockade was effective when the antag-onist was administered into the portal circulation but not afterinfusionintothesystemiccirculation.Theworkisastimulustosearch for specific afferent adenosine receptors that would gainready access to the space of Mall and mitigate against liver-induced impairment of renal function—prognostically one of the gravest complications of both chronic and acute liver fail-ure. (See H EPATOLOGY   2006;44:813-822.) Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis Studies on the renalmechanisms of ex-cessive water reten-tion, which causesdilutional hypona-tremia, in associa-tion with advancedliver disease are en-tering a new phase. Water reabsorptionfrom renal tubules requires not only a favorable solute concen-tration gradient but also pores for the water molecules to exitrenal tubules via a family of proteins named aquaporins. Excre-tion of aquaporin 2 in urine has been shown to correlate withvasopressin-stimulated water retention in experimental animaland human models of overhydration and water deprivation.Vasopressinhasanimmediateeffectonaquaporin2concentra-tions within the apical membrane of collecting duct principalcells by stimulating its incorporation from a reservoir of cyto-plasmic vesicles and a longer term effect by stimulating genetranscription. Given that 3%-4% of renal aquaporin is shedinto the urine on a daily basis, increased vasopressin activity isreflected by an increase in urinary aquaporin 2 excretion inexperimental animals and in human congestive cardiac failure.Inaccessibility of renal tissue for direct studies in patients withcirrhosis has resulted in conflicting reports based on indirectevidence. Esteva-Font et al. report a significant fall in urinary aquaporin 2 excretion in patients with cirrhosis and ascites, whichisstillmoremarkedinthepresenceofhyponatremiaandhepatorenal syndrome. (See Fig.) Furthermore, they found nocorrelation of aquaporin 2 excretion with vasopressin activity.The patients studied by Esteva-Font et al. were chosen becauseof their stable state; e.g., hyponatremia, when studied, had ex-isted for an average of 49 days. These single time point obser-vations would therefore appear to reflect a steady state in whichan escape mechanism dissociated aquaporin 2 expression fromits augmentation by vasopressin. The authors argue that shouldsuch tachyphylaxis not operate, progressive hyponatremia  wouldhavebeenaninevitableandfatalconsequence.Dynamicstudies are therefore required in patients with cirrhosis of theacute changes that result in water retention and hyponatremia,during which it is likely that aquaporin 2 responsiveness tovasopressin will be preserved and pathogenetically implicated.(See H EPATOLOGY   2006;44:1555-1563.) 1375
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