Jetra so velik organ in veliko količino jetrnega tkiva je treba poškodovati, preden oseba doživi simptome bolezni. Simptomi so lahko odvisni tudi od vrste bolezni jeter. Ko se simptomi pojavijo, lahko vključujejo:
Zdravljenja, ki se uporabljajo pri bolnikih s PBC, lahko razdelimo na:
Uničenje žolčnih vodov v PBC vodi do zadrževanja nekaterih strupenih žolčnih kislin v jetrnih celicah (hepatocitih). Te strupene žolčne kisline naj bi povzročile smrt hepatocitov in postopno izgubo delovanja jeter. Ursodeoksiholna kislina (UDCA je okrajšava za to kemično ime) je naravna žolčna kislina, ki jo v majhnih količinah proizvajajo normalni hepatociti. UDCA je na voljo za predpisovanje kot ursodiol (Urso-250, Actigal in generični pripravki). Pri peroralnem zaužitju se UCDA absorbira iz črevesja, ga vzamejo in predelajo hepatociti ter se z žolčem prenese nazaj v črevo. UDCA ima vsaj štiri ugodne učinke na PBC:
Štiri obsežna klinična preskušanja so primerjali učinkovitost in varnost UDCA z neaktivnim zdravilom (placebo). Ta nadzorovana preskušanja so bila opravljena pri simptomatskih in asimptomatskih bolnikih s spektrom tkivnih nenormalnosti (patologije) na njihovih biopsijah jeter, od zgodnje bolezni do ciroze. Zdravljenje z UDCA je privedlo do izboljšanja nenormalnosti jetrnih krvnih preiskav, znatno zmanjšalo povišane ravni bilirubina, alkalne fosfataze, gama-glutamil transferaze (GGT) in holesterola. UDCA pa ni izboljšala utrujenosti ali preprečila ali izboljšala osteoporoze in je imela spremenljiv učinek na srbenje. Tri od štirih preskušanj so uporabile podoben odmerek UDCA (13-15 mg na kg telesne mase na dan) in so bile združene za analizo skupno 548 bolnikov.
Rezultati kombinirane analize so pokazali, da je UDCA znatno povečala preživetje po do 4 letih zdravljenja, brez potrebe po presaditvi jeter. V četrti obsežni študiji so uporabili nižji odmerek UDCA (10 do 12 mg na kg na dan). Rezultati te študije so se nekoliko razlikovali od rezultatov drugih treh študij. Ta je pokazal korist zdravljenja z UDCA predvsem pri bolnikih z ravnmi bilirubina pod 2 mg/dL. Druge tri študije, analizirane samostojno ali skupaj, pa niso potrdile tega opažanja o bilirubinu. Pravzaprav je vsaka od teh študij dejansko pokazala korist za bolnike z napredovalo boleznijo in povišano ravnjo bilirubina. Poleg tega je UDCA zmanjšal razvoj portalne hipertenzije. Pomembno je omeniti, da kljub očitnim koristim zdravljenje z UDCA predvsem upočasni napreduje in ne zdravi PBC.
Vse bolnike s PBC, ki imajo nenormalne jetrne teste, ne glede na stopnjo biopsije jeter ali fazo naravnega napredovanja bolezni, je verjetno treba zdraviti z UDCA. Odmerek mora biti običajno med 13 in 15 mg na kg telesne mase na dan. Bolniki lahko jemljejo UDCA kot enkratni odmerek ali deljeni odmerek, ne da bi to vplivalo na njegove klinične koristi. UDCA je zelo varna za dolgotrajno uporabo. Primarni stranski učinek je driska, ki je posledica neuspešne absorpcije vse UDCA iz črevesja. Bolniki, ki imajo drisko, lahko pogosteje jemljejo manjše odmerke in poskušajo ohraniti priporočeni skupni dnevni odmerek. Po drugi strani pa lahko bolniki, ki nimajo driske, poskusijo vzeti večje količine na odmerek, s ciljem vzeti le en odmerek (spet priporočeni skupni odmerek) na dan pred spanjem.
Kolhicin, zdravilo, ki zmanjšuje vnetje in brazgotinjenje, se uporablja predvsem za zdravljenje artritisa, ki ga povzroča protin. Tri randomizirana, kontrolirana preskušanja v PBC so pokazala, da je kolhicin v primerjavi s placebom zmerno upočasnil napredovanje nenormalnih krvnih preiskav, vendar ni zmanjšal simptomov ali preprečil napredovanja patologije jeter (nenormalnosti tkiva na biopsiji). Ena od preskušanj je dejansko pokazala, da kolhicin izboljša preživetje. Ta vtis boljšega preživetja s kolhicinom pa ni bil utemeljen. Pravzaprav se zdi, da je navidezno izboljšano preživetje posledica nepričakovano visoke stopnje umrljivosti (smrtnosti) med bolniki, ki so v tej študiji prejemali neaktivno zdravilo. Koristi kolhicina so tako majhne, da se le redko priporoča.
Imunosupresivna zdravila, na primer kortikosteroidi, azatioprin, ciklosporin (Sandimmune, Neoral, Gengraf) in metotreksat (Rheumatrex, Trexall) zavirajo imunske reakcije. Ta zdravila so teoretično privlačna sredstva za zdravljenje PBC, na podlagi koncepta, da gre za avtoimunsko bolezen. Več randomiziranih kontroliranih študij je testiralo imunosupresivna zdravila v PBC. Vendar nobena od teh študij ni pokazala podaljšanega preživetja bolnikov.
Kortikosteroidi, na primer, prednizon, prednizolon in budezonid (Entocort) zavirajo začetek imunskih odzivov, vključno s tistimi začetnimi odzivi, potrebnimi za perpetuacijo avtoimunskih reakcij. Izvedeno je bilo randomizirano (zdravljenje je bilo dodeljeno naključno) kontrolirano preskušanje, v katerem so primerjali placebo z nizkim odmerkom prednizolona v obdobju 3 let. Ta študija je pokazala, da je prednizolon izboljšal delovanje jeter in ni bistveno povečal stopnje redčenja ali demineralizacije kosti. (Osteoporoza je možni stranski učinek steroidov). V drugem randomiziranem preskušanju so primerjali UDCA in placebo z UDCA in prednizolonom pri bolnikih z zgodnjimi fazami PBC. Čeprav je bilo izboljšanje delovanja jeter podobno v obeh skupinah, je le kombinacija UDCA in prednizolona povzročila izrazito izboljšanje biopsije jeter.
Omeniti velja, da so bile glavne koristi kortikosteroidov opažene pri bolnikih z zgodnjim stopnje bolezni na biopsiji jeter. Kljub temu ta zdravljenja niso privedla do popolne remisije ali ozdravitve. Poleg tega niti velikost niti trajanje teh preskušanj nista zadostovala za določitev učinka na preživetje brez presaditve jeter. V skladu s tem je potrebnih več podatkov za potrditev koristi in varnosti PBC steroidov samih ali v kombinaciji z UDCA. Kljub temu so te študije ovrgle prejšnje mnenje, da bi kortikosteroidi povzročili hitro napredovanje osteoporoze bolezni kosti pri bolnikih s PBC.
Budezonid je steroid, ki se hitreje predeluje (metabolizira) v jetrih in bi zato verjetno manj poškodoval kosti kot drugi steroidi. To zdravilo so preučevali pri izbranih bolnikih s PBC, ki so imeli suboptimalne (manj kot ugodne) odzive na UDCA. Na žalost je bil budezonid v tej skupini neučinkovit. Pravzaprav je znatno poslabšal osteoporozo in ni preprečil napredovanja PBC. Nasprotno pa je randomizirano preskušanje, v katerem so primerjali UDCA in placebo s kombinacijo budezonida in UDCA, pokazalo, da je kombinacija učinkovitejša, medtem ko je bilo redčenje kosti (izguba mineralne gostote) primerljivo v obeh skupinah. Toda tudi tukaj je potrebnih več podatkov za potrditev koristi in varnosti te kombinacije.
Imuran preprečuje nastajanje novih limfocitov (belih krvnih celic, ki sodelujejo pri imunskih odzivih) z blokiranjem celične delitve (razmnoževanja) limfocitov. Posledica tega delovanja je zmanjšanje števila novih vnetnih celic, ki vstopajo na mesta vnetja. Velika študija, ki je primerjala učinek azatioprina z neaktivnim zdravilom (placebo) pri 248 bolnikih s PBC, pa ni pokazala nobene koristi. Zato tega zdravila trenutno ne priporočamo za uporabo pri bolnikih s PBC izven raziskovalnih protokolov.
Ciklosporin je močno imunosupresivno zdravilo, ciklosporin (Sandimmune, Neoral, Gengraf) se uporablja predvsem za preprečevanje zavrnitve presajenih organov. Zdravilo preprečuje proizvodnjo pomembnega signala, ki je potreben za delitev (razmnoževanje) limfocitov in nastanek vnetja. Velika študija 349 bolnikov s PBC, ki je primerjala ciklosporin z neaktivnim zdravilom, je pokazala nekaj koristi od ciklosporina. Vendar pa je zaradi pogostnosti neželenih učinkov visokega krvnega tlaka in zmanjšanega delovanja ledvic to zdravilo nesprejemljivo za dolgotrajno uporabo.
Metotreksat zavira imunski sistem in preprečuje delitev celic. To zdravilo se uspešno uporablja pri hudem revmatoidnem artritisu in imunološki kožni bolezni, imenovani luskavica. Začetna omejena preskušanja pri bolnikih s PBC niso pokazala koristi, resni neželeni učinki pa so vključevali razjede v ustih, izpadanje las in pljučnico. Poleg tega so v predhodnih poročilih o randomiziranih, kontroliranih preskušanjih zdravljenja PBC z metotreksatom v Evropi opazili višjo stopnjo oblike pljučnice, ki povzroča brazgotinjenje pljuč, od pričakovane. Poleg tega je nedavno objavljeno randomizirano, kontrolirano preskušanje nizkih odmerkov metotreksata pri PBC pokazalo resno toksičnost v obdobju šestih let. Trenutno poteka veliko preskušanje v Združenih državah, ki primerja samo UDCA s kombinacijo UDCA in metotreksata. Trenutno je prezgodaj priporočati uporabo metotreksata za zdravljenje PBC zunaj kliničnih preskušanj.
FDA je maja 2016 odobrila zdravilo Ocaliva za zdravljenje PBC v kombinaciji z ursodeoksiholno kislino (UDCA) pri odraslih z neustreznim odzivom ali intoleranco na UDCA ali kot posamezno zdravljenje pri odraslih, ki ne prenašajo UDCA. Pri takih bolnikih je skoraj 50 % pokazalo izboljšanje jetrnih testov. Najpogostejši neželeni učinek je pruritus, opažen pri več kot 50 % bolnikov. Najpogostejši neželeni učinki so utrujenost, bolečine in nelagodje v trebuhu, bolečine v sklepih, bolečine v srednjem delu grla, omotica, zaprtje in srbenje.
Holestiramin je peroralno zdravilo, ki se ne absorbira v črevesju. Zdravilo se veže (veže) na snovi v črevesju, vključno s tistimi, ki so prišle iz žolča, in jih nato odstrani iz telesa v gibanje črevesja. Verjetno je holestiramin koristen, ker veže žolčne kisline in neidentificirane snovi, ki povzročajo srbenje, potem ko se absorbirajo iz črevesja v krvni obtok. Holestiramin je najučinkovitejša terapija za večino bolnikov s holestatskim srbenjem. Za optimalne učinke je treba holestiramin jemati ob obrokih, ko je pretok žolča v črevesje največji. Bolnikom z žolčnikom je priporočljiv nekoliko večji odmerek z zajtrkom, saj se v tem času sprosti žolč, shranjen čez noč v žolčniku.
Pomembno je omeniti, da se holestiramin lahko veže tudi na zdravila. Zato je pomembno, da jemljete druga zdravila eno uro pred ali dve uri po holestiraminu. Običajni odmerek je 8 gramov z zajtrkom, 4 grame s kosilom in 4 grame z večerjo. Holestiramin se ne raztopi dobro v tekočinah in je pri zaužitju pogosto peskast. Če ga vmešate v gazirane pijače, pa lahko zmanjšate to težavo.
Glavni stranski učinek holestiramina je zaprtje. Zaprtje se pojavi, ker zdravilo veže žolčne kisline, ki bi sicer dale na voljo več vode v debelem črevesu za mehčanje blata. Neželeni učinki ciklosporina vključujejo:
Drugo zdravilo, ki veže žolčne kisline, ki ga lahko poskusite za lajšanje srbenja, je kolestipol (Colestid).
Sprva je bilo ugotovljeno, da antibiotik rifampin (Rifidin) izboljša srbenje zaradi holestaze pravzaprav po naključju. Nato je študija bolnikov s PBC, ki je vključevala prehod med rifampinom in neaktivno spojino (placebo), pokazala, da je rifampin zmanjšal srbenje pri odmerku 150 mg dva ali trikrat na dan. To zdravilo lahko traja do en mesec, da postane učinkovito, vendar ne sme trajati dlje. Zato, če zdravilo po enem mesecu ni učinkovito, ga je treba prekiniti. Vsi bolniki s PBC nimajo koristi od tega zdravila.
Način delovanja rifampina je slabo razumljen. Lahko inducira biokemične poti v hepatocitih, ki teoretično lahko spremenijo okolje žolčne kisline v teh celicah. Neželeni učinki rifampina vključujejo zvišanje bilirubina, temen urin, hepatitis (redkeje), zmanjšano število krvnih ploščic (majhnih elementov, ki pomagajo ustaviti krvavitev s površine reza) in poškodbe ledvic.
Dejstvo, da se pri nekaterih bolnikih, ki prejemajo opiatne droge (kot je morfij), pojavi srbenje, je privedlo do hipoteze, da lahko srbenje pri holestazi povzročijo naravni opiati telesa, imenovani endorfini. Da bi preverili to hipotezo, so bolnike s PBC, ki so imeli srbenje, zdravili s peroralnim zdravilom nalmefenom, antagonistom (deluje proti ali blokira delovanje) opiatov. Srbenje se je izboljšalo v 9-mesečnem obdobju. Pri nekaterih bolnikih, zdravljenih z opiatnim antagonistom, pa so se pojavili zelo neprijetni simptomi odtegnitve opiatov ko so bili njihovi naravni endorfini inhibirani. Zato to zdravilo ni primerno za dolgotrajno uporabo pri PBC. Kontrolirana študija, v kateri so primerjali intravenski opiatni antagonist, imenovan nalokson (Narcan), z neaktivnimi intravenskimi tekočinami, je pokazala, da je nalokson izboljšal srbenje pri bolnikih s PBC. Ker ga je treba dajati intravensko, je tudi nalokson neprimeren za dolgotrajno uporabo.
Pred kratkim je bil peroralni opiatni antagonist, naltrekson (Revia), testiran v majhnem, randomiziranem, kontroliranem preskušanju pri bolnikih s PBC s srbenjem. Pri 50 % bolnikov je izboljšal srbenje in ni povzročil simptomov odtegnitve opiatov. Naltrekson je prav tako izboljšal simptome utrujenosti in depresije, po možnosti s povrnitvijo sposobnosti spanja ponoči, ko je srbenje najhujše. Vendar pa so potrebne prihodnje študije, da bi ocenili njegovo varnost, kako dolgo ga je mogoče dajati in ali se bodo bolniki sčasoma ne odzivali (odporni) na njegove učinke.
V nenadzorovanih študijah so bolniki s PBC, ki so imeli hudo srbenje, opravili postopek, imenovan plazmafereza. (Nenadzorovane študije so študije, v katerih zdravljenja ni primerjano z drugimi zdravljenji ali placebom.) Pri tem postopku se kri odstrani iz telesa in tekoča faza (imenovana plazma) krvi se loči od krvnih celic in trombocitov. Plazmo nato perkoliramo skozi kolono, ki vsebuje aktivno oglje. Na koncu se plazma ponovno pomeša s krvnimi celicami in se intravensko vrne bolniku. Ideja je, da bi oglje odstranilo nekaj spojin ali spojin (zaenkrat neznanih) iz plazme, ki so povzročile srbenje. Nenavadno je bilo pri mnogih bolnikih lajšanje srbenja za obdobja od dni do mesecev. Vendar pa niso bila izvedena nobena kontrolirana preskušanja (v primerjavi z drugimi zdravljenji ali placebom). Zato ta postopek še vedno velja za eksperimentalnega in se ne uporablja pogosto.
Ali lahko običajno priporočene terapije za osteoporozo zadovoljivo zdravijo ali preprečijo osteoporozo pri bolnikih s PBC, še ni jasno. Vendar pa je smiselno zagotoviti zadostno količino kalcija in vitamina D v prehrani. Vitamin D je potreben za absorpcijo kalcija iz črevesja. Zadostne količine kalcija lahko zaužijemo z uživanjem mlečnih izdelkov, kot sta mleko ali jogurt, ali z dopolnitvijo prehrane s 1000 do 1500 mg kalcijevega karbonata. Kalcijev karbonat, pripravljen iz lupin ostrig v prahu, lahko kupite v prosti prodaji. Običajno je dodaten vitamin D, ki ga vsebuje dnevni multivitamin, dovolj, da zadovolji dnevne potrebe. Izpostavljenost kože sončni svetlobi prav tako poveča proizvodnjo vitamina D v telesu.
Pri ženskah po menopavzi s PBC lahko hormonsko nadomestno zdravljenje z estrogenom zmanjša tveganje za osteoporozo. Estrogen, ki je na voljo v peroralni obliki ali kot obliž, ki omogoča absorpcijo estrogena skozi kožo, je varen za ženske s PBC. Ne pozabite pa, da obstaja polemika o uporabi estrogenskega nadomestnega zdravljenja pri ženskah po menopavzi, ki so zbolele za rakom dojke, zaradi možnega tveganja ponovitve raka. Obstaja tudi zaskrbljenost zaradi dolgotrajne uporabe estrogenov s progestinom pri povečanju tveganja za koronarno srčno bolezen, možgansko kap in pljučno embolijo pri zdravih ženskah v menopavzi. Zato je treba po posvetovanju z zdravnikom individualno določiti, ali uporabljati estrogen ali ne. Another alternative to estrogen to protect bone density in patients with PBC is the bisphosphonates, which are FDA-approved drugs for the prevention of osteoporosis. Too few studies have been performed using other drugs (for example, fluoride or calcitonin) for osteoporosis to recommend their use in PBC.
Elevated levels of cholesterol in the blood are common in patients with PBC, and xanthomas (fatty deposits that appear as yellowish firm nodules in the skin) occur in about 25% of those patients with elevated cholesterol. Diets with low cholesterol content do not consistently lower serum cholesterol in these patients, because production of cholesterol by the liver is stimulated in patients with PBC. Cholestyramine, the oral medication that is often used to treat itching, can, at the same time, reduce the levels of serum cholesterol to a modest degree.
Clofibrate (Atromid) should not be used for treating elevated serum cholesterol in PBC because it elevates (rather than lowers) the cholesterol levels in these patients. Moreover, this drug may worsen xanthomas and cause formation of gallstones containing cholesterol. Two studies indicate that UDCA therapy significantly reduces serum levels of cholesterol and is recommended for use in patients with xanthomas. A new class of drugs called statins inhibits formation of cholesterol and, to a lesser degree, triglycerides. The safety and effectiveness of the statins, however, have not been adequately studied in PBC. One of the common side effects of statins is liver injury. Thus, their use in a person with liver disease requires careful monitoring by a physician.
Reduction of dietary fat is the treatment of choice for fat malabsorption (poor absorption of fat in the gut). The idea is that if the dietary intake of fat is decreased, more of this fat will be absorbed. The goal of the low-fat diet would be to alleviate the diarrhea caused by the fat malabsorption, while still providing enough fat for adequate nutrition. If this diet does not help, a supplement of special fats called medium-chain triglycerides (MCT) can be ingested. MCT can replace as much as 60% of the calories provided by ordinary dietary fat, which is mostly long-chain triglycerides. MCT is a special type of fat preparation that does not require bile acids for its absorption and is actually absorbed more easily than the usual dietary fat. As noted earlier, PBC patients with malabsorption of fat should also be tested for celiac sprue.
It is recommended that patients with PBC take a multivitamin supplement without minerals to increase the dietary intake of fat-soluble vitamins. If the quantities of bile acids flowing through the bile ducts to the gut are marginal, intestinal absorption of the fat-soluble vitamins may not be adequate, even with supplements. Two strategies exist for this situation. First, patients can take Liqui-E with meals. Liqui-E is an over-the-counter liquid preparation of vitamin E that also increases the absorption of other fat-soluble vitamins in the diet or in multivitamin preparations. Second, the fat-soluble vitamins A and K can be given by injection into the muscle once a month. Remember, however, that women who might become pregnant, should not receive injections of vitamin A, because it can cause birth defects.
Retention of salt and water can lead to swelling of the ankles and legs (edema) or abdomen (ascites) in patients with cirrhosis. Diuretics are medications that work in the kidneys to combat retention of fluid by eliminating salt and water into the urine. A combination of the diuretics spironolactone (Aldactone) and furosemide (Lasix) can reduce or eliminate the swelling in most people. During treatment with diuretics, it is important to monitor kidney function by measuring serum levels of blood urea nitrogen (BUN) and creatinine to determine if the doses of the diuretics are safe. Sometimes, when the diuretics do not work, a long needle is used to draw out the fluid directly from the abdomen (a procedure called paracentesis).
If large varices (distended veins) develop in the esophagus or upper stomach or any episodes of bleeding from varices have occurred, physicians should consider specific therapy for the varices. Treatment with propranolol (Inderal), a drug in a class called beta-blockers, is effective in preventing initial bleeding or rebleeding from varices in patients with cirrhosis. This drug, however, has not been proven to prevent bleeding in patients with portal hypertension who do not have cirrhosis.
Other methods are available to prevent or treat varices. These methods include:
PBC patients with an abnormal sleep cycle, impaired thinking, odd behavior, or other signs of hepatic encephalopathy usually should be treated with a low protein diet and oral lactulose. Dietary protein is restricted because it is a source of the toxic compounds present in hepatic encephalopathy. The lactulose, which is a liquid medication, traps the toxic compounds in the colon. Consequently, they cannot be absorbed into the bloodstream and cause the symptoms of encephalopathy. To be sure that adequate lactulose is present in the colon at all times, the patient should adjust the dose to produce 2 to 3 semiformed bowel movements a day. If symptoms of encephalopathy persist, the oral antibiotics, such as rifaximin, can be added to the treatment regimen.
The blood filtration function of an enlarged spleen usually results in only mild reductions of red blood cells (anemia), white blood cells (leukopenia) and platelets (thrombocytopenia) that do not require treatment. Severe anemia, however, may require blood transfusions or treatment with erythropoietin or epoetin alfa (Epogen, Procrit), a hormone that stimulates production of red blood cells. If the numbers of white blood cells are severely reduced, another hormonal drug, called granulocyte-colony stimulating factor (G-CSF) is available to increase the white blood cells. An example of an available G-CSF drug is filgrastim (Neupogen).
No FDA-approved medication is available yet to increase the number of platelets. As a necessary precaution, patients with low platelets should not use aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS) since these drugs can hinder the function of platelets. If a low number of platelets is associated with significant bleeding, transfusions of platelets usually should be given. Surgical removal of the spleen (called splenectomy) should be avoided, if possible, because of the risk of excessive bleeding during the operation and the risk of anesthesia in advanced liver disease.
Dry eyes: For chronically dry eyes, use artificial tears containing methylcellulose without preservatives. These artificial tears can prevent the complications of dry eyes, such as ulcers of the cornea.
Dry mouth: Patients with dry mouth have a reduced amount of watery saliva but maintain production of thick saliva. Chewing gum or sucking on a small object can stimulate more watery saliva. Others may need to moisten the mouth with fluids. It is imperative that all patients with dry mouth take adequate amounts of fluids to help with swallowing during meals or when taking oral medications. It is also recommended that these patients have frequent dental appointments to check for cavities.
Dry vagina: Lubricating jelly is suggested to prevent painful sexual intercourse. If a woman is postmenopausal, estrogen creams are also recommended to improve the function of the cells lining the vagina.
PBC patients with Raynaud's phenomenon should restrict exposure to the cold. They can wear warm clothing, gloves, and shoes when they must be in cold environments. Some patients find that using gloves also helps avoid problems when they handle ice-cold articles, for example frozen food packages and cold cans of soda. All patients with Raynaud's phenomenon should stop smoking cigarettes because smoking causes reduced blood flow in the blood vessels of the hands and feet. Drugs called calcium channel blockers help the symptoms in the hands and feet of some patients. At the same time, unfortunately, however, these drugs may worsen swallowing difficulties associated with scleroderma.
Skin tightening, calcification, or telangiectasia: There is no known therapy to prevent or reverse skin tightening, calcium deposits, or telangiectasias in patients with scleroderma.
Swallowing problems and heartburn: As previously mentioned, patients with scleroderma may experience heartburn or difficulty swallowing. It is recommended that patients with these symptoms or other evidence of scleroderma or the CREST syndrome:
Cholesterol gallstones may be prevented by the UDCA used for the long-term treatment of the PBC itself. (UDCA taken orally can actually dissolve cholesterol gallstones in a minority of patients.) No treatment is necessary for patients who have gallstones that are not causing symptoms. These patients should usually just be observed because they will probably never develop symptoms from their gallstones.
An operation (cholecystectomy) to remove the gallbladder and its gallstones should be considered if the gallstones have been causing symptoms. These symptoms ordinarily are bouts of rather characteristic abdominal pain. This surgery usually should not be done, however, if a patient has advanced cirrhosis because of the increased risk of complications from both the surgery and the PBC. In this situation, less risky procedures can be considered or, if the gallstones are the cholesterol type, UDCA (if not already being used to treat the PBC) can be given reasonably safely to try to dissolve the gallstones.
Most often, people will contact their primary care health-care professional with questions about the color of their stool. These includes health-care professionals who care for infants and children and adults. Depending upon the cause of the stool color change, certain specialists may need to be involved. For example, for red or black stool due to bleeding, a gastroenterologist may be needed to perform endoscopy, to look for a bleeding source in the stomach or intestine. Patients with PBC are generally treated by gastroenterologists and/or hepatologists. Development of complications may require the need for other specialists. For example, an endocrinologist may be needed for the treatment of metabolic bone disease (osteoporosis). Patients who develop hepatocellular carcinoma may need the help of several specialists including an oncologist, interventional radiologist, and a liver surgeon. Patients with advanced liver disease including cirrhosis of the liver should be referred to a transplant center as they may need a liver transplant at some stage in the future.
Liver transplantation is a life-saving operation for those patients with PBC who are at risk of premature death due to liver failure or the complications of cirrhosis and portal hypertension. The Mayo Risk Score provides an accurate estimate of the future outcome (prognosis) for patients, regardless of whether they are being treated with ursodeoxycholic acid. The United Network for Organ Sharing (UNOS) permits patients with PBC to be listed for a liver transplant once their estimated survival with PBC for an additional year is 95% or less. It is recommended that physicians calculate the Mayo Risk Score at least yearly in all patients with PBC who have cirrhosis.
Most PBC candidates for transplantation have advanced cirrhosis with decompensated liver disease, which also is referred to as liver failure. Decompensated liver disease means that the patients have low levels of serum albumin and blood clotting factors made in the liver and complications of portal venous hypertension such as ascites, variceal bleeding, encephalopathy, or hypersplenism. Patients are classified as having decompensated cirrhosis whether or not the complications respond to medical therapy.
Rarely, before advanced cirrhosis develops, transplantation of the liver is warranted in a few clinically disastrous situations in PBC. Examples of such situations include recurrent fractures due to advanced osteoporosis or severe, debilitating itching unrelieved by any medical therapy, and even more rarely the hepatopulmonary syndrome (breathing difficulty in advanced cirrhosis). The regional review committees of UNOS accept applications for transplantation in these special circumstances and decide on a patient-by-patient basis if liver transplantation is indicated.
The outcome of liver transplantation in PBC is excellent. The survival of patients two or more years after transplantation is generally 80%. This impressive survival rate is greater than the survival of patients transplanted for most other types of liver diseases. The titers of AMA fall following successful liver transplantation, but they do not usually disappear. A minority of patients, however, develops recurrent PBC in the transplanted liver. Studies are being performed to see if reducing the maintenance doses of immunosuppressive drugs more slowly after transplantation can prevent recurrence of PBC. Once recurrent PBC is diagnosed, ursodeoxycholic acid therapy is started to retard progression. Patients with recurrent PBC rarely will need a second liver transplant.
The goal of ongoing and future research in PBC is to better understand the processes (mechanisms) that initiate and perpetuate the inflammation that destroys first the small caliber bile ducts and later the hepatocytes. Logically, a more complete understanding of these mechanisms will reveal new strategies for therapy, designed to block specific crucial steps in the progression of disease.
PBC is such a slowly progressive disease that it is often initially diagnosed after the development of cirrhosis. Future therapies will probably include strategies that differ for patients with early disease compared to those with advanced disease. Presumably, patients with early phases of PBC would benefit more from therapies that block immunologic mechanisms of bile duct destruction than would patients whose bile ducts have already been destroyed. Conversely, patients whose bile ducts have already been destroyed may benefit more from therapies that prevent the formation of scar tissue and the toxic consequences of cholestasis.
The key to success is support of both basic science and clinical research in PBC, which have not been adequately funded in the past. Several promising research strategies are being pursued to reveal the mechanisms involved in developing PBC. For example, studies are in progress to evaluate the genetic (hereditary) characteristics of patients with PBC who have close relatives with the disease. By studying all of these patients with PBC and comparing them with other family members without PBC, it may be possible to better understand the predispositions to this disease. In addition, a large-scale study is underway in the United States that will compare PBC patients with healthy people of the same age and gender. The points of comparison will include their life experiences, habits, diet, medical and surgical histories, childbearing history, and exposures to environmental toxins and medications. This study likewise should provide important clues regarding predispositions to PBC.
Studies also are in progress to see if PBC may be initiated (triggered) by an infection with either bacteria or viruses. For example, studies are ongoing to confirm or disprove the notion that proteins of infectious organisms stimulate AMA autoantibodies (and the autoantibodies just happen to react to antigens present in the mitochondria). Other studies are dissecting the mechanisms involved in the lymphocyte migration toward small bile ducts and the lymphocyte killing of bile duct epithelial cells. These studies involve not only patients with PBC, but also several animal models in which T-lymphocytes destroy small bile ducts in an identical manner to that seen in PBC. These studies ultimately should identify new ways to treat PBC by, for example, blocking the killing of bile ducts by T-lymphocytes.
Finally, the issue of scar tissue formation in PBC and other diseases associated with cholestasis is now being researched in the hope of finding a way to prevent the development of cirrhosis. If cirrhosis can be prevented, even if ongoing inflammation of the liver continues, many patients might not develop the complications of portal venous hypertension and the progression to liver failure.
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