1 STANDARD TREATMENT GUIDELINES ORGAN TRANSPLANT: LIVER Ministry f Health & Family Welfare Gvt. f India
2 Grup Head Crdinatr f Develpment Team Dr Subash Gupta Cnsultant Liver Surgen, Indraprastha Apll Hspital New Delhi
3 Treatment Guidelines fr liver diseases and transplantatin 1. Diagnsis f chrnic liver disease Algrithm fr management f icterus: 1. Patients presenting first time with jaundice frm a liver disease shuld have the fllwing tests: a) Liver functin tests, b) INR c) CBC d) Ultrasund f the abdmen. 2. Raised INR ver 1.7 has minus prtents and will require referral t a higher centre 3. Patients shuld then be separated in t bstructive (SOJ) r medical jaundice. 4. Patients with SOJ shuld be referred t gastrenterlgist/gi surgen. 5. Patients with medical jaundice shuld be then further divided in t acute hepatitis r chrnic liver disease. Additinal tests such as HBsAg, anti HCV, and anti Hep E IgM may be cnducted t define this further. 6. Patients with chrnic liver disease shuld then underg testing in a tertiary centre t see if they have a treatable liver cnditin such as HVOO (Budd Chiari Syndrme), autimmune hepatitis r Wilsn s disease. 7. Patients with advanced chrnic liver disease shuld then be categrized in t Child s A, B r C disease. Thse with Child s C disease shuld be referred t a transplant centre. Patients with Child s A and B cirrhsis shuld be advised t see a transplant hepatlgist at sme pint t discuss future treatment pssibilities. 2) Guidelines fr management f Liver disease: a) Alchlic liver disease: The mainstay f treatment is alchl abstinence. May require help frm a psychiatrist. Hwever it may nt be clear whether alchl has caused liver damage r there has been anther assciated factr such as NASH, hepatitis C r hemachrmatsis r diabetes. Management principles are in accrdance with general measures t manage chrnic liver disease. Patients presenting with acute severe alchlic steathepatitis are usually nt cnsidered fr transplant especially in a predminant cadaver prgram. The treatment f these patients is with intensive care including dialysis and ventilatry supprt. Nutritin is an imprtant cmpnent. It pses an ethical issue whether these patients shuld have the ptin f LRLT. The treating clinicians are under immense pressure frm the family fr this treatment ptin. At this mment, till a cnsensus is reached, a case-by-case decisin shuld be taken after cunseling the family and the ptential dnr and after an pinin frm a psychiatrist. b) Hepatitis B
4 1) Evaluatin f patients newly diagnsed with chrnic HBV infectin shuld include histry, physical examinatin and labratry testing as utlined belw: Histry and physical examinatin Cmplete bld cunts with platelets, liver functin tests and prthrmbin time/inr Tests fr HBV replicatin HBeAg/anti-HBe, HBV DNA Tests t rule ut viral c-infectins anti-hcv, and anti-hiv in thse at risk Ultrasund upper abdmen Upper gastrintestinal endscpy Tests t screen fr HCC AFP and ultrasund Liver bipsy in thse with suspected chrnic hepatitis 2) Patients are classified in the fllwing grups fr treatment purpse: inactive carrier state, chrnic hepatitis B (HBeAg psitive r HBeAg negative grups) and cirrhsis. Once cirrhsis is diagnsed, all attempts shuld be made t identify its cmplicatins such as ascites, GI bleed, hepatic encephalpathy, renal dysfunctin, spntaneus bacterial peritnitis, and hepatcellular carcinma. 3) HBeAg-psitive patients: HBeAg-psitive patients with persistently nrmal ALT shuld be tested fr ALT at 3-6 mnth intervals. ALT alng with HBV DNA shuld be tested mre ften when ALT levels becme elevated. HBeAg status shuld be checked every 6-12 mnths. 4) HBeAg-negative patients: a) HBeAg-negative patients with nrmal ALT and HBV DNA <2,000 IU/ml shuld be tested fr ALT every 3 mnths during the first year t verify that they are truly in the inactive carrier state and then every 6-12 mnths. b) Use f interfern fr hepatitis B shuld be limited t higher centres with extensive experience. 5) In thse wh need treatment, ptins include ral antivirals such as entecavir, tenfvir, telbivudine r pegylated interfern in selected subgrup f patients. 6) Patients with decmpensated cirrhsis: treatment shuld be initiated with an ral antiviral agent, which has high viral suppressin and lw risk f resistance. a. Entecavir r tenfvir wuld be an apprpriate treatment in this setting. b. IFN shuld nt be used in patients with decmpensated cirrhsis. c. Treatment is indicated even if HBV DNA level is lw. 7) Treatment f patients awaiting Liver Transplantatin. a. In thse wh are being cnsidered fr liver transplantatin, aim is t make the patient HBV DNA negative r achieve at least 2 lg reductin in HBV DNA lad prir t transplantatin. b. Treatment f patients with advanced liver disease is advised in rder t reduce the risk f HBV recurrence in graft in thse wh underg liver transplantatin. 8) Patients with hepatitis B related cirrhsis with cmplicatins shuld be referred t a liver transplant centre. c) Hepatitis C: The hepatitis C virus (HCV) has a prevalence f 1 t 2% in India.
5 1. 55% t 85% f individuals wh develp acute hepatitis C infectin will develp chrnic hepatitis. 2. The risk f develping cirrhsis in them is up t 25% ver perids f 25 years. 3. The diagnsis f acute r chrnic HCV infectin generally requires testing f serum fr bth antibdy t HCV (anti-hcv) and fr HCV RNA. Treatment Treatment decisins shuld be individualized based n 1) the severity f liver disease, 2) the ptential fr serius side effects, 3) the likelihd f treatment respnse and 4) the presence f cmrbid cnditins. Treatment decisins are ften based n liver bipsy findings. HCV RNA shuld be tested (quantitative assay) at the initiatin f treatment and at regular intervals there after. The ptimal therapy fr chrnic HCV infectin is the cmbinatin f peginterfern and ribavirin. Fr gentype 1 and 4, treatment with peginterfern plus ribavirin shuld be administered fr 48 weeks. Fr gentypes 2 and 3, treatment with peginterfern plus ribavirin shuld be administered fr 24 weeks. 50% f patients with gentype 1 and 4 and 80% with gentype 2 and 3 remain persistently HCV RNA negative after stpping therapy. The mst cmmn adverse events are influenza like side effects (fatigue, headache, fever and rigrs), psychiatric symptms (depressin, anxiety), anemia and neutrpenia. Patients with HCV-related cmpensated cirrhsis (CTP class A) can be treated with the standard regimen f pegylated interfern and ribavirin but will require clse mnitring fr adverse events. Patients with HCV-related decmpensated cirrhsis shuld be referred fr cnsideratin f liver transplantatin.
6 Interfern-based therapy may be initiated at a lwer dse in patients with decmpensated cirrhsis (CTP class B and C), as lng as experienced clinicians administer treatment with vigilant mnitring fr adverse events. Treatment can be initiated with half dses that are increased incrementally as tlerated at 2-week intervals (referred t as a LADR, lw accelerating dse regimen), supplemented with grwth factrs if required. d) Wilsn's Disease Patients with cirrhsis with neur-psychiatric manifestatins shuld be evaluated fr Wilsn's disease. Hwever, the type f the liver disease can be highly variable, ranging frm asymptmatic with nly bichemical abnrmalities t acute liver failure. It shuld be suspected in any patient presenting with acute hepatic failure with Cmbsnegative intravascular hemlysis, mdest elevatins in serum amintransferases, r lw serum alkaline phsphatase and rati f alkaline phsphatase t bilirubin f <2. If Wilsn's disease is suspected, patients shuld underg Kayser-Fleischer ring examinatin by slit-lamp. Other tests include estimatin f serum cerulplasmin and basal 24 hrs urinary excretin f cpper. An extremely lw serum cerulplasmin level (<50 mg/l r <5 mg/dl) shuld be taken as strng evidence fr the diagnsis f Wilsn's disease. Penicillamine challenge studies may be perfrmed fr the diagnsis f Wilsn's disease in selected cases. In ccasinal cases, estimatin f hepatic parenchymal cpper cntent by liver bipsy may be necessary. The drugs used fr its treatment include D-penicillamine, Trientine and Zinc. Patients with acute liver failure due t Wilsn's disease shuld be referred fr liver transplantatin urgently as withut transplant, mrtality is very high. e) Hemchrmatsis As this is a genetic disease and prgressin t cirrhsis can be prevented, screening f target ppulatin is imprtant. i) Symptmatic patients Unexplained manifestatins f liver disease r a presumably knwn cause f liver disease with abnrmality f ne r mre indirect serum irn markers Type 2 diabetes mellitus, particularly with hepatmegaly, elevated liver enzymes, atypical cardiac disease r early-nset sexual dysfunctin Early-nset atypical arthrpathy, cardiac disease, and male sexual dysfunctin ii) Asymptmatic patients First-degree relatives f a cnfirmed case f hemchrmatsis Individuals with abnrmal serum irn markers discvered during rutine testing
7 Individuals with unexplained elevatin f liver enzymes r the serendipitus finding f asymptmatic hepatmegaly r radilgic detectin f enhanced cmputed tmgraphy attenuatin f the liver Investigatins Serum irn Ttal irn binding capacity % saturatin Serum ferritin Percent saturatin greater than 45% and serum ferritin greater than 150ng/ml suggests hereditary hemchrmatsis / irn verlad states, and patient shuld be evaluated further. Patients shuld underg genetic testing fr HFE mutatins (C282Y and H63D). Smetimes, liver bipsy may be necessary t evaluate fr cirrhsis and irn verlad. Patients with prven hemchrmatsis shuld underg therapeutic phlebtmy. Fr thse with advanced liver disease, therapeutic phlebtmy shuld be stpped as liver transplantatin will ffer definitive treatment f) Autimmune Hepatitis Autimmune hepatitis (AIH) is an unreslving inflammatin f the liver f unknwn cause affecting wmen mre frequently. An acute nset f illness is cmmn (40%), and a fulminant presentatin, characterized by hepatic encephalpathy within 8 weeks f disease nset, is pssible. Diagnstic Criteria Diagnsis f Autimmune Hepatitis (AIH) ften represents a clinical challenge Interface hepatitis is the histlgic hallmark f the syndrme,2 and prtal plasma cell infiltratin typifies the disrder. Neither histlgic finding is disease specific, and the absence f prtal plasma cells des nt preclude the diagnsis Liver bipsy examinatin is essential t establish the diagnsis and evaluate disease severity t determine the need fr treatment. A scring system has been prpsed t assess the strength f the diagnsis Diagnstic Scring System A value f 6 r mre pints makes the diagnsis f AIH very likely, a value f 7 r 8 pints demnstrates definite AIH
8 Sub-classificatins Three types f AIH have been prpsed based n differences in their immunserlgic markers They d nt have distinctive etilgies r respnses t crticsterid therapy Treatment Indicatins: Treatment may nt be indicated in patients with inactive cirrhsis, preexistent cmrbid cnditins, r drug intlerances The indicatins fr treatment are shwn in Table 2 Treatment Regimens: Tw treatment regimens are cmparable with each ther and superir t nnsteridal therapies in the management f severe AIH in adults (Table 3) Prednisne in cmbinatin with azathiprine r a higher dse f prednisne alne is the apprpriate treatment fr severe AIH in adults Sixty-five percent f patients enter remissin within 18 mnths, and 80% achieve remissin within 3 years (mean duratin f treatment t remissin, 22 mnths) Liver bipsy assessment prir t terminatin f treatment is preferred and recmmended, but nt essential, in the management f patients wh satisfy clinical and labratry criteria fr remissin g) HCC; HCC ftens cexists with cirrhsis and with hep B liver disease. Screening interval shuld be 6 mnths using ultrasund. Ndules < less than 1 cm, fllw up scans every 3 mnths fr 2 years, if n grwth, revert t 6 m sans
9 Ndules greater than 1 cm, CT/MRI, typical features, treat like HCC, atypical secnd cntrast scan, bipsy if nt clear Management recmmendatins Single lesin, resectin if gd liver functin, HVPG <10 mmhg. N pre r pst adjuvant therapy. Liver Transplant if within UCSF criteria Preperative therapy if wait list is likely t exceed 6 mnths Lcal ablatin if resectin/transplant can nt be dne. Alchl injectin fr HCC less than 2 cm, therwise RFA TACE is rcmmened as firt line nn curative therapy fr nn surgical patients with large multifcal HCC withut vascular r extrahepatic spread. Srefinib fr thse wh can nt have surgery, TACE, lcal ablatin and still have preserved liver functin. Radiactive particles may be useful but enugh data has nt accrued t give guidelines. h) Pregnancy & Jaundice Jaundice in pregnancy can either be due t a. Exacerbatin f a preexisting liver disease, b. Cincidental liver disease acquired during pregnancy r c. Pregnancy related liver disrder. A preexisting liver disease as well as cincidental liver disease acquired/detected during pregnancy shuld be managed as in a nn pregnant state, the chice f medicatins are dictated by the safety prfile fr the fetus. Interfern is nt t be used in pregnancy. A pregnant female n therapy fr Chrnic Hepatitis B shuld be cntinued n the medicatin she is n Lamivudine and tenfvir have the best safety prfile in pregnancy with emerging evidence fr entecavir as well. Hepatitis E in pregnancy This can run a very fulminant curse, with a higher risk f develping acute liver failure cmpared t nn-pregnant ppulatin as well as higher risk f death if ALF develps. There is n evidence that terminatin f pregnancy decreases incidence f acute liver failure r mrtality in patients with acute viral hepatitis. Terminatin f pregnancy after develpment
10 f ALF has als nt shwn t decrease mrtality. Management f the patient with acute viral hepatitis is supprtive, and viral hepatitis is nt an indicatin fr terminatin f pregnancy, caesarean sectin, r discuragement fr breastfeeding. Chrnic liver disease and pregnancy Chrnic liver disease like autimmune hepatitis (AIH) and Wilsn s disease may flare up during pregnancy. These patients shuld be maintained n the medicatins they were n befre pregnancy, with flares being treated with sterids in AIH. Gallstnes and biliary disease is treated in the same way as in withut pregnancy. Surgery is avided if pssible in 1 st and 3 rd trimester, fr increased risk f abrtin and premature labr, respectively. Chledchlithiasis is treated with ERCP and papilltmy/stne extractin irrespective f the trimester. Pregnancy related liver disease Fr pregnancy related liver disrders, evaluatin f jaundice in pregnancy depends n the type f symptms and the time f nset f symptms in relatin t the week f gestatin. a) Hyperemesis gravidarum Severe nausea and vmiting are the key features f hyperemesis gravidarum, which ccurs predminantly in the first trimester. It ccurs mst ften in wmen less than 25 years f age wh are verweight, multiparus, and with multiple births. Treatment is symptmatic. If nausea and vmiting is accmpanied by headache and peripheral edema, it may indicate preeclampsia and, if accmpanied by abdminal pain with r withut hyptensin in late pregnancy, may indicate hepatic rupture. b) Preeclampsia and HELLP syndrme usually ccurs after 20 weeks f gestatin and is characterized by hypertensin, prteinuria, and edema. It is generally a disease f primigravidas. Jaundice is usually nt a feature f preeclampsia, but is seen with HELLP syndrme (Hemlysis, elevated liver enzymes and lw platelets) as well as hepatic rupture. Bth these cnditins are assciated with preeclampsia. Treatment fr all three cnditins is delivery after stabilizatin f the mther. c) Pruritus is the characteristic feature f intrahepatic chlestasis f pregnancy. It typically invlves the palms f the hands and sles f the feet initially and then affects the rest f the bdy. Jaundice typically fllws the pruritus. It is mst cmmn in third trimester f pregnancy but may ccur in secnd and rarely in first als. Maternal utcme is benign, pruritus reslves quickly after delivery. In the fetus, maternal intrahepatic chlestasis has been assciated with an increased incidence f prematurity, perinatal deaths, fetal distress, and mecnium staining f amnitic fluid. Treatment is symptmatic. Antihistaminics are nt f much help. Chlestyramine and UDCA have been used with sme success. d) Acute fatty liver f pregnancy (AFLP) is a rare and ptentially fatal disease that generally ccurs in the last trimester f pregnancy. AFLP ccurs mre cmmnly during first pregnancies, with multiple gestatins, and with male fetuses. They present with prdrmal symptms f abdminal pain and then jaundice. Mre severe manifestatins include prgressive liver failure, cagulpathy, encephalpathy and renal dysfunctin with liguria r uremia.
11 AFLP has a very pr prgnsis fr bth mther and fetus unless early diagnsis and prmpt terminatin f pregnancy is dne. Early delivery is the mainstay f therapy. Orthtpic liver transplantatin may be required in patients with AFLP and fulminant hepatic failure wh d nt imprve despite delivery and intensive supprtive care 2) Management f cmplicatins f cirrhsis: Frequency f bld tests in Chrnic liver disease Patients with chrnic liver disease need t be mnitred s that they can be transplanted befre they deterirate. Further rgan availability may nt be immediate. MELD scre Status rectificatin Lab values nt lder than >25 Every week 48 h 18 t 24 Every mnth 7 days 11 t 18 Every 3 mnths 14 days 0 t 10 Every 12 mnths 30 days i) Gastrintestinal bleeding ii) Ascites: Endscpy: Patients with upper GI bleed shuld have an endscpy dne within 8 hurs f presentatin. The initial management is with smatstatin infusin. If n Endscpy, varices are identified, they shuld be placed n regular endscpic band ligatin. Endscpic management is the mainstay and failure f endscpic management shuld lead t cnsideratin f TIPS prcedure. Surgical shunts are generally nt indicated in cirrhtics. If shunt surgery is t be dne, a Mescaval shunt is the shunt f chice. Recmmendatins fr Endscpy a) At the time the diagnsis f cirrhsis is made. b) Repeat every 2 years if n varices at initial screening and n decmpensatin, if decmpensatin, at time f decmpensatin and every year. c) Small varices which have nt bled, EGD every 1 year r put them n beta blckers and n fllw up EGD. d) Patients n beta-blckers, adjust dse t the maximal tlerated dse, if treated with EVL, repeat every 1-2 weeks till bliteratin and then surveillance EGD at 1-3 mnths later and then every 6-12 mnths fr recurrence. Salt and fluid restrictin
12 Bed rest Daily weight recrd Diuretics t be started; hwever if there is develpment f renal impairment, hypnatremia r encephalpathy, patient shuld be advised liver transplantatin. Large vlume paracentesis shuld be advised if the patient is nt a fit candidate fr transplant. TIPS may be cnsidered if the liver functin is gd. There is n rle fr peritnevenus shunt because f the high cclusin rate and LIMITED EFFICACY. Indicatins fr TIPS Refractry variceal bleeding Ascites intlerant t LVP Hepatic hydrthrax Hepatrenal syndrme Budd Chiari Syndrme TIPS nt indicated fr GAVE iii) SBP a) hspital admissin b) ascitic tap and cell cunt c) Injectin albumin d) I/v antibitics e) bserve renal functin f) prphylaxis with quinlnes iv) Hepatic Hydrthrax Defined as a significant pleural effusin, usually >500 ml, in a patient with cirrhsis f liver but n primary cardiac r pulmnary disease Occurs usually with alchlic cirrhsis Develps in rughly 4% t 10% f ESLD patients HH can ccur even in the absence f ascites Liver transplantatin is the mst definitive cure Uncmmn presentatin f HH is spntaneus bacterial empyema (SBEM) Cnservative Management Prtcl restrict daily sdium intake t 90 meq
13 a trial f diuretics (spirnlactne and fursemide) Increase dses until the pleural effusin is cntrlled r side effects preclude greater dses N mre than 1.5 liters f fluid shuld be aspirated during therapeutic thracentesis risk f unilateral pulmnary edema r hyptensin Send the fluid fr SAAG Cytlgy fr malignant cells Bichemistry ADA PCR fr TB After aspiratin, cnfirm lung expansin with an X-ray lung. If there is n expansin even after tapping t dryness, then btain a CT scan f the chest t rule ut any underlying lung fibrsis. Hepatic hydrthrax and liver transplantatin In patients with cirrhsis and hydrthrax wh are planned fr liver transplantatin, it is essential demnstrate lung expansin prir t the transplantatin. If there is n reasn fr the lungs nt t expand ther than re-accumulating intrapleural fluid r the patient needs multiple aspiratins t prevent re-accumulatin, then temprarily place an ICD prir t planned date f peratin v) Renal impairment in cirrhtics a) Judicius use f nephrtxic drugs, avid when pssible b) Avid IV cntrast during pre-transplant imaging, hwever it may be essential t image the prtal vein prir t a high risk LRLT c) Optimizatin f extracellular fluid vlume and vascnstrictin: Albumin / d)terlipressin/nradrenaline/ctretide and middrine e) Treat sepsis, such as SBP, f) If albumin is indicated, then reassess the need fr albumin every 48 hrs vi) Encephalpathy: Hepatic encephalpathy (HE) is a cmmn manifestatin seen in bth acute and chrnic liver failure. Several factrs influence its utcme such as infectin, hypxemia, GI hemrrhage, r electrlyte disturbances. It is classified in t fllwing clinical stages: Grade 1. Trivial lack f awareness. Shrtened attentin span. Hypersmnia, insmnia, r inversin f sleep pattern. Asterixis can be detected. Grade 2. Lethargy r apathy. Disrientatin. Inapprpriate behavir. Slurred speech. Obvius asterixis. Grade 3. Grss disrientatin. Bizarre behavir. Semistupr t stupr. Asterixis generally absent. Grade 4. Cma.
14 Several precipitating factrs fr HE have been identified such as: GI hemrrhage, infectins, electrlyte disturbances, use f sedatives, cnstipatin, and excessive dietary prtein. Treatment guidelines: Avidance and preventin f precipitating factrs Nutritin. Imprve prtein intake by feeding dairy prducts and vegetablebased diets. Lactulse. Dsing aims at tw t three sft bwel mvements per day. Use f antibitics such as metrnidazle, ampicillin r rifaximin Refer fr liver transplantatin in apprpriate candidates. Patients in deeper stages f HE may need prphylactic tracheal intubatin. A nasgastric tube is placed fr patients in deep encephalpathy. Avid sedatives whenever pssible. Lactulse can be administered via enema r nasgastric tube in deep encephalpathy. Dsing every hur until stl evacuatin appears ptimizes ral dsing. vii) Hepatpulmnary Syndrme (HPS) Patients with chrnic liver disease shuld be evaluated fr Hepatpulmnary syndrme if they have dyspnea, cyansis r clubbing, and arterial bld gases shw lw PaO2 (<80mmHg). Patients may cmplain f platypnea and have rthdexia. HPS may be present with minimal symptms f chrnic liver disease. HPS is defined by the triad f liver disease, increased alvelar-arterial xygen gradient 15mmHg while breathing rm air, and intrapulmnary vascular dilatatins. The diagnsis is usually based n psitive bubble cntrast echcardigraphy and 99m Tc labeled macraggregated albumin scan (MAA scan). It is imprtant that ther cardi-pulmnary causes shuld be excluded befre labelling a patient as having HPS. Mainstay f therapy is supplemental xygen. Patients with trublesme HPS shuld be referred t a liver transplant centre as HPS may regress cmpletely fllwing liver transplantatin. viii) Prt-pulmnary hypertensin (PPH) Prtpulmnary hypertesin shuld be lked fr in patients with liver disease wh cmplain f exertinal dyspnea. Based n degree f elevatin in mpap, it can be classified as mild (mpap = 25 t 35 mm Hg), mderate (mpap = 35 t 50 mm Hg) and severe (mpap > 50 mm Hg).
15 Transthracic echcardigraphy and, smetimes, right heart catheterizatin are needed t establish the diagnsis f PPH. Prstacyclin (epprstenl) is a ptent vasdilatr and platelet aggregatin inhibitr that results in clinical imprvement in PPH. Bsentan and Sildenafil are rally available drugs that imprve pulmnary hemdynamics in primary pulmnary hypertensin. Mderate t severe PPH (mean pulmnary artery pressure >50 mm Hg) is a cntraindicatin t liver transplantatin because f periperative mrtality f apprximately 40% and lack f reversibility f pulmnary hypertensin. Nn transplant surgery in cirrhsis: In general surgery is prly tlerated in patients with advanced cirrhsis and therefre shuld be taken up fr surgery with cautin. They ften present with hernias and this shuld be managed by cntrlling ascites first. Chlelithiasis and cirrhsis: In patients with cirrhsis, categry Child s B and C, elective surgery shuld be avided, as risk f decmpensatin is very high with cnsequent mrtality. Safe medicines in cirrhsis: NSAIDs shuld nt be given as it may cause GI bleeding. Anti TB drugs shuld be prescribed with cautin and with regular mnitring f liver functin tests every 2 weeks. Aminglycsides t be avided as they may cause nephrtxicity when used with diuretics. Diabetes in decmpensated cirrhsis shuld be treated with Insulin rather than with OHAs. The antiepileptic valprate shuld be avided. In general cautin must be exercised in prescribing medicines in patients with chrnic liver disease as quite ften these medicines are metablized in the liver. Indigenus medicines and in particular Ayurvedic medicines shuld be avided. Liver Transplantatin 1. Indicatin fr transplantatin a) Chrnic liver disease i) Child s C cirrhsis ii) Child s B cirrhsis with an episde f life threatening decmpensatin such as SBP, renal dysfunctin, refractry ascites, recurrent GI bleeding refractry t endscpic management r recurrent HE. iii) Chlestatic liver disease: impairing quality f life such as severe itching, steprsis and recurrent chlangitis, presence f a dminant stricture withut evidence f chlangicarcinma
16 b) Tumurs: i) HCC a. If within UCSF criteria (UCSF criteria is a. Single ndule less than 6.5 cm in size, b. nt mre than 3 ndules with cumulative diameter less than 8 cms) ii) Neurendcrine tumurs T be cnsidered fr transplantatin under exceptinal circumstances such as n evidence f extrahepatic disease, and evidence f slw prgressin f disease. A perid f waiting t assess bilgical behaviur f tumur wuld be desirable. iii) Chlangicarcinma Althugh the May grup has successfully transplanted patients with chlangicarcinma, in general they shuld nt be cnsidered fr transplantatin, as the results are pr. iv) Pediatric tumurs a. Hepatblastma pst three cycles f chemtherapy if nt resectable and absence f extrahepatic disease with the exceptin f stable pulmnary metastasis b. HCC in children can be transplanted beynd UCSF criteria prvided they are Hep B and C negative. c. Indicatin in acute liver failure: Pediatrics: In general, patients fr ALF in this age grup have been selected fr transplant based n Kings Cllege criteria. Hwever the current evidence frm King s Cllege grup suggests that patients shuld be cnsidered fr transplant, nce the INR is greater than 4 with r withut encephalpathy. It is als realised that symptms f encephalpathy can be easily missed in an irritable child. Outcme f transplant in children with grade III r IV cma is nt gd and therefre these children shuld be transplanted nly in exceptinal circumstances. Adults: The King s Cllege criteria are a gd guide. Hwever large vlumes centres have accumulated enugh experience t decide n their wn the indicatin fr transplant in a particular patient. i) Listing fr transplant as is prevalent in the West has little meaning in India where rgan harvesting and allcatin is nt yet a regular feature. ii) Patients with nn hyperacute liver failure in Grade III r IV cma shuld be
17 transplanted early as withut transplant the utcme is dismal. iii) INR shuld be mnitred withut FFP supprt, as the use f FFP has nt been shwn t imprve survival. iv) A prgressive wrsening INR r deteriratin in sensrium are gd indicatrs fr need f transplant. v) Patients f ALF in renal r multirgan failure such as requirement fr high FiO2 d nt d well after transplant and therefre shuld nly be cnsidered fr transplant under exceptinal cnditins. Paracetaml verdse culd be ne exceptin as renal failure can be an early feature. 2. Management f ALF: a) Nurse in a quiet rm with head elevatin. b) I/v fluids and measures t reduce cerebral edema such as i/v Mannitl, 3% hypertnic saline and hypthermia. c) Watch fr hypglycemia d) Renal supprt; Institute dialysis early, rle f MARS is cntrversial e) Antibitics and antifungal prphylaxis shuld be started. f) Elective ventilatin shuld be dne if the patient is Grade III r mre f cma g) N FFP shuld be given, unless an invasive prcedure is planned. h) Shuld be referred t a transplant centre if the INR> 2.5. All patients f ALF shuld be managed in cnsultatin with a Liver Transplant centre s that smth transfer can be rganized if the patient is nt recvering. i) Intracranial pressure measurement is generally nt practiced in India because unequivcal advantages f this has nt been shwn 3. Acute n chrnic liver disease: a. These patients with shuld be referred fr transplant as sn as the diagnsis is made, as the prgnsis is dismal therwise. Thse with encephalpathy shuld be transplanted early. b. Alchlic steathepatitis is usually acute n chrnic liver disease and alchl abstinence may imprve prgnsis. This situatin is different frm ther causes f ACLF 4 Renal Dysfunctin and Liver Transplantatin i) High Risk Grups wh need renal prtectin during Liver Transplantatin
18 Creatinine > 1.5 at the time f transplant Duratin f renal failure (Cr. > 1.5) > 2 weeks in the preceding 6 mnths GFR < 40 ml/min Renal dysfunctin requiring dialysis in the preceding 6 mnths Pre-Transplant renal dysfunctin: medical renal disease with prteinuria >500 mg/24 hurs indicative f nephrpathy ii). Indicatins fr cmbined liver and kidney transplant Serum creatinine > 2 mg/dl in patients wh als have chrnic renal disease Dialysis > 8 weeks GFR < 30 ml/minute Kidney bipsy: (usually nt pssible because f lw platelet and deranged INR) > 30% glmerulsclersis > 30% interstitial fibrsis, r bth Irreversible kidney damage Primary Hyperxaluria iii). Cntra indicatins and delisting criteria fr liver transplantatin Abslute Cntraindicatins: a) Extrahepatic malignancy (unless patients meet standard nclgic criteria fr cure as in certain neur-endcrine malignancies metastatic t the liver with prf f treatment f primary disease). b) Hepatcellular cancers knwn t be radilgically / macrscpically invlving a majr intra-hepatic vascular structure. c) Primary severe pulmnary artery hypertensin d) Sepsis unrespnsive t treatment. e) Cma with evidence f irreversible brain injury (particularly relevant in patients with acute liver failure and may als be relevant t a select few patients with chrnic liver disease). f) Severe, uncrrectable cngenital anmalies g) Majr disease in ther rgan system (diffuse crnary artery disease that is uncrrectable, endstage COPD, etc) h)current substance abuse (narctics). Relative Cntraindicatins (if amelirated befre transplantatin, the transplant peratin can prceed) a) Chlangicarcinma b) Age: Generally > 70 years preclude the benefits f transplantatin. Hwever, chrnlgic age is nt unifrmly indicative f the status f health and marginal exceptins can be made n a case by case basis keeping in view the verall state
19 f health and pssibilities f being able t lead a fruitful & satisfactry life subsequent t transplant. c) Respiratry failure requiring > 50% O2 d) Advanced malnutritin e) Inability t understand r adhere t pst-perative regimen f) Alchlics in recvery and ther prir substance abusers wh have dcumented abstinence fr a minimum f three mnths and have undergne a thrugh multidisciplinary assessment (including scial and psychiatric evaluatin) may be cnsidered fr liver transplantatin if they pssess apprpriate psychscial supprt systems s that they can cmply with lifelng immunsuppressive therapy and be expected t maintain permanent abstinence frm all addictive substances. g)individuals with alchl cnsumptin where reasnable dubt exists regarding its cntributin t the genesis f end stage liver disease r thse individuals with alchlism wh were unaware f their chrnic liver disease presenting with an acute n chrnic liver disease unlikely t survive the minimum abstinence perid, can be cnsidered n a case by case basis fr transplantatin if apprpriate psych-scial supprt and mtivatin and insight fr abstinence is certified by the psychiatrist designated fr the transplant prgram. h) HIV infectin may nt be a cntraindicatin if the viral lad is negative and CD4+ T cell cunts are >250 cells/dl and the patient des nt suffer frm pprtunistic infectins. The histry f Pnuemcystis Carinii pneumnia is nt a cntraindicatin fr transplantatin. 2. Live liver dnr selectin: 18-55, bld grup cmpatible, BMI < 33 1 st r 2 nd degree relatives, Gvt. Auth Cmmittee in case the dnr is nt a near relative Healthy, n addictins, Detailed systemic wrk up HBsAg, HCV, HIV negative Triphasic CT scan f abdmen, fr Liver Attenuatin index (steatsis), vlumetry, vascular map MRCP, fr mapping biliary tree Ideal GRWR 0.8, remnant 30% Cntraindicatins Steatsis > 30% Abnrmal LFT (transaminases x 2) Inadequate graft r remnant vlume Abnrmal anatmy Systemic disease 3. Immunsuppressin
20 The standard immunsuppressin in liver transplant is a triple drug regimen begun within 24 hurs f transplantatin. In patients with renal failure, IL2 receptr antagnists may be used based n centre s preference. Lw dse CNI culd be anther alternative. At the mment, there is n strng evidence fr tailring immunsuppressin based n etilgy f the liver disease except that sterid bluses shuld be avided in patients transplanted fr hepatitis C. Cyclsprine may increase SVR in transplanted patients wh are given treatment with IFN. Sirlimus may have a rle in patients underging transplant fr HCC. Mst centres taper sterids between 3 t 6 mnths pst transplant. Hwever in sme patients, renal impairment may be an issue and these patients may be given lng term sterids tgether with either MMF r azathiprine. The standard regimen is as fllws: a) CNI, either Tacrlimus r Cyclsprine Tacrlimus trugh levels in first mnth shuld be between 5 t 10 ng/ml and later maintained between 5 t 8 ng/ml. Cyclsprine trugh level in the first mnth shuld be between 200 t 300 ng/ml and later reduced t 100 t 200 ng/ml. Centres may chse t adjust dse based n C2 level as well. b) MMF r azathiprine: MMF is given in the dse 500 mg twice a day r the equivalent Myfrtic 360 mg twice a day. In selected patients except thse with AIH, PSC, PBC, MMF can be discntinued after 1 year Azathiprine shuld be given in dse 1 mg/kg bdy weight nce a day. TLC shuld be mnitred frequently and the drugs stpped if the TLC is less than c) Sterids: Sterids are given at the time f transplantatin during the anhepatic phase in the dse f 500 mg and then gradually tapered in the next few days t 20 mg per day. In the next few mnths the sterids are gradually tapered ff unless the preperative diagnsis was an autimmune cnditin d) Renal sparing prtcl: MMF + sterids + delayed CNI, may cnsider IL2 receptr blckade, May als be used in thse with neurlgical txicity e) Treatment f Acute rejectin: Sterid bluses usually 500 mg f methyl prednislne fr three days is given preferably after a liver bipsy. Sterid resistant rejectin shuld be cnfirmed by a review f liver bipsy slides and by ruling ut biliary, vascular and infective issues. ATG/Thymglbulin is the standard drug t be used fr sterid resistant rejectin in the dse f? 5-15 mg / kg/day, (ATG) r Thymglbulin 0.5 t 2 mg/kg/day infused ver 4 t 6 hurs after premedicatin fr 7 t 14