Biliary Atresia, Changing Trends in Management: Outlook of a Pediatric Liver Transplant Surgeon.

DEAR FRIENDS

It is a privilege and honor to write the editorial for this issue specially dedicated to the changing trends in the management of “Biliary Atresia” (BA).

Despite umpteen chapters in textbooks and numerous publications, several lacunae exist in the understanding and management of BA among primary physicians and surgeons, such as what are the exact “management and outcome determining factors,” what is the best age or case to perform Kasai Porto-Enterostomy (KPE), or when to perform primary or sequential liver transplant, and how to optimize “Native Liver Survival” (NLS).

Popularly known as “Extra-Hepatic Bilary Atresia” (EHBA) is a misnomer as the inflammatory process is “progressive” and involves both intra- and extra-hepatic bile ducts (Panductular). The exact immunological trigger which induces a “cascade” of events leading to progressive destruction of the bile ducts with the pathological hallmark of “fibrosclerosing-obliterative cholangiopathy” is elusive and unstoppable. Hence, BA is best addressed as “Progressive Pan-ductular Obliterative Cholaniopathy” (PPOC).

The four clinical phenotypes should be differentiated for prognostic and surgical implications: Isolated BA, BA associated with laterality defects (asplenia or polysplenia [BA splenic malformation (BASM)], situs inversus, and intestinal malrotation), BA with other major congenital malformations (abnormal portal vein [PV], absent vena cava), and cystic BA.[1]

Progressive Panductular Obliterative Cholangiopathy (PPOC) is best diagnosed by POC (Per-Operative Cholangiography). In cystic BA, ultrasonography may show a portal cyst resembling infantile choledochal cyst where magnetic resonance cholangiopancreatography can differentiate the two (intrahepatic biliary radicle dilatation in the latter). “Cyst puncture cholangiogram” can differentiate noncommunicating from communicating variants of “cystic” BA where portal cyst communicates with hypoplastic or irregularly cystic intrahepatic ducts in the latter.[2]

T. Renu Kumar

Early diagnosis and grade of “liver fibrosis” at presentation and rate of progressive liver fibrosis after KPE are the critical outcome determining factors in BA, rather than the usual perception of “age at presentation.” Only 20% of BA cases are referred before 60 days,[3] and average age at presentation to specialized center in India is 3.5 months.[4] Screening for BA by incorporating a “Stool Color Card” (SCC Screening) along with well-baby card of the Indian Academy of Pediatrics can improve awareness and enhance early referrals.[5]

Differential Diagnosis

BA is the most commonly misdiagnosed entity in 'Overlapping Cholestatic Syndromes' (OCS) in infants. Alagille syndrome, Progressive Familial Intrahepatic Cholestasis type-3, Neonatal Sclerosing Cholangitis syndrome and cystic fibrosis can all resemble BA on liver biopsy or POC. Hence in OCS prior gene mutational studies like cholestatic gene Panel or Clinical Exome Sequencing can confirm or exclude the differentials in the context, and can also discover unidentified novel gene mutations. Genotyping also help in interpretation of POC, there by avoiding KPE in non BA cases.

TIMING AND TYPE OF SURGERY IN BILIARY ATRESIA

In cases without kasai porto-enterostomy

A reliable biomarker to predict timing and type of surgery in BA (only KPE ± sequential Liver Transplantation [LT] or primary LT) is unknown. BA can present at any age during infancy with variable grade of “liver fibrosis.” KPE performed within 60 days of age failed to establish adequate bile flow in 35.3% of cases.[67] Conversely, few infants presenting after 90 days of age can also benefit from KPE.[48] Hence, grade of “liver fibrosis” is the guiding principle for KPE rather than “age.”[4] Hence, its “age” versus “liver fibrosis” at presentation and the latter appears to be the critical prognostic indicator. However, in most centers across the world, majority of BA cases are subjected to KPE without the evaluation for grade of 'liver fibrosis'.

A multicenter prospective study can be conducted to determine the effectiveness of KPE in each grade of liver fibrosis (F1–F4) and to establish criteria for primary LT. Unlike liver biopsy (invasive, subjective, and indiscriminative), “fibroscan” is a noninvasive, accurate, and reproducible test well validated in children for grading liver fibrosis,[9] using S (S1 and S2 modes) or M probes depending child's thoracic perimeter.[10] The 3 in 1 multipurpose probe of Fibrotouch machine is also very convenient for grading liver fibrosis even in small infants irrespective of thoracic perimeter. Fibroscan can categorize BA as per METAVIR scoring for liver fibrosis (F0–F4). F0 (no fibrosis) and F1 (mild fibrosis) cases can be offered KPE, irrespective of the age of presentation even in 'seniors' presenting after 100 days. F2 (moderate fibrosis) and F3 (advanced fibrosis) can still be subjected to KPE given the “hopeful” benefit of doubt; however, these cases should be monitored for progressive cirrhosis leading to failed KPE or decompensations and promptly evaluated for sequential LT.

F4 suggests “established cirrhosis,” and a liver stiffness measurement cutoff value >15.15 kPa correlates well with confirmed cirrhosis on liver biopsy.[11] Established cirrhosis is irreversible and rapidly progressive in BA, and these cases decompensate after KPE (and most are lost to follow up – personal experience). Irrespective of age, compensated cirrhosis stage (on fibroscan/liver biopsy/nodularity of the liver at KPE) provides a “therapeutic window” for primary LT, even in the absence of synthetic liver dysfunction. Protocol primary LT in cases referred after “100 days” does not have a survival advantage, but “noncirrhosis” at KPE showed some survival benefit;[12] hence, “late KPE” is still justified in the absence of established cirrhosis. Already, an observational study has been started by the US National Library of Medicine: Fibroscan in Pediatric Cholestatic Liver Disease Study Protocol, to evaluate the role of noninvasive fibroscan to detect and quantify liver fibrosis in BA and other cholestatic disorders.[13]

FOLLOW-UP AND INDICATIONS OF LIVER TRANSPLANT IN BILIARY ATRESIA AFTER KASAI PORTOENTEROSTOMY

Among all pediatric surgeries, KPE has the highest failure rate.[11] “Failed KPE” defined as “early absence of bile flow or late development of cirrhosis despite good bile flow.”[1] After failed KPE without bile flow, very few survive beyond 24–36 months of age without LT.[14] “Total serum bilirubin (TSB) at 3 months after KPE more than 6 mg/dL” (bili@3m>6mg%) suggests failed KPE and is an indication for LT; there is a clear difference in 2-year transplant-free survival (TFS) between children with TSB <2 mg/dL and those with TSB >6 mg/dL (84% vs. 16%; P < 0.001).[14] Likewise, after KPE if jaundice resolves by 3 months, the 10-year TFS is 75%–90%; conversely, if jaundice persists, the 3-year TFS is only 20%. Thus, children who do not demonstrate good bile flow and clearance of jaundice by 3 months after KPE should be evaluated for early LT, ideally by 6–9 months of age.[1]

KPE is a palliative surgery; several modifications have improved “Jaundice Disappearance Rate” (JDR) and prolonged NLS;[8] however, both depend on the grade and “rate” of progressive liver fibrosis, pre- and post-KPE, respectively. The progressive liver damage can continue despite the “so-called” successful KPE, slowly in cases with adequate bile flow and rapidly in cases with no bile flow, leading to decompensated cirrhosis requiring early sequential LT.[1]

Successful KPE does not mean adequate bile flow with clearance of jaundice, rather should strictly mean “lifelong” “NLS.” Unfortunately, NLS is only 20% at 20 years after KPE.[15] Unlike KPE, LT is curative; hence, all BA cases should be assessed and monitored for liver fibrosis and its progression pre- and post-KPE, respectively, for “timely” LT.

Other indications for LT after KPE are “failure to thrive,” hepatic osteodystrophy with fractures, recurrent bacterial cholangitis, recurrent infections with multidrug-resistant organisms, life-threatening sepsis, recurrent hospitalizations, poor quality of life, complicated portal hypertension with variceal bleeding, significant ascites ± spontaneous bacterial peritonitis, symptomatic thrombocytopenia, porto pulmonary hypertension, and intractable pruritus. Rarely for hepatocellular carcinoma and cholangiocarcinoma developing in BA. Importantly, Hepato-Pulmonary Syndrome (HPS) and Hepato-Renal Syndrome (HRS) are only cured by “early” LT.[1]

SURGICAL ISSUES UNIQUE TO LIVER TRANSPLANTATION IN BILIARY ATRESIA

During recipient hepatectomy

Vascularized adhesions, portosystemic collaterals, coagulopathy, and thrombocytopenia can predispose to excessive bleeding. Risk of hollow viscus injury can be prevented by meticulous dissection and cautious use of electrocautery. Vena cava can be flimsy, fragile, and firmly adherent to caudate lobe and pose a risk of caval thinning.

During graft implantation

Hepatic artery is usually of good calibre in BA, however anamalous PV (atretic, preduodenal), anomalous hepatic veins, and vena cava (absent or hypoplastic) can complicate vascular inflow and outflow reconstruction. Kinking, telescoping, tension, and narrowing of all vascular anastomosis should be avoided using modified meticulous anastomotic techniques or using cryopreserved vascular grafts for reconstructing atretic PV or vena cava, to ensure laminar inflow and outflow.

The Therapuetic window

Living-related LT (LRLT) is the procedure of choice; it is elective, reduces waiting-list mortality, and allows procurement of an “ideal” liver graft (usually left lateral segment-LLS) with short cold ischemia time. Irrespective of age, LRLT can be 'timed perfectly' to utilize the 'therapuetic Window' that each case offers, before significant malnutrion, decompensations and infections settle in.

Optimal Age/weight and Outcome

The perception that certain optimal age and/or weight are a prerequisite for successful pediatric transplantation is not true.[16] With advances in surgical technique, pediatric anesthesia and critical care, and multidisciplinary team approach, excellent outcomes have been achieved even in very young and small infants.[17] In India, the 5- and 10-year survival rates in children after LRLT are 98% and 90%, respectively.[18]

Financial Support and Post op Immunosuppression for LT

LT is a costly affair; however, few state governments have allocated “special relief funds” for transplant cases. Most transplant centers have financial coordinators for “cost cutting” and “fundraising” to decrease financial burden. Compared to adult LT cost is low, living donor safety, longterm outcome and graft tolerance are superior for pediatric liver transplants. Steroid-free tacrolimus-based immunosuppression (IS) seems to promote long-term graft acceptance under minimal IS (Prope tolerance – tacrolimus monotherapy, with very safe mean trough blood levels <4 ng/mL) or no IS (operational tolerance – graft survival in the absence of maintenance IS).[19] In BA, gender-matched maternal livers have decreased rates of graft failure compared to gender-mismatched paternal liver.[20]

MESSAGE

In BA primary screening, early referral, grading and monitoring of liver fibrosis pre- and post KPE respectively are crucial for optimizing outcome. Compensated cirrhosis stage (F4 on fibroscan/liver biopsy/nodular liver at KPE) provides a “therapeutic window” for primary LT though a long-term comparative study is required. Constituting an “Indian BA Registry” and developing a “standardized central” screening program and “management protocols” can optimize the overall outcome in BA.