- Email: [email protected]
Nontransplant surgical interventions in progressive familial intrahepatic cholestasis
Journal of Pediatric Surgery (2009) 44, 821–827
www.elsevier.com/locate/jpedsurg
Nontransplant surgical interventions in progressive familial intrahepatic cholestasis Adam Rahn Davis a,⁎, Philip Rosenthal a,b , Thomas B. Newman a,c a
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California, San Francisco, CA 94143, USA b Department of Surgery, University of California, San Francisco, CA 94143, USA c Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94107-1762, USA Received 3 June 2008; revised 22 July 2008; accepted 22 July 2008
Key words: Progressive familial intrahepatic cholestasis; Outcome; Biliary diversion; Children; Ileal bypass
Abstract Background: Progressive familial intrahepatic cholestasis (PFIC) is a family of rare childhood diseases that was universally fatal until the development of liver transplant. In the last 20 years, the use of nontransplant surgery to treat PFIC has become the standard of care. There are various surgical techniques that have been performed. There are no reviews evaluating the outcome of these operations. Methods: A systematic search of the literature for articles evaluating the outcome of nontransplant surgical interventions in PFIC patients was performed. Data from these studies was abstracted and summarized. Results: No trials have been performed addressing nontransplant surgical interventions in PFIC patients. We analyzed 11 case series and case reports. Generally, patients had successful outcomes (81%) with cessation of progression of disease and resolution of symptoms. Treatment failures were often associated with more advanced disease. Discussion: There is no evidence to demonstrate a superiority of one type of nontransplant surgical intervention in PFIC patients. We propose the development of a registry and standardization of outcomes measurements to allow improved comparison of results. © 2009 Elsevier Inc. All rights reserved.
1. Background Progressive familial intrahepatic cholestasis (PFIC) is a family of rare genetic disorders that affect the ability of the hepatocyte to transport bile salts into the biliary tree. As their name implies, these genetic abnormalities cause progressive cholestasis over the patient's lifetime that is ⁎ Corresponding author. Tel.: +1 415 476 5892; fax: +1 415 476 1343. E-mail addresses: [email protected] (A.R. Davis), [email protected] (P. Rosenthal), [email protected] (T.B. Newman). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2008.07.018
generally associated with profound intractable pruritis. Left untreated, the disorders lead to cirrhosis and death before adolescence [1-4]. Recently the genetic underpinnings of these disorders have been identified. PFIC type I is caused by a mutation to the FIC1 gene which codes for a type IV P-type adenosine triphosphatase (ATPase), the function of which remains unknown [5]. Progressive familial intrahepatic cholestasis type II is caused by a bile salt export protein deficiency [6]. These 2 types are characterized by a low serum gammaglutamyltransferase (GGT) level in the face of continuing cholestasis [7,8]. Type III, which is caused by a deficiency
822 Table 1
A.R. Davis et al. Nontransplant surgical interventions for progressive familial intrahepatic cholestasis: studies
Study
Study design
Whitington and Whitington [13]
Case series
Emond and Whitington [18]
No. of subjects
Procedure
Age at time of procedure (y) (range or mean [SD])
Outcomes measured
4
PEBD
3-9
Case series
8
PEBD
10.5 (7.1) ⁎
Standard serum labs, total serum bile acids, light microscopy, pruritis Standard serum labs, growth, pruritis
Hollands et al [14]
Case series
5
Ileal bypass
1.2-17
Standard serum labs, light microscopy, pruritis
Ismail et al [19]
Comparative case series
16
PEBD
Not Reported
Standard serum labs, total serum bile acids
Rebhandl et al [17]
Case report
1
Appendiceal PEBD
13
Standard serum labs, total serum bile acids, pruritis
Melter et al [20]
Case series
6
PEBD
1.7-12.5
Standard serum labs, total serum bile acids, growth, pruritis
Ng et al [21]
Case series
4
PEBD
2.3-10.5
Kalicinski et al [22]
Comparative case series
21 PEBD, 5 IB
0.8-16
Standard serum labs, total serum bile acids, growth, pruritis Bilirubin, total serum bile acids, growth, pruritis
Kurbegov et al [23]
Case series
3
PEBD
1.0-5.4
Standard serum labs, serum bile acid profile, light microscopy, electron microscopy, growth, pruritis
Metzelder et al [16]
Case series
4
Laparoscopic PEBD
0.3-3.1
Standard serum labs, total serum bile acids
Bustorff-Silva et al [5]
Case series
2
1 PEBD, 2 PIBD
3 (PEBD), 15-17 (PIBD)
Standard serum labs, light histology, pruritis
24
UDCA indicates ursodeoxycholic acid; OLTx, orthotopic liver transplant. * Mean and SD of age only apply to the 6 patients who showed a clinical response. Follow-up “Successful” Complications Author conclusions period (y) outcome
in multidrug resistance protein 3, is associated with high serum GGT levels, less pruritis, and a later onset [7-9]. Before the development of liver transplantation, therapy for these patients was generally ineffective. With the advent
Notes
of liver transplantation, many PFIC patients were treated with this life-saving procedure [10]. At one time, PFIC was among the 5 most common indications for liver transplantation in children [11,12]. Though curative of their primary disease,
Nontransplant surgical interventions in PFIC
823
Table 1 (continued) Follow-up period (y)
“Successful” outcome
Complications
Author conclusions
Notes
3-8
4/4
1 Revision of stoma
PEBD is a an effective intervention in PFIC and should be considered as a primary treatment modality.
–
2.3-4.9
6/8
PEBD should be used as primary treatment once diagnosis is confirmed.
The 2 treatment failures were cirrhotic on preprocedure biopsy.
0.5-1.8
4/5
12/16
IB is safe and effective, but longer follow-up is needed before recommendation as primary intervention. PEBD should be performed if UDCA therapy fails or there is moderate fibrosis; OLTx should be done for cirrhotic patients.
None of their patients were noted to have diarrhea.
0.5-3
2
1/1
1
6/6
1 Hemoperitoneum, 2 stomal herniation, 2 compensated cirrhotics to OLTx 1 Anastomotic bleed requiring reoperation, 1 wound infection 2 Stomal revisions, 1 intestinal obstruction requiring surgery, a qfewq episodes of cholangitis Retraction of stoma nipple and abscess near stoma 1 Intestinal obstruction requiring surgery
1.3-6.5
4/4
None reported
1-4
15/20 PEBD, 2/5 IB
1.2-5
3/3
1 PEBD converted to IB for high stomal output, 1 IB converted to PEBD for poor clinical response 1 Stomal revision, 1 mild stomal bleeding
0.1-0.2
4/4
None
Not Reported
2/2
None reported
these transplanted patients would continue to suffer morbidities associated with life-long immunosuppression. A better therapeutic modality was desired. In 1988, the first report of treating PFIC with nontransplant surgery was published by
The use of the appendix should add to the surgeons' options for PEBD. PEBD improves growth and should be performed if UDCA therapy fails; OLTx should be done for cirrhotic patients. PEBD prevents long-term progression of liver disease.
One treatment failure was cirrhotic at time of procedure; one had recurrent hepatitis of unknown etiology that did not abate after PEBD. –
Normalization of serum lipid panel was demonstrated. –
IB is not as effective as PEBD in preventing the long-term progression of liver disease.
4/5 of the IB patients had initial response, but only 2 maintained response.
PEBD besides clinical improvement is associated with near normalization of pathology, improved growth, and normalization of serum bile acid profile. Laparoscopic PEBD is feasible; long-term outcomes remain unclear. PIBD is an attractive surgical option; long-term follow-up studies are needed.
–
-
Neither patient had diarrhea nor any episodes of cholangitis after PIBD
Whitington and Whitington [13]. Whitington and Whitington reported on a procedure called partial external biliary diversion (PEBD), in which a 10- to 15-cm jejunal conduit was anastomosed from the gallbladder to the abdominal
824 cutaneous surface where a permanent stoma was created for bile drainage. Two other procedures have been developed to manage PFIC, an ileal bypass (IB) in which the patient receives an ileocolonic anastomosis that bypasses the distal 15% of the small bowel interfering with the enterohepatic circulation of bile salts [14] and partial internal biliary diversion (PIBD) in which a 15- to 20-cm jejunal conduit is created that connects the gallbladder to the colon for bile drainage [15]. Two variants on the original PEBD have also been described; one using a laparoscopic technique [16] and the other using an appendiceal conduit [17]. In this systematic review, we will examine the evidence of efficacy of nontransplant surgical interventions in the treatment of PFIC. We will also investigate the comparative efficacy of the various procedures and the quality of the studies regarding this topic. Finally, we will propose future directions of study.
2. Methods Case reports, case series, and clinical trials reporting on the outcome of nontransplant surgical outcomes were included in this study. A PubMed search using the terms “Byler biliary diversion,” “Progressive familial biliary diversion,” “Byler surgery,” and `qProgressive familial surgery” was performed. In addition, PubMed was searched using the MeSH term “Cholestasis, Intrahepatic/surgery.” The title of each article returned by this search was reviewed. All articles that pertain to the topic of the review were read by a single reviewer. The references of these articles were examined in order to find other pertinent articles. If the article reports on the outcome of a patient or series of patients who underwent a nontransplant surgical intervention to manage their PFIC, it was included. Non-English articles were excluded. Data were abstracted from each article in a nonblinded fashion by a single reviewer, with spot-checks by other authors. Data abstracted included study design, number of subjects, type of procedure, age range of patients at time of intervention, pre- and postsurgical serum laboratory values, pre- and postsurgical histology, pre- and postsurgical growth parameters, pre- and postsurgical pruritis, and transplant-free survival. Data were abstracted at the individual level if available or study averages if individual level data were not available. Because of the heterogeneity of the articles with respect to measured outcomes, we did not do any quantitative analysis of the data.
3. Results We found 11 articles that met our inclusion criteria [13-23]. One article that may have fit our criteria was not reviewed, secondary to inability to obtain the full text version
A.R. Davis et al. of the article [24]. The key characteristics of the reviewed articles are summarized in Table 1. There have been no clinical trials or controlled studies addressing nontransplant surgical interventions in patients with PFIC; all of the articles are case reports or case series. Two of the articles were comparative case series. In one, the outcome of PEBD was compared with that of transplant [19]. In the other, PEBD was compared to ileal bypass [22]. All of the studies reported the procedure, and all of them except for Kurbegov described the actual surgical technique [23]. There was minimal variation in the surgical technique described for each procedure. The only notable variation was that the initial three ileal bypass procedures reported by Hollands et al [14] did not yet have a standard technique for deciding the length of ileum to be bypassed. There was little consistency in what type of outcome data were reported in the studies. Most used quantitative values for laboratory data, although a few used descriptive data such as “laboratory signs of cholestasis were reduced in all patients.” [16] The type of laboratory data collected also varied. Seven of the 11 studies reported pre- and postsurgical values for serum alanine transaminase (ALT). Six reported pre- and postsurgical serum total bilirubin levels. Seven reported pre- and postsurgical serum bile salt levels. Other laboratory tests reported in some of the studies included serum aspartate transaminase (AST), GGT, conjugated bilirubin, prothrombin time, albumin, alkaline phosphatase, cholesterol, and fractionated bile salts. Postsurgical histology was reported in 4 of the studies. Only Kurbegov et al. [23] reported pathology in a systematic manner, with histological scores. Theirs was also the only study to examine electron microscopy. Pruritis was reported in nearly all the studies; 4 used the numerical scoring system developed by Whitington and Whitington [13]. Growth was reported on in 5 studies but quantified in only 3. The length of follow-up varied from 6 weeks to 8 years. All of the studies defined their PFIC cases as progressive cholestasis with low GGT values with other causes of chronic liver disease being excluded. This means that surgery on PFIC type III patients was not evaluated in these studies and has not been reported in the literature. The timing of the surgical intervention in regard to the natural history of disease varied, with an age range of 4 months to 17 years, and there was a variation in disease progression at the time of surgery. This heterogeneity in severity of disease at the time of surgery makes it difficult to compare outcomes. Generally, patients did well. Of the 78 patients who underwent a nontransplant surgical intervention, 63 (81%) had a “successful outcome.” Generally these outcomes were dramatic with resolution of symptoms, cessation of the progression to liver failure, and histologic improvements when examined. Of the 15 who did not have a successful outcome, 3 were reported to have been cirrhotic at the time of surgery, 3 were reported to have received surgery “late after diagnosis with moderate fibrosis,” and one was
Nontransplant surgical interventions in PFIC reported to have a recurrent hepatitis of unknown etiology both prior to and after external diversion was performed. Of the 8 remaining patients with poor outcomes, 4 were in ileal bypass patients, 2 of whom initially had a good response but had a return of symptoms and laboratory abnormalities after 12 months. The authors did not hypothesize on why the last 4 non-ileal bypass patients had poor outcomes. Patients who underwent PEBD had successful outcomes in 83% (55/66) of cases. This included four successful laparoscopic PEBDs and a successful appendiceal PEBD. Ileal bypass was successful in 6 of 10 cases; however, the length of follow-up for these patients was not uniform, and the one study with more than a year of follow-up showed that an initial response did not equate to a sustained one. Both patients who underwent PIBD had successful outcomes. Responders had dramatic improvement in their laboratory values. In the 43 patients in whom both were reported, the mean postsurgical serum ALT level was 48 IU/L, a decrease from a mean presurgical ALT level of 107 IU/L (variance and range cannot be calculated because individual data were not reported in all studies). Serum total bilirubin levels decreased from a mean of 5.6 to 1.7 mg/dL in the 42 patients in whom they were reported. Serum bile salts decreased from a mean of 258 μmol/L to 55 μmol/L in the 56 patients in whom they were reported. The 4 studies that had postsurgical pathology specimens included 7 patients who had pre- and postsurgical biopsies. These 7 patients showed markedly improved histology. Whitington and Whitington [13] showed presurgical biopsies with hepatocellular and canalicular cholestasis, moderate ballooning, giant cell transformation, and portal fibrosis. Postsurgical biopsies in 2 of his patients demonstrated minimal fatty changes with otherwise normal histology. Hollands et al [14] reported on ileal bypass, including one patient who had both pre and postsurgical histology. Initial biopsy showed hepatic fibrosis, and the postsurgical biopsy demonstrated “significant improvement.” Bustorff-Silva reported on one patient who had a liver biopsy before and after PEBD. The initial biopsy showed moderate inflammation, increased portal fibrosis, portoportal septum, and cholestasis. A repeat biopsy 11 months later showed “no signs of progressive liver disease” [15]. Kurbegov et al [23] was the only study that examined histology in a quantitative manner. It was also the only study to examine electron microscopy. Cholestasis was graded 0 to 3. Presurgically, the 3 patients had values of 3, 3, and 1. After PEBD, they all had a value of 0. Inflammatory infiltrates were graded 0 to IV. All 3 patients had values of II before surgery. After their operation, the values were I, I, and 0. Portal tract fibrosis was also graded 0 to IV, and each of the patients had a II prior to surgery. After their procedure the fibrosis values were I, I, and 0. Kurbegov et al were also able to document the disappearance of Byler bile and the near normalization of electron microscopic findings.
825 Nearly all of the studies commented on pruritis. Four of the studies, including 16 patients, used a 0-to-4 scale developed by Whitington et al [13]. In these, pruritis improved from 3.7 ± 0.5 (mean ± SD) preoperatively to 0.25 ± 1.0 after surgery. The other studies also reported resolution of pruritis in most patients. Of the 5 studies that mentioned growth, 4 reported improved growth velocity. One reported no change. Three studies quantified these changes in some manner. Ng et al [21] had a patient who went from a weight at the fifth percentile and a height less than the 5th percentile at the time of her procedure to a weight between the 25th and 50th percentile and a height between the 90th and 95th percentile 6 1/2 years later. Another of the Ng et al patients went from a weight and a height between the 5th and 10th percentile at the time of procedure to both between the 25th and 50th percentile after 51/2 years. Kurbegov et al [23] and Melter et al [16] both measured height z-scores before and after the procedure and saw the z-scores increase from a mean of −2.8 to −1.4. Complications were not reported systematically. Revisions of stomas were performed for 4 children. Intestinal obstruction requiring surgery was reported for 2 children. High output from a PEBD stoma motivated an ileal bypass in one case, and an adolescent who found the PEBD stoma interfering with her quality of life subsequently had a PIBD. It is interesting to note some complications that were not seen. Partial internal biliary diversion was hypothesized to place patients at risk for osmotic diarrhea and cholangitis. Neither of the 2 patients who received PIBD had either cholangitis or diarrhea.
4. Discussion Although outcomes are not consistently defined or measured in the studies of nontransplant surgical interventions for PFIC, some conclusions can be drawn from these existing reports and they suggest future areas for study. It is clear even without randomized controlled studies that children with PFIC do better with nontransplant surgical interventions than they do with the natural history of disease, which is uniformly fatal. It appears that the success rate is high enough that many patients may do better with a nontransplant procedure than transplant given the posttransplant morbidities associated with immunotherapy. Successful outcomes have been demonstrated, with marked improvements in clinical symptoms, laboratory values, growth, and histology. Two issues may lend us caution when trying to generalize this success: (1) it is possible that these studies were published by the world's experts in PFIC care, and perhaps, the outcome is not as successful in less experienced hands, and (2) because these are retrospective reports, less successful outcomes may not have been reported creating bias in this review.
826 These studies provide some evidence that those with more advanced disease are most likely to have a poor outcome with nontransplant surgical procedures. This may encourage clinicians to consider a surgical intervention early in the course of disease before significant hepatic scarring develops. On the other hand, there is no clear evidence about which procedure is preferred. One study suggests that the effects of ileal bypass may be attenuated over time; this could be owing to adaptation of the remaining bowel. However, it is also possible that bypassing a different length of bowel may lead to a different outcome. Partial internal biliary diversion has been avoided because of concerns about cholangitis. This feared complication did not occur in the two reported patients who underwent this procedure. Future research on this subject would benefit from creation of a national registry of PFIC patients, with clear inclusion and exclusion criteria and standard data collection on treatments and outcomes. Failing that, consistent measurements performed in each study would improve our ability to assess evidence in the treatment of this rare disease. We propose that all patients have their laboratory measurements reported quantitatively with a standard follow-up time of 6 months and 3 years. This would allow assessment of early changes and long-term sustainability of response. Growth should be measured at the time of the procedure and annually for at least 3 years and reported in height and weight z-scores for age. Pruritis should be measured using the scoring tool of Whitington and Whitington [13]. Histology should be reported in a quantifiable manner by a blinded pathologist at the time of diagnosis, at the time of a procedure and, if available, at time of follow-up. The 2 most important remaining questions are (1) how to manage patients with more advanced disease and (2) which procedure is superior. Regarding the first question, is an attempt of diversion or bypass still beneficial even in advanced disease? Even if there is a low probability of success, does the occasional responder outweigh the risk of an additional surgery prior to transplant? Where is this line? Regarding the second question, more knowledge regarding posttransplant complications and quality of life is needed. If PIBD has a similar complication profile to PEBD, then it is likely that many patients would prefer a stoma free life. The effects on quality of life of having a biliary cutaneous drain are not known. A randomized trial comparing PEBD to PIBD is indicated, given the current equipoise of the two procedures. Nontransplant surgical interventions have greatly improved the outcome of PFIC patients and prevented many transplants. Unanswered questions remain, regarding patients with more severe disease and the optimal procedure to perform. Our ability to optimally treat these patients would be increased by creation of a national registry with standardized inclusion criteria and data collection and randomized trials of interventions.
A.R. Davis et al.
References [1] Clayton RJ, Iber FL, Ruebner BH, et al. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child (1960) 1969;117(1):112-24. [2] Linarelli LG, Williams CN, Phillips MJ. Byler's disease: fatal intrahepatic cholestasis. J Pediatr 1972;81(3):484-92. [3] Maggiore G, Bernard O, Riely CA, et al. Normal serum gammaglutamyl-transpeptidase activity identifies groups of infants with idiopathic cholestasis with poor prognosis. J Pediatr 1987;111(2): 251-2. [4] Riely CA. Familial intrahepatic cholestatic syndromes. Semin Liver Dis 1987;7(2):119-33. [5] Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998;18(3):219-24. [6] Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999;117(6):1370-9. [7] Colombo C, Okolicsanyi L, Strazzabosco M. Advances in familial and congenital cholestatic diseases. Clinical and diagnostic implications. Dig Liver Dis 2000;32(2):152-9. [8] Jacquemin E. Progressive familial intrahepatic cholestasis. Genetic basis and treatment. Clin Liver Dis 2000;4(4):753-63. [9] de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998;95(1):282-7. [10] Soubrane O, Gauthier F, DeVictor D, et al. Orthotopic liver transplantation for Byler disease. Transplantation 1990;50(5):804-6. [11] Esquivel CO, Iwatsuki S, Gordon RD, et al. Indications for pediatric liver transplantation. J Pediatr 1987;111(6 Pt 2):1039-45. [12] Whitington PF, Balistreri WF. Liver transplantation in pediatrics: indications, contraindications, and pretransplant management. J Pediatr 1991;118(2):169-77. [13] Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988;95(1):130-6. [14] Hollands CM, Rivera-Pedrogo FJ, Gonzalez-Vallina R, et al. Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus. J Pediatr Surg 1998;33(2): 220-4. [15] Bustorff-Silva J, Sbraggia Neto L, Olimpio H, et al. Partial internal biliary diversion through a cholecystojejunocolonic anastomosis—a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report. J Pediatr Surg 2007; 42(8):1337-40. [16] Metzelder ML, Bottlander M, Melter M, et al. Laparoscopic partial external biliary diversion procedure in progressive familial intrahepatic cholestasis: a new approach. Surg Endosc 2005;19(12):1641-3. [17] Rebhandl W, Felberbauer FX, Turnbull J, et al. Biliary diversion by use of the appendix (cholecystoappendicostomy) in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 1999;28(2): 217-9. [18] Emond JC, Whitington PF. Selective surgical management of progressive familial intrahepatic cholestasis (Byler's disease). J Pediatr Surg 1995;30(12):1635-41. [19] Ismail H, Kalicinski P, Markiewicz M, et al. Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion. Pediatr Transplant 1999;3(3):219-24. [20] Melter M, Rodeck B, Kardorff R, et al. Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients. Am J Gastroenterol 2000;95(12):3522-8. [21] Ng VL, Ryckman FC, Porta G, et al. Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 2000;30(2): 152-6.
Nontransplant surgical interventions in PFIC [22] Kalicinski PJ, Ismail H, Jankowska I, et al. Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass. Eur J Pediatr Surg 2003; 13(5):307-11. [23] Kurbegov AC, Setchell KD, Haas JE, et al. Biliary diversion for progressive familial intrahepatic cholestasis: improved liver mor-
827 phology and bile acid profile. Gastroenterology 2003;125(4): 1227-34. [24] Wanty C, Joomye R, Van Hoorebeek N, et al. Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy. Acta Gastroenterol Belg 2004; 67(4):313-9.
www.elsevier.com/locate/jpedsurg
Nontransplant surgical interventions in progressive familial intrahepatic cholestasis Adam Rahn Davis a,⁎, Philip Rosenthal a,b , Thomas B. Newman a,c a
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California, San Francisco, CA 94143, USA b Department of Surgery, University of California, San Francisco, CA 94143, USA c Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94107-1762, USA Received 3 June 2008; revised 22 July 2008; accepted 22 July 2008
Key words: Progressive familial intrahepatic cholestasis; Outcome; Biliary diversion; Children; Ileal bypass
Abstract Background: Progressive familial intrahepatic cholestasis (PFIC) is a family of rare childhood diseases that was universally fatal until the development of liver transplant. In the last 20 years, the use of nontransplant surgery to treat PFIC has become the standard of care. There are various surgical techniques that have been performed. There are no reviews evaluating the outcome of these operations. Methods: A systematic search of the literature for articles evaluating the outcome of nontransplant surgical interventions in PFIC patients was performed. Data from these studies was abstracted and summarized. Results: No trials have been performed addressing nontransplant surgical interventions in PFIC patients. We analyzed 11 case series and case reports. Generally, patients had successful outcomes (81%) with cessation of progression of disease and resolution of symptoms. Treatment failures were often associated with more advanced disease. Discussion: There is no evidence to demonstrate a superiority of one type of nontransplant surgical intervention in PFIC patients. We propose the development of a registry and standardization of outcomes measurements to allow improved comparison of results. © 2009 Elsevier Inc. All rights reserved.
1. Background Progressive familial intrahepatic cholestasis (PFIC) is a family of rare genetic disorders that affect the ability of the hepatocyte to transport bile salts into the biliary tree. As their name implies, these genetic abnormalities cause progressive cholestasis over the patient's lifetime that is ⁎ Corresponding author. Tel.: +1 415 476 5892; fax: +1 415 476 1343. E-mail addresses: [email protected] (A.R. Davis), [email protected] (P. Rosenthal), [email protected] (T.B. Newman). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2008.07.018
generally associated with profound intractable pruritis. Left untreated, the disorders lead to cirrhosis and death before adolescence [1-4]. Recently the genetic underpinnings of these disorders have been identified. PFIC type I is caused by a mutation to the FIC1 gene which codes for a type IV P-type adenosine triphosphatase (ATPase), the function of which remains unknown [5]. Progressive familial intrahepatic cholestasis type II is caused by a bile salt export protein deficiency [6]. These 2 types are characterized by a low serum gammaglutamyltransferase (GGT) level in the face of continuing cholestasis [7,8]. Type III, which is caused by a deficiency
822 Table 1
A.R. Davis et al. Nontransplant surgical interventions for progressive familial intrahepatic cholestasis: studies
Study
Study design
Whitington and Whitington [13]
Case series
Emond and Whitington [18]
No. of subjects
Procedure
Age at time of procedure (y) (range or mean [SD])
Outcomes measured
4
PEBD
3-9
Case series
8
PEBD
10.5 (7.1) ⁎
Standard serum labs, total serum bile acids, light microscopy, pruritis Standard serum labs, growth, pruritis
Hollands et al [14]
Case series
5
Ileal bypass
1.2-17
Standard serum labs, light microscopy, pruritis
Ismail et al [19]
Comparative case series
16
PEBD
Not Reported
Standard serum labs, total serum bile acids
Rebhandl et al [17]
Case report
1
Appendiceal PEBD
13
Standard serum labs, total serum bile acids, pruritis
Melter et al [20]
Case series
6
PEBD
1.7-12.5
Standard serum labs, total serum bile acids, growth, pruritis
Ng et al [21]
Case series
4
PEBD
2.3-10.5
Kalicinski et al [22]
Comparative case series
21 PEBD, 5 IB
0.8-16
Standard serum labs, total serum bile acids, growth, pruritis Bilirubin, total serum bile acids, growth, pruritis
Kurbegov et al [23]
Case series
3
PEBD
1.0-5.4
Standard serum labs, serum bile acid profile, light microscopy, electron microscopy, growth, pruritis
Metzelder et al [16]
Case series
4
Laparoscopic PEBD
0.3-3.1
Standard serum labs, total serum bile acids
Bustorff-Silva et al [5]
Case series
2
1 PEBD, 2 PIBD
3 (PEBD), 15-17 (PIBD)
Standard serum labs, light histology, pruritis
24
UDCA indicates ursodeoxycholic acid; OLTx, orthotopic liver transplant. * Mean and SD of age only apply to the 6 patients who showed a clinical response. Follow-up “Successful” Complications Author conclusions period (y) outcome
in multidrug resistance protein 3, is associated with high serum GGT levels, less pruritis, and a later onset [7-9]. Before the development of liver transplantation, therapy for these patients was generally ineffective. With the advent
Notes
of liver transplantation, many PFIC patients were treated with this life-saving procedure [10]. At one time, PFIC was among the 5 most common indications for liver transplantation in children [11,12]. Though curative of their primary disease,
Nontransplant surgical interventions in PFIC
823
Table 1 (continued) Follow-up period (y)
“Successful” outcome
Complications
Author conclusions
Notes
3-8
4/4
1 Revision of stoma
PEBD is a an effective intervention in PFIC and should be considered as a primary treatment modality.
–
2.3-4.9
6/8
PEBD should be used as primary treatment once diagnosis is confirmed.
The 2 treatment failures were cirrhotic on preprocedure biopsy.
0.5-1.8
4/5
12/16
IB is safe and effective, but longer follow-up is needed before recommendation as primary intervention. PEBD should be performed if UDCA therapy fails or there is moderate fibrosis; OLTx should be done for cirrhotic patients.
None of their patients were noted to have diarrhea.
0.5-3
2
1/1
1
6/6
1 Hemoperitoneum, 2 stomal herniation, 2 compensated cirrhotics to OLTx 1 Anastomotic bleed requiring reoperation, 1 wound infection 2 Stomal revisions, 1 intestinal obstruction requiring surgery, a qfewq episodes of cholangitis Retraction of stoma nipple and abscess near stoma 1 Intestinal obstruction requiring surgery
1.3-6.5
4/4
None reported
1-4
15/20 PEBD, 2/5 IB
1.2-5
3/3
1 PEBD converted to IB for high stomal output, 1 IB converted to PEBD for poor clinical response 1 Stomal revision, 1 mild stomal bleeding
0.1-0.2
4/4
None
Not Reported
2/2
None reported
these transplanted patients would continue to suffer morbidities associated with life-long immunosuppression. A better therapeutic modality was desired. In 1988, the first report of treating PFIC with nontransplant surgery was published by
The use of the appendix should add to the surgeons' options for PEBD. PEBD improves growth and should be performed if UDCA therapy fails; OLTx should be done for cirrhotic patients. PEBD prevents long-term progression of liver disease.
One treatment failure was cirrhotic at time of procedure; one had recurrent hepatitis of unknown etiology that did not abate after PEBD. –
Normalization of serum lipid panel was demonstrated. –
IB is not as effective as PEBD in preventing the long-term progression of liver disease.
4/5 of the IB patients had initial response, but only 2 maintained response.
PEBD besides clinical improvement is associated with near normalization of pathology, improved growth, and normalization of serum bile acid profile. Laparoscopic PEBD is feasible; long-term outcomes remain unclear. PIBD is an attractive surgical option; long-term follow-up studies are needed.
–
-
Neither patient had diarrhea nor any episodes of cholangitis after PIBD
Whitington and Whitington [13]. Whitington and Whitington reported on a procedure called partial external biliary diversion (PEBD), in which a 10- to 15-cm jejunal conduit was anastomosed from the gallbladder to the abdominal
824 cutaneous surface where a permanent stoma was created for bile drainage. Two other procedures have been developed to manage PFIC, an ileal bypass (IB) in which the patient receives an ileocolonic anastomosis that bypasses the distal 15% of the small bowel interfering with the enterohepatic circulation of bile salts [14] and partial internal biliary diversion (PIBD) in which a 15- to 20-cm jejunal conduit is created that connects the gallbladder to the colon for bile drainage [15]. Two variants on the original PEBD have also been described; one using a laparoscopic technique [16] and the other using an appendiceal conduit [17]. In this systematic review, we will examine the evidence of efficacy of nontransplant surgical interventions in the treatment of PFIC. We will also investigate the comparative efficacy of the various procedures and the quality of the studies regarding this topic. Finally, we will propose future directions of study.
2. Methods Case reports, case series, and clinical trials reporting on the outcome of nontransplant surgical outcomes were included in this study. A PubMed search using the terms “Byler biliary diversion,” “Progressive familial biliary diversion,” “Byler surgery,” and `qProgressive familial surgery” was performed. In addition, PubMed was searched using the MeSH term “Cholestasis, Intrahepatic/surgery.” The title of each article returned by this search was reviewed. All articles that pertain to the topic of the review were read by a single reviewer. The references of these articles were examined in order to find other pertinent articles. If the article reports on the outcome of a patient or series of patients who underwent a nontransplant surgical intervention to manage their PFIC, it was included. Non-English articles were excluded. Data were abstracted from each article in a nonblinded fashion by a single reviewer, with spot-checks by other authors. Data abstracted included study design, number of subjects, type of procedure, age range of patients at time of intervention, pre- and postsurgical serum laboratory values, pre- and postsurgical histology, pre- and postsurgical growth parameters, pre- and postsurgical pruritis, and transplant-free survival. Data were abstracted at the individual level if available or study averages if individual level data were not available. Because of the heterogeneity of the articles with respect to measured outcomes, we did not do any quantitative analysis of the data.
3. Results We found 11 articles that met our inclusion criteria [13-23]. One article that may have fit our criteria was not reviewed, secondary to inability to obtain the full text version
A.R. Davis et al. of the article [24]. The key characteristics of the reviewed articles are summarized in Table 1. There have been no clinical trials or controlled studies addressing nontransplant surgical interventions in patients with PFIC; all of the articles are case reports or case series. Two of the articles were comparative case series. In one, the outcome of PEBD was compared with that of transplant [19]. In the other, PEBD was compared to ileal bypass [22]. All of the studies reported the procedure, and all of them except for Kurbegov described the actual surgical technique [23]. There was minimal variation in the surgical technique described for each procedure. The only notable variation was that the initial three ileal bypass procedures reported by Hollands et al [14] did not yet have a standard technique for deciding the length of ileum to be bypassed. There was little consistency in what type of outcome data were reported in the studies. Most used quantitative values for laboratory data, although a few used descriptive data such as “laboratory signs of cholestasis were reduced in all patients.” [16] The type of laboratory data collected also varied. Seven of the 11 studies reported pre- and postsurgical values for serum alanine transaminase (ALT). Six reported pre- and postsurgical serum total bilirubin levels. Seven reported pre- and postsurgical serum bile salt levels. Other laboratory tests reported in some of the studies included serum aspartate transaminase (AST), GGT, conjugated bilirubin, prothrombin time, albumin, alkaline phosphatase, cholesterol, and fractionated bile salts. Postsurgical histology was reported in 4 of the studies. Only Kurbegov et al. [23] reported pathology in a systematic manner, with histological scores. Theirs was also the only study to examine electron microscopy. Pruritis was reported in nearly all the studies; 4 used the numerical scoring system developed by Whitington and Whitington [13]. Growth was reported on in 5 studies but quantified in only 3. The length of follow-up varied from 6 weeks to 8 years. All of the studies defined their PFIC cases as progressive cholestasis with low GGT values with other causes of chronic liver disease being excluded. This means that surgery on PFIC type III patients was not evaluated in these studies and has not been reported in the literature. The timing of the surgical intervention in regard to the natural history of disease varied, with an age range of 4 months to 17 years, and there was a variation in disease progression at the time of surgery. This heterogeneity in severity of disease at the time of surgery makes it difficult to compare outcomes. Generally, patients did well. Of the 78 patients who underwent a nontransplant surgical intervention, 63 (81%) had a “successful outcome.” Generally these outcomes were dramatic with resolution of symptoms, cessation of the progression to liver failure, and histologic improvements when examined. Of the 15 who did not have a successful outcome, 3 were reported to have been cirrhotic at the time of surgery, 3 were reported to have received surgery “late after diagnosis with moderate fibrosis,” and one was
Nontransplant surgical interventions in PFIC reported to have a recurrent hepatitis of unknown etiology both prior to and after external diversion was performed. Of the 8 remaining patients with poor outcomes, 4 were in ileal bypass patients, 2 of whom initially had a good response but had a return of symptoms and laboratory abnormalities after 12 months. The authors did not hypothesize on why the last 4 non-ileal bypass patients had poor outcomes. Patients who underwent PEBD had successful outcomes in 83% (55/66) of cases. This included four successful laparoscopic PEBDs and a successful appendiceal PEBD. Ileal bypass was successful in 6 of 10 cases; however, the length of follow-up for these patients was not uniform, and the one study with more than a year of follow-up showed that an initial response did not equate to a sustained one. Both patients who underwent PIBD had successful outcomes. Responders had dramatic improvement in their laboratory values. In the 43 patients in whom both were reported, the mean postsurgical serum ALT level was 48 IU/L, a decrease from a mean presurgical ALT level of 107 IU/L (variance and range cannot be calculated because individual data were not reported in all studies). Serum total bilirubin levels decreased from a mean of 5.6 to 1.7 mg/dL in the 42 patients in whom they were reported. Serum bile salts decreased from a mean of 258 μmol/L to 55 μmol/L in the 56 patients in whom they were reported. The 4 studies that had postsurgical pathology specimens included 7 patients who had pre- and postsurgical biopsies. These 7 patients showed markedly improved histology. Whitington and Whitington [13] showed presurgical biopsies with hepatocellular and canalicular cholestasis, moderate ballooning, giant cell transformation, and portal fibrosis. Postsurgical biopsies in 2 of his patients demonstrated minimal fatty changes with otherwise normal histology. Hollands et al [14] reported on ileal bypass, including one patient who had both pre and postsurgical histology. Initial biopsy showed hepatic fibrosis, and the postsurgical biopsy demonstrated “significant improvement.” Bustorff-Silva reported on one patient who had a liver biopsy before and after PEBD. The initial biopsy showed moderate inflammation, increased portal fibrosis, portoportal septum, and cholestasis. A repeat biopsy 11 months later showed “no signs of progressive liver disease” [15]. Kurbegov et al [23] was the only study that examined histology in a quantitative manner. It was also the only study to examine electron microscopy. Cholestasis was graded 0 to 3. Presurgically, the 3 patients had values of 3, 3, and 1. After PEBD, they all had a value of 0. Inflammatory infiltrates were graded 0 to IV. All 3 patients had values of II before surgery. After their operation, the values were I, I, and 0. Portal tract fibrosis was also graded 0 to IV, and each of the patients had a II prior to surgery. After their procedure the fibrosis values were I, I, and 0. Kurbegov et al were also able to document the disappearance of Byler bile and the near normalization of electron microscopic findings.
825 Nearly all of the studies commented on pruritis. Four of the studies, including 16 patients, used a 0-to-4 scale developed by Whitington et al [13]. In these, pruritis improved from 3.7 ± 0.5 (mean ± SD) preoperatively to 0.25 ± 1.0 after surgery. The other studies also reported resolution of pruritis in most patients. Of the 5 studies that mentioned growth, 4 reported improved growth velocity. One reported no change. Three studies quantified these changes in some manner. Ng et al [21] had a patient who went from a weight at the fifth percentile and a height less than the 5th percentile at the time of her procedure to a weight between the 25th and 50th percentile and a height between the 90th and 95th percentile 6 1/2 years later. Another of the Ng et al patients went from a weight and a height between the 5th and 10th percentile at the time of procedure to both between the 25th and 50th percentile after 51/2 years. Kurbegov et al [23] and Melter et al [16] both measured height z-scores before and after the procedure and saw the z-scores increase from a mean of −2.8 to −1.4. Complications were not reported systematically. Revisions of stomas were performed for 4 children. Intestinal obstruction requiring surgery was reported for 2 children. High output from a PEBD stoma motivated an ileal bypass in one case, and an adolescent who found the PEBD stoma interfering with her quality of life subsequently had a PIBD. It is interesting to note some complications that were not seen. Partial internal biliary diversion was hypothesized to place patients at risk for osmotic diarrhea and cholangitis. Neither of the 2 patients who received PIBD had either cholangitis or diarrhea.
4. Discussion Although outcomes are not consistently defined or measured in the studies of nontransplant surgical interventions for PFIC, some conclusions can be drawn from these existing reports and they suggest future areas for study. It is clear even without randomized controlled studies that children with PFIC do better with nontransplant surgical interventions than they do with the natural history of disease, which is uniformly fatal. It appears that the success rate is high enough that many patients may do better with a nontransplant procedure than transplant given the posttransplant morbidities associated with immunotherapy. Successful outcomes have been demonstrated, with marked improvements in clinical symptoms, laboratory values, growth, and histology. Two issues may lend us caution when trying to generalize this success: (1) it is possible that these studies were published by the world's experts in PFIC care, and perhaps, the outcome is not as successful in less experienced hands, and (2) because these are retrospective reports, less successful outcomes may not have been reported creating bias in this review.
826 These studies provide some evidence that those with more advanced disease are most likely to have a poor outcome with nontransplant surgical procedures. This may encourage clinicians to consider a surgical intervention early in the course of disease before significant hepatic scarring develops. On the other hand, there is no clear evidence about which procedure is preferred. One study suggests that the effects of ileal bypass may be attenuated over time; this could be owing to adaptation of the remaining bowel. However, it is also possible that bypassing a different length of bowel may lead to a different outcome. Partial internal biliary diversion has been avoided because of concerns about cholangitis. This feared complication did not occur in the two reported patients who underwent this procedure. Future research on this subject would benefit from creation of a national registry of PFIC patients, with clear inclusion and exclusion criteria and standard data collection on treatments and outcomes. Failing that, consistent measurements performed in each study would improve our ability to assess evidence in the treatment of this rare disease. We propose that all patients have their laboratory measurements reported quantitatively with a standard follow-up time of 6 months and 3 years. This would allow assessment of early changes and long-term sustainability of response. Growth should be measured at the time of the procedure and annually for at least 3 years and reported in height and weight z-scores for age. Pruritis should be measured using the scoring tool of Whitington and Whitington [13]. Histology should be reported in a quantifiable manner by a blinded pathologist at the time of diagnosis, at the time of a procedure and, if available, at time of follow-up. The 2 most important remaining questions are (1) how to manage patients with more advanced disease and (2) which procedure is superior. Regarding the first question, is an attempt of diversion or bypass still beneficial even in advanced disease? Even if there is a low probability of success, does the occasional responder outweigh the risk of an additional surgery prior to transplant? Where is this line? Regarding the second question, more knowledge regarding posttransplant complications and quality of life is needed. If PIBD has a similar complication profile to PEBD, then it is likely that many patients would prefer a stoma free life. The effects on quality of life of having a biliary cutaneous drain are not known. A randomized trial comparing PEBD to PIBD is indicated, given the current equipoise of the two procedures. Nontransplant surgical interventions have greatly improved the outcome of PFIC patients and prevented many transplants. Unanswered questions remain, regarding patients with more severe disease and the optimal procedure to perform. Our ability to optimally treat these patients would be increased by creation of a national registry with standardized inclusion criteria and data collection and randomized trials of interventions.
A.R. Davis et al.
References [1] Clayton RJ, Iber FL, Ruebner BH, et al. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child (1960) 1969;117(1):112-24. [2] Linarelli LG, Williams CN, Phillips MJ. Byler's disease: fatal intrahepatic cholestasis. J Pediatr 1972;81(3):484-92. [3] Maggiore G, Bernard O, Riely CA, et al. Normal serum gammaglutamyl-transpeptidase activity identifies groups of infants with idiopathic cholestasis with poor prognosis. J Pediatr 1987;111(2): 251-2. [4] Riely CA. Familial intrahepatic cholestatic syndromes. Semin Liver Dis 1987;7(2):119-33. [5] Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998;18(3):219-24. [6] Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999;117(6):1370-9. [7] Colombo C, Okolicsanyi L, Strazzabosco M. Advances in familial and congenital cholestatic diseases. Clinical and diagnostic implications. Dig Liver Dis 2000;32(2):152-9. [8] Jacquemin E. Progressive familial intrahepatic cholestasis. Genetic basis and treatment. Clin Liver Dis 2000;4(4):753-63. [9] de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998;95(1):282-7. [10] Soubrane O, Gauthier F, DeVictor D, et al. Orthotopic liver transplantation for Byler disease. Transplantation 1990;50(5):804-6. [11] Esquivel CO, Iwatsuki S, Gordon RD, et al. Indications for pediatric liver transplantation. J Pediatr 1987;111(6 Pt 2):1039-45. [12] Whitington PF, Balistreri WF. Liver transplantation in pediatrics: indications, contraindications, and pretransplant management. J Pediatr 1991;118(2):169-77. [13] Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988;95(1):130-6. [14] Hollands CM, Rivera-Pedrogo FJ, Gonzalez-Vallina R, et al. Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus. J Pediatr Surg 1998;33(2): 220-4. [15] Bustorff-Silva J, Sbraggia Neto L, Olimpio H, et al. Partial internal biliary diversion through a cholecystojejunocolonic anastomosis—a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report. J Pediatr Surg 2007; 42(8):1337-40. [16] Metzelder ML, Bottlander M, Melter M, et al. Laparoscopic partial external biliary diversion procedure in progressive familial intrahepatic cholestasis: a new approach. Surg Endosc 2005;19(12):1641-3. [17] Rebhandl W, Felberbauer FX, Turnbull J, et al. Biliary diversion by use of the appendix (cholecystoappendicostomy) in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 1999;28(2): 217-9. [18] Emond JC, Whitington PF. Selective surgical management of progressive familial intrahepatic cholestasis (Byler's disease). J Pediatr Surg 1995;30(12):1635-41. [19] Ismail H, Kalicinski P, Markiewicz M, et al. Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion. Pediatr Transplant 1999;3(3):219-24. [20] Melter M, Rodeck B, Kardorff R, et al. Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients. Am J Gastroenterol 2000;95(12):3522-8. [21] Ng VL, Ryckman FC, Porta G, et al. Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 2000;30(2): 152-6.
Nontransplant surgical interventions in PFIC [22] Kalicinski PJ, Ismail H, Jankowska I, et al. Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass. Eur J Pediatr Surg 2003; 13(5):307-11. [23] Kurbegov AC, Setchell KD, Haas JE, et al. Biliary diversion for progressive familial intrahepatic cholestasis: improved liver mor-
827 phology and bile acid profile. Gastroenterology 2003;125(4): 1227-34. [24] Wanty C, Joomye R, Van Hoorebeek N, et al. Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy. Acta Gastroenterol Belg 2004; 67(4):313-9.