Abstract
Background:
Severe pruritus caused by progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (AGS) is refractory to medical treatment. Surgical interruption of the enterohepatic circulation is considered the mainstay of alleviating distressing symptoms and delaying cirrhosis.
Aim and Objectives:
This study aims to evaluate the short-term effect of partial external biliary diversion (PEBD) on pruritus, liver disease progression, patient's growth, and quality of life.
Material and Methods:
This prospective cohort study enrolled children with PFIC and AGS from July 2019 to July 2021, whose guardians consented to the PEBD procedure. A standard surgical approach was performed by a single surgeon. Outcomes were measured subjectively and objectively pre- and post-procedure using the pruritus 5-D itching score, Paediatric Quality of Life Inventory scale (PedsQL), growth parameters, bile acids level, and liver function tests. Patients’ follow-up period ranged from 6 to 12 months.
Results:
Seven patients had PEBD procedure; five with PFIC and two with AGS. A significant improvement was detected in the 5-D itching score (p-value < 0.001), PedsQL (p-value < 0.001), and bile acids level (p-value 0.013). The preexisting growth failure was ameliorated. The downward trend in the bilirubin level was not significant. No influential difference in the other liver function tests occurred. No intra-operative complications encountered. Only one case had a post-operative stoma prolapse which was managed surgically.
Conclusion:
PEBD procedure could be considered as an effective and safe treatment options for intractable pruritus in patients with PFIC or AGS, providing preserved synthetic liver functions.
Keywords: PFIC, AGS, intractable pruritus, partial external biliary diversion
INTRODUCTION
Intractable pruritus due to either progressive familial intrahepatic cholestasis (PFIC) or Alagille syndrome (AGS) is a distressing symptom that often not responding to medical treatment.[1] The cause of cholestatic pruritus is uncertain, however, it may include a brain pathway involving a variety of pruritogenic substances, including bile acid.[2] Medical treatment frequently fails to reduce cholestasis symptoms and its detrimental consequences, thus surgical intervention is required.[3,4]
Surgery aims to disrupt the enterohepatic cycle and induce remission of cholestasis and pruritus.[1] Biliary diversion methods include gallbladder-colonic bypass, ileal exclusion, partial internal biliary diversion (PIBD), and partial external biliary diversion (PEBD) procedure. In more severe cases, liver transplantation needs to be performed.[5,6] Although patients with PFIC typically require liver transplantation, the initial partial biliary diversion procedure would relieve jaundice-associated pruritus, reduce plasma bile acid level, improve the plasma lipoprotein profile and improve liver histopathology.[7,8]
Patients with PFIC and AGS may benefit from a better understanding of the correlations between laboratory parameters and clinical responses to the treatment options by assessing whether prospective biomarkers for short-or long-term outcomes are effective. In this study, we aim to evaluate the short-term efficacy of PEBD procedure for children with chronic intrahepatic cholestasis subjectively and objectively assessing pruritus progression, hepatic biomarkers, child's growth, and quality of life.
MATERIALS AND METHODS
This manuscript was prepared in concordance with the recommendations of strengthening the reporting of observational studies in epidemiology.[9] The study's protocol was approved and registered by the local ethics committee of Cairo University Teaching hospitals (Ref MD110-2019). Guardians of eligible children signed written informed consent before study enrollment.
Study design and patients
A prospective cohort study was conducted on children with PFIC or AGS who presented to the Pediatric Surgery Department and the Pediatric Hepatology Unit of Cairo University Specialized Pediatric Hospital from July 2019 to July 2021. We included children diagnosed clinically with PFIC or AGS whose ages were over 1 year and met the indications of surgery. PEBD indications included complaining from severe intractable pruritus, not responding to medical treatment, growth failure, and nutritional deficiencies.[10]
Children with severe hepatic impairment or pruritus secondary to skin diseases were excluded from this study.
Preoperative assessment
Before surgery, many measurements were used to assess and monitor disease progression. These included growth parameters, laboratory tests, and radiographic evaluation tools.
Children's growth parameters assessment included weight and height. They were assessed for pruritus preoperatively using the five-dimensional (5D) pruritus score,[11] while their health-related quality of life (HRQL) was assessed using the Paediatric Quality of Life Inventory™ 4.0 Generic Core Scale (PedsQL™) scores.[12]
In addition, we collected the findings of complete blood count (CBC), prothrombin concentration (PC), internationalized ratio (INR), and liver function tests (LFTs) including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), albumin, and total and direct bilirubin. Further assessment included upper gastrointestinal endoscopy, echocardiography; abdominal ultrasound; and fibroscan. The findings of fibroscan were classified according to the metavir fibrosis score.[13]
Operative technique and follow-up
The patients were hospitalized the night before the surgery where piperacillin-tazobactam, metronidazole, and Vitamin K were commenced intravenously.
A standardized PEBD procedure was performed by a single surgeon, through a right subcostal incision, where a properistaltic jejunal conduit was constructed between the gallbladder and the abdominal wall in the right upper quadrant. A 10–15 cm segment of proximal jejunum was isolated at a point approximately 20–30 cm from the duodenojejunal junction. The bowel continuity was restored through an end-to-end anastomosis. The separated jejunal flap was crossed through the transverse mesocolon. The proximal end of the jejunal conduit was anastomosed end-to-side to the gall bladder fundus posteriorly, while its distal end was pulled out through the abdominal wall in the right upper quadrant to be sutured to the skin as an ostomy [Figures 1 and 2]. A liver biopsy was performed to determine the extent of fibrosis.
Figure 1.
Surgical steps of PEBD (a) identifying 10 to 15–cm segment of proximal jejunum (b) isolation at a point approximately 20 to 30 cm from the duodeno-jejunal junction to create the jejunal conduit (c) crossing of the jejunal conduit through the meso-colon (d) the anastomosis between the gallbladder and the upper end of the conduit then to create the stoma. PEBD: Partial external biliary diversion
Figure 2.
Diagrammatic illustration of PEBD. PEBD: Partial external biliary diversion
Patients started oral feeding and medications day 1 postoperative. Patients were discharged after reaching full oral feeds and completing their recovery.
Following biliary diversion surgery, patients were first seen after 2 weeks then regularly evaluated at the pediatric hepatic outpatient clinic every 3 months. The 5Ds pruritus score and anthropometric measurements (weight and height), along with CBC, PC, INR, and LFTs were assessed. In addition, the stoma was reviewed for possible complications. After 6 months, the PedsQLTM and bile salts levels were assessed. The cholesterol level was evaluated after 1 year. No liver biopsies were performed throughout the follow-up period.
Outcome assessment
The main outcome was the clinical improvement indexed by the 5D pruritus score and the PedsQLTM, along with the bile salt level assessment. The secondary outcome was the growth improvement monitored by weight and height pre- and postoperative.
Statistical analysis
Statistical analysis was performed using IBM Corp. (2013) IBM SPSS Statistics for Windows, Version 22.0. IBM Corp., Armonk, NY. Numerical data were expressed as medians with minimum and maximum ranges, and categorical data were described as percentages. Chi-square and ANOVA tests were used to study the relationships between variables. Statistical significance was defined as P < 0.05.
RESULTS
Seven patients with intractable pruritus due to chronic cholestatic liver disease were enrolled, including PFIC (n = 5; 71.4%) and AGS (n = 2; 28.6%). The patients’ diagnoses were established through clinical findings and laboratory parameters rather than further genetic testing because of the high cost of genetic testing and being not widely available. All of them were females, their median age at time of operation was 4 years, ranging from 2 to 12. The median preoperative weight was 11.7 kg (range: 7.4–20.8). The median height was 85 cm, ranging from 70 to 118. All patients were under-weight and had short stature (CDC Z-Score was <−2). All children had thickened, lichenified skin with scratch marks, while multiple distressing xanthomas were experienced by only one patient with AGS [Figure 3]. The median preoperative 5D-score was 24 (range: 23–25) [Figure 4], while the median preoperative HRQL was 14.5 (range: 6.5–25) [Figure 4].
Figure 3.
(a) Thickened, lichenified skin of one of the enrolled cholestatic cases (b) xanthoma over cubital fossa in one of AGS cases (c and d) post-PEBD procedure skin improvement and disappearance of xanthoma. AGS: Alagille syndrome, PEBD: Partial external biliary diversion
Figure 4.
(a) The trend in the 5-D pruritus score during pre- and post-operative follow-up, (b) The trend in the scores of HRQL during pre- and post-operative follow-up, (c) The trend in Z-Score of weight and height during pre-and post-operative follow-up. HRQL: Health-related quality of life
The median values of the total bilirubin, direct bilirubin, and LFTs levels are present in [Table 1]. According to fibroscan assessment three patients (43%) had mild liver fibrosis (F1), one patient (14%) had mild to moderate fibrosis (F2), one (14%) had moderate fibrosis (F3) and one (14%) had marked fibrosis/cirrhosis (F4). Upper endoscopy of the cohort showed gastropathy in four patients (57%) and asymptomatic esophageal varices in one. Echocardiography showed mild bilateral pulmonary stenosis in one patient with AGS (14%).
Table 1.
The trend in laboratory parameters in the cohort during pre- and postoperative follow-up
| Variables | Median (minimum–maximum) | P | |||||
|---|---|---|---|---|---|---|---|
|
| |||||||
| Preoperative | 2 weeks postoperative | 3 months postoperative | 6 months postoperative | 9 months postoperative | 12 months postoperative | ||
| Hb (g/dL) | 11.5 (10–12.2) | 10.3 (8–11.6) | 10.9 (8.5–12.4) | 10.8 (8.7–16.7) | 11.1 (9–12) | 11.9 (9.2–12.2) | 0.159 |
| TLC (109/L) | 11.6 (7–14.7) | 9.8 (8.6–12.9) | 9.2 (6–11.3) | 9.1 (5–12.1) | 8.5 (5.8–10) | 9 (7–11) | 0.173 |
| PLT (109/L) | 384 (170–564) | 376 (174–582) | 345 (174–488) | 318 (138–365) | 280 (102–369) | 286 (152–311) | 0.503 |
| INR | 1.09 (1–1.1) | 1.1 (1.1–1.13) | 1.1 (1–1.13) | 1.1 (1–1.13) | 1.1 (1.01–1.12) | 1.1 (1.07–1.12) | 0.194 |
| PC (%) | 90.6 (87–100) | 91 (84.7–97) | 90.3 (83.9–99) | 84 (64–99) | 87 (84–99) | 89 (79.5–96.5) | 0.099 |
| Bilirubin total | 11.9 (2.9–20.9) | 10.3 (2–21.4) | 10.5 (2.8–25.1) | 9.9 (2.7–17.9) | 9.7 (2.2–18.8) | 12.1 (9–24.7) | 0.121 |
| Bilirubin direct | 10 (1.5–19.2) | 5.6 (1.5–11.2) | 7.5 (1.6–14.5) | 6.5 (1.2–11.8) | 6.1 (1.36–12) | 7.9 (4.8–19.1) | 0.361 |
| AST (U/L) | 205 (31–336) | 181 (62–328) | 174 (56–639) | 183 (48–305) | 208 (167–263) | 249 (193–288) | 0.67 |
| ALT (U/L) | 145 (34–219) | 146 (44–363) | 138 (34–383) | 162 (31–251) | 230 (165–343) | 206 (167–263) | 0.361 |
| GGT (U/L) | 69 (22–574) | 70 (27–537) | 98 (23–637) | 91 (21–533) | 149 (39–517) | 68 (37–457) | 0.617 |
| ALP (U/L) | 593 (314–1113) | 324 (262–779) | 526 (257–1043) | 537 (323–1010) | 491 (347–1016) | 413 (330–330) | 0.267 |
| Albumin (mg/dL) | 3.4 (2.1–3.8) | 3.5 (3–4.9) | 3.5 (2.2–4.6) | 3.7 (2.6–4.83) | 3.6 (2.8–4.3) | 3.7 (2.9–3.9) | 0.059 |
| Bile salt (umol/L) | 154 (29.5–216) | 80.5 (18.4–110) | 80 (14–104) | 0.013* | |||
| Cholesterol (mg/dL) | 132 (76–734) | 100.5 (69–315) | 0.59 | ||||
P <0.05 was considered statistically significant, Hb: Hemoglobin, TLC: Total leucocyte count, PLT: Platelets, INR: Internationalized ratio, PC: Prothrombin concentration, AST: Aspartate aminotransferase, ALT: Alanine amino transferase, ALP: Alkaline phosphatase, GGT: Gamma-glutamyl transferase
All patients were given fat-soluble Vitamins A, D, E, and K, as well as a nutritionally supportive diet high in medium-chain triglycerides and cholestyramine, while four received ursodeoxycholic acid (UDCA), three received sertraline, three received ondansetron, and one patient received rifampicin before surgery with no improvement of pruritus.
Histopathological assessment of the liver biopsies that were obtained intraoperatively revealed that one patient had mild fibrosis (F1), two (28.5%) had mild to moderate fibrosis (F2), one (14%) had moderate fibrosis and two (28.5%) had marked fibrosis (F4).
The surgery went uneventful in all patients and lasted between 120 and 150 min (median = 135). None of the patients required intraoperative blood transfusion. On the first postoperative day, the oral feed was introduced, commencing with clear fluid, and proceeding to semisolid and solid food, alongside their usual oral vitamins. The children's postoperative pain score on the Wong-Baker facial pain-related scale[14] ranged from 2 to 4 on the first postoperative day and from 0 to 2 on a subsequent day. Paracetamol (10 mg/kg/dose) was given to the youngsters to alleviate their agony.
The postbiliary diversion follow-up period ranged from 3 to 12 months with a mean of 6 months. The median bile production of the biliary stoma was 95 mL/day (range: 30–120).
All the enrolled patients witnessed the improvement of pruritus, decrease of their 5-D score significantly from 24 (range: 23–25) preoperative to 5 (range: 5–7) throughout the postoperative follow-up time (P < 0.001) [Figure 4]. Their skin became softer with the absence of scratch marks and the disappearance of xanthomas [Figure 3]. Likewise, the sleep pattern of all patients and their parents improved, and all of the patients resumed their daily activities. Consequently, the HRQL for all patients was significantly improved through time with P = 0.003 over an average of 6 months follow-up and P < 0.001 after a year [Figure 4].
On follow-up, there was an improvement of the Z-Score of both weight and height in 86% of our cohort, only one patient who did not achieve a noticeable growth improvement. Z-Score Median of weight and height changed from −4.7 to −1.16, and −4.18 to −2.3, respectively [Figure 4].
The bile salt level decreased significantly from 154 umol/dl (range: 29.5–216) to 80 umol/dl (range: 14–104) postoperatively (P = 0.013). A nonsignificant change occurred in the hemoglobin, platelet, PC, INR, ALT, AST, GGT, ALP, albumin and cholesterol levels through the follow-up period, along with nonsignificant decrease in both total and direct bilirubin [Table 1].
Intraoperative complications were not accounted for any of our patients. Considering the early postoperative complications, none of our patients experienced surgical site infection or anastomotic leak. Moreover, none of them experienced complications in the form of dehydration, cholangitis, adhesive intestinal obstruction, or skin macerations around the stoma. However, only one patient developed stoma prolapse and bleeding that was corrected surgically by stoma refashioning. None of our patients required a pruritus medication postoperatively.
DISCUSSION
Intractable cholestatic pruritus results in poor HRQL and sleepless nights.[1] PEBD procedure was highly effective at alleviating the distressing symptoms related to the cholestatic disease due to either PFIC or AGS in our cohort, regardless of the different grades of fibrosis. Scaling pruritus objectively may be challenging, as it involves both physical and emotional aspects of the condition. Through this cohort follow-up time, 5-D pruritus score was used to evaluate the severity of pruritus and showed both early and significant post-PEBD procedure improvement, which is consistent with the reported early response that occurs within days to weeks.[15,16] Despite the reported partial response post-PEBD and the use of UDCA, there was no recurrent attacks of pruritus necessitating a medication among our patients.[5,16,17] In addition, pruritus ameliorated the scratch marks disappeared. This occurred in concordance with improvement the sleep patterns of the patients and their family. The improved quality of life was also defined by school attendance and ability to resume normal activity with peers.[18] The quality of life was monitored through PedsQLTM score that showed a significant increase. The improvement of growth parameters represented by weight and height through the follow-up period in 86% of the patients was noticed over the short follow-up period and could be considered as an improvement of HRQL.[5,15]
The PEBD procedure mechanism of action is not totally clarified. The interlude in the enterohepatic circulation of bile acid followed by a reduction of the bile acid pool could decrease the load of the transport process deficient.[5] In our cohort, there was a significant decrease in the level of bile acid from 154 umol/dl to 80 umol postoperatively (P = 0.013), which was also mentioned by others.[19] The early bile acid decrease following PEBD is considered a key predictive factor for responders’ detection and long-term success.[16,17]
Although the changes of both total and direct bilirubin in this cohort did not exhibit a statistical significance result, different studies analysis demonstrated that a decline in bilirubin level was an early biochemical parameter of PEBD procedure responders.[8,16,20]
The progression of liver disease was supposed to be assessed through the LFTs to avoid invasive postoperative liver biopsy. Different LFTs including AST, ALT, GGT, and ALP did not show any improvement. This was supported by a systemic review in which changes in liver functions value did not necessarily occur in parallel to the clinical improvement.[16] Moreover, the improvement of cholestasis was accompanied with amelioration of cholesterol levels.[1,21]
The enrolled patients’ coagulation profiles and albumin levels did not change significantly postoperative, demonstrating a preserved liver's synthetic function, which ran in parallel with Yang et al. findings.[5]
The histopathological assessment of intraoperative liver biopsies revealed different degrees of fibrosis. Regardless of the severity of fibrosis among our patients, they all reported relief from pruritus and a decrease in bile acid levels. Despite the patients through different studies had moderate to significant fibrosis, the degree of hepatic fibrosis was assumed to be a key factor for a good response after PEBD procedure advocating the earlier intervention.[1,5,7,22]
The occurrence of stoma prolapse requiring surgical refashioning is accepted as a common correctable complication.[5,17]
PIBD is a relatively new procedure with few to no long-term follow-up data; however, published studies concur that pruritus was significantly reduced in all patients. It has lower morbidity since there is no stoma and an anastomosis to the midportion of the ascending colon is performed alternatively.[1,23] Though the most often described consequence following PIBD is choleretic diarrhea caused by bile salt colonic irritation. Rectal bleeding may occur in the first few days after surgery due to bile acid irritation, the risk of colon cancer induced by bile acids is questionable. Herein, a regular colonoscopy may be considered for PIBD follow-up. In addition, cholangitis is a potential threat, but it has yet to be recorded in the literature.[23]
As long as there were no other distressing stoma-related complications within this cohort, Proper stoma construction followed by appropriate care and monitoring for any possible complications can be considered as the mainstay of parents’ satisfaction. This runs in the diversity of publications that assumed the presence of stoma as a limitation of PEBD procedure.
CONCLUSION
PEBD procedure is found to be effective at alleviating pruritus related to cholestasis in our cohort. This is accompanied by enhanced quality of life and improved growth regardless of the different degrees of liver fibrosis. Adequate stoma care is the key factor to avoid troublesome complications. Early reduction of bile acid level represents a biochemical marker for clinical improvement post-PEBD. Lack of histopathological follow-up for the progression of the disease represented a limitation to determine whether PEBD can only serve as a bridge to liver transplantation or can be a permanent treatment option. Both a larger cohort and a longer-term follow-up are recommended.
Key Messages
Intractable pruritus is the most distressing symptom impairing the quality of life in cholestatic children.
Partial external biliary diversion is an effective treatment for cholestatic pruritus.
Bile acid level reduction represents a biochemical marker of clinical improvement.
Proper stoma care is required to avoid complications
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
I would like to thank Nourhan Khaled for her sincere work in editing and formatting the graphics.
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