Liver transplant in primary sclerosing cholangitis: Current trends and future directions

Table 1 Staging of primary sclerosing cholangitis based on the four-stage system developed

Primary sclerosing cholangitis stages		Histological finding
Stage I	Portal stage	Presence of portal hepatitis and edema confined to the portal triads with mononuclear infiltration
Stage II	Periportal stage	The inflammation progresses to the periportal space causing periductal fibrosis with dilation of the portal triads. There is absence of bridging necrosis or septal fibrosis
Stage III	Septal stage	Characterized by the presence of fibrous septae and/or bridging fibrosis
Stage IV	Cirrhosis	Established cirrhosis with the presence of fibrous septa and nodular regeneration

Table 2 Overview of the clinical scores for predicting prognosis in primary sclerosing cholangitis and its components that include serum-based biomarkers and clinical features

Clinical scores	Components
Mayo risk score	Age, bilirubin, histological stage, hemoglobin and presence of inflammatory bowel disease
Revised Mayo risk score	Age, bilirubin, albumin, aspartate aminotransferase and variceal bleeding
Amsterdam–Oxford model	Primary sclerosis cholangitis (PSC) subtype, age at PSC diagnosis, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin and platelets
Short-term United Kingdom-pSC risk score	Bilirubin, albumin, hemoglobin, and platelets count at diagnosis
Long-term United Kingdom-pSC risk score	Age at diagnosis, bilirubin at the second year, alkaline phosphatase at the second year, albumin at the second year, platelets at the second year, presence of extrahepatic biliary disease at diagnosis, and variceal hemorrhage by the second year
Primary sclerosing cholangitis risk estimate tool	Bilirubin, albumin, alkaline phosphatase, platelets, aspartate transaminases, hemoglobin, sodium, PSC duration and age
Model for end stage liver disease	Dialysis at least twice in the past week, creatinine, bilirubin, international normalized ratio and sodium
Child-Pugh score	Bilirubin, albumin, international normalized ratio, ascites and encephalopathy

Table 3 Overview of important clinical trials and meta-analysis assessing medications used in management of primary sclerosing cholangitis

Ref.	Year	Type	Objective	Results
				Death	Symptoms (fatigue, pruritus)	Liver transplantation	Histological improvement	Marker values (bilirubin, GGT, ALP, ALT or AST)	Cholangiographic changes	Cholangiocarcinoma	Adverse events
Ursodeoxycholic acid
Shi et al[74]	2009	Meta-analysis of RCT (8 RCT, 465 patients)	Evaluate the effect and safety of UDCA in PSC	No significant effect	No significant effect	No significant effect	Significant difference	No significant effect	No significant effect on improvement	No significant difference on incidence	No significant difference on incidence
Othman et al[61]	2012	Meta-analysis of RCT (7 RCT, 553 patients)	Investigate the efficacy of UDCA in PSC	No significant effect	No significant effect	No significant effect	No significant effect	Significantly decrease ALP, GGT, bilirubin, ALT or AST	No significant effect on improvement	No significant difference on incidence	No significant difference on incidence
Poropat et a[62]	2011	Meta-analysis of RCT (8 RCT, 592 patients)	Assess the beneficial and harmful effects of BA for patients with PSC	No significant effect	No significant effect	No significant effect	No significant effect	Significantly decrease ALP, GGT, bilirubin or AST. Not significant effect on albumin	No significant effect on improvement	No significant difference on incidence	No significant difference on incidence
Triantos et al[63]	2011	Meta-analysis of RCT (8 RCT, 567 patients)	Evaluate if UDCA is useful for PSC	No significant effect	No significant effect	No significant effect	No significant effect	Not reported	Not reported	No significant difference on incidence	Not reported
Immunosuppressive therapies: glucocorticoids, cyclosporine, tacrolimus, methotrexate and mycophenolate mofetil
Peng et al[69]	2017	Meta-analysis of RCT (7 RCT, 266 patients)	Evaluate the safety and efficiency of IA for the treatment of PSC	No significant effect	Not reported	No significant effect	Not reported	No significant improvement on liver biochemistry except AST	Not reported	Not reported	Significant increase on incidence
Liu et al[70]	2022	Meta-analysis (7 RCT and 14 observational, 737 patients)	Assess the efficacy and adverse effects of immunomodulators in adult patients with PSC	Not reported	Not reported	Not reported	Not reported	Significantly decrease ALP. Not significant effect on bilirubin and AST	Not reported	Not reported	16.1% of patients had severe AEs1
Antibiotics
Shah et al[75]	2019	Meta-analysis of clinical trials (3 RCT and 2 open labeled trials, 124 patients)	Assess the effect of antibiotic therapy (vancomycin, metronidazole, rifaximin and minocycline) in PSC with or without inflammatory bowel disease	Not reported	Not reported	Not reported	Not reported	Significant reduction in ALP and bilirubin	Not reported	Not reported	8.9 % of patients had severe AEs1
Probiotics
Vleggaar et al[76]	2008	RCT that included 14 patients	Assess potential beneficial effects of probiotics in PSC	Not reported	No significant effect	Not reported	Not reported	No significant effect on bilirubin, ALP, GGT, AST, ALT, prothrombin, albumin or bile salts	Not reported	Not reported	Not reported
Newer drugs
Fickert et al[72]	2017	RCT that included 161 patients	Evaluate the safety and efficacy of three doses of oral nor UDCA compared with placebo in patients with PSC	Not reported	No significant effect	Not reported	Not reported	Significantly decrease ALP, GGT, ALT or AST	Not reported	Not reported	14 patients had severe AE1

¹Results of this outcome were not included in the meta-analysis. It was derived from the assessment of individual studies. GGT: Gamma-glutamyl; ALP: Alkaline phosphatase; AE: Adverse effects; RCT: Randomized controlled trial; AST: Aspartate Aminotransferase; ALT: Alanine transaminase; PSC: Primary sclerosing cholangitis; UDCA: Ursodeoxycholic acid; BA: Bile acids.

Table 4 Inclusion and exclusion criteria for patients with cholangiocarcinoma being considered for Model For End Stage Liver Disease exception points

Inclusion criteria	Exclusion criteria
Evidence of positive tumor cells or cells strongly suspicious for CCA on biopsy	Evidence of extra hepatic disease or lymph node enlargement
Malignant appearing stricture on radiograph and 1 of the following criteria (a or b or c)	Previous malignancy excluding skin or cervical cancer within 5 yr before diagnosis of cholangiocarcinoma
a. Ca 19-19 > 100 U/mL in the absence of acute bacterial cholangitis	History of abdominal radiotherapy
b. Polysomy on fluorescence in-situ hybridization	Uncontrolled infection before treatment
c. Hilar mass < 3 cm in radial diameter on cross-sectional imaging	Prior attempt of surgical tumors reaction and subsequent violation of tumor plane
-	Any medical condition precluding transplantation
-	Any transperitoneal biopsy including percutaneous and/or endoscopic ultrasonographic-guided fine needle aspiration

CCA: Cholangiocarcinoma.

Table 5 Role of multidisciplinary team involved in the process of liver transplantation

Role	Description
Transplant hepatologist	A medical doctor who specializes in liver disease
Liver transplant surgeon	Evaluates the patient and determines whether a liver transplant is the best option by considering surgical contraindications
Transplant nurse coordinator	Serves as the primary contact for the patient throughout the transplant process, ensures that testing is up-to-date, and provides education on the transplant process
Transplant social worker	Focuses on the psychological and social aspects of end-stage liver disease and provides mental health support as needed
Transplant nutritionist	Assesses the patient's nutritional status, including weight patterns and dietary intake, and makes recommendations for an optimal diet
Financial coordinator	Reviews the patient's medical insurance coverage and assists with obtaining adequate coverage for the transplant
Transplant pharmacist	Reviews the patient's medication list for any contraindications before the transplant and provides education on new medications after the transplant

Table 6 Psychological instruments for psychosocial evaluation of transplant patients

Instrument name	Description	Scoring/rating	Reliability	Validity
Beck depression inventory	Self-report measure of depressive symptoms	21-item scale, higher scores indicate more severe depressive symptoms	High test-retest reliability, internal consistency, and concurrent validity	Established validity in measuring depressive symptoms in various populations
Hamilton depression rating scale	Clinician-rated scale to assess severity of depressive symptoms	17-item scale, higher scores indicate more severe depressive symptoms	High inter-rater reliability, internal consistency, and concurrent validity	Established validity in measuring depressive symptoms in various populations
General health questionnaire	Self-report measure of general mental health	12-item or 28-item scale, higher scores indicate poorer mental health	High internal consistency, test-retest reliability, and concurrent validity	Widely used in assessing mental health in general populations
Primary care evaluation of mental disorders-patient health questionnaire	Self-report measure of common mental disorders	9-item scale, higher scores indicate greater severity of mental disorder symptoms	High sensitivity and specificity, test-retest reliability, and convergent validity	Widely used in primary care settings to screen for mental disorders
Transplant evaluation rating scale	Clinician-rated scale to assess psychosocial functioning in transplant recipients	10 aspects of psychosocial functioning rated on a 5-point scale, higher scores indicate better adjustment	Good inter-rater reliability and validity in liver transplant recipients	Specific to evaluating psychosocial functioning in transplant recipients
Psychosocial assessment of candidates for transplantation	Clinician-rated scale to assess psychosocial acceptability of transplant candidates	8 subscales rated on a 5-point scale, with initial and final overall ratings	Established reliability and validity in evaluating psychosocial acceptability of transplant candidates	Widely used in evaluating transplant candidate suitability
Stanford integrated psychosocial assessment for transplantation	Clinician-rated scale to assess psychosocial functioning in transplant candidates	Comprehensive assessment covering multiple domains of psychosocial functioning	Limited data on reliability and validity, but shows promise in transplant candidate evaluation	Developed specifically for evaluating psychosocial functioning in transplant candidates