Guideline review: British Society of Gastroenterology/UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis

Abstract

New British Society of Gastroenterology/UK-PSC guidelines have recently discussed the current state-of-the-art on primary sclerosing cholangitis and outlined key elements for the management of this disease. The current lack of effective pharmacological treatments to prevent progression of liver fibrosis to cirrhosis limits our ability to modify the natural history of the disease. However, a personalised approach and structured follow-up could allow earlier diagnosis and management of complications and favour access to liver transplantation, which remains the only available treatment. Our commentary overviews the updates and summarises the key recommendations of the recent guidelines for the management of primary sclerosing cholangitis.

Key points.

• All patients with primary sclerosing cholangitis should be provided with a lifelong structured follow-up.

• An active management of symptoms and clinical events improves the quality of life of the patients and is associated with better outcomes.

• Ongoing surveillance for the development of inflammatory bowel disease, cirrhosis and its complications, cholangiocarcinoma and gallbladder cancer should be provided to all patients.

• In case of either symptomatic, advanced or complex disease, an early referral to expert centres is recommended to provide patients with the best expertise and care.

• A multidisciplinary decision-making should support every clinical decision lacking robust evidence.

• At present, no pharmacological treatment can prevent the progression of the disease. Ursodeoxycholic acid, corticosteroids and immunosuppressant agents have proved to be ineffective. Hence, such treatments should be avoided.

• Endoscopic therapy for dominant strictures is still debated. The indication must be assessed in multidisciplinary meetings. The presence of malignancies must be excluded prior to the procedure.

• Liver transplantation is the only treatment able to modify the natural history of the disease. Referral should be performed in line with national guidelines and eligibility should be assessed with a multidisciplinary approach.

Commentary

Diagnosis

Primary sclerosing cholangitis (PSC) is a rare chronic immune-mediated cholestatic liver disease causing inflammation, fibrosis and destruction of the bile ducts. PSC is characterised by a cholestatic pattern on liver biochemistry. As other chronic liver diseases, it can progress to cirrhosis and cause the development of portal hypertension and hepatic decompensation. The estimated incidence of PSC ranges from 0.91 to 1.3 per 100 000 person-year.¹ In the UK, PSC represents a significant cause of morbidity and advanced liver disease secondary to PSC accounts for about 15% of adult liver transplantations.²

Patients often present with an incidental unexplained finding of cholestatic abnormalities in the liver blood tests and normal ultrasound appearances. Magnetic resonance cholangiopancreatography (MRCP) is the main imaging modality for the diagnosis of PSC, possessing similar sensitivity and specificity as endoscopic retrograde cholangiopancreatography (ERCP). There is no diagnostic autoantibody in PSC, but appropriate investigations to exclude secondary sclerosing cholangitis (eg, IgG4, HIV) must be undertaken in order to confirm the diagnosis (table 1).

Table 1.

Causes of secondary sclerosing cholangitis, differential diagnosis and main investigations

Disease	Investigation
Cholangiocarcinoma	MRCP/MRI Biliary brushing/biopsy
IgG4-SC	IgG4 subtype dosage and ratio Immunohistochemical staining on liver biopsy
Traumatic or ischaemic bile duct injury	History MRCP
Choledocholithiasis	Abdominal US MRCP
Hilar lymphadenopathy	Abdominal US MRI/CT
Ampullary or pancreatic cancer	MRCP/MRI
Acute or chronic pancreatitis	Lipase Abdominal CT/MRI
Choledochal varices (portal biliopathy)	Abdominal US MRI
HIV cholangiopathy	HIV serology
Chronic biliary infestation (liver fluke, ascaris)	History, risk factors Serology
Congenital (choledochal cysts, biliary atresia)	History US
Papillary stenosis	Abdominal US MRCP
Critical illness ischaemic cholangiopathy	History MRCP
Recurrent pyogenic cholangitis	History
Hereditary haemorrhagical telangiectasia	History and physical examination Liver US/MRI In case of clinical suspicion, referral for specific investigation
Systemic mastocytosis	History and physical examination In case of clinical suspicion, referral for specific investigation
Langerhans' cell histiocytosis X	History and physical examination In case of clinical suspicion, referral for specific investigation
Drugs	History

MRCP, magnetic resonance cholangiopancreatography; US, ultrasound.

The characteristic features on MRCP are sufficient to diagnose classical, large duct PSC; therefore, liver biopsy is not required in most cases. However, liver histopathology is useful if there is a clinical suspicion of a PSC variant/overlap syndrome or IgG4 sclerosing cholangitis. Small duct PSC is the main variant syndrome, accounting for 5% of cases. It is characterised by the presence of cholestatic liver blood tests and histological findings of PSC in the absence of the bile duct alterations at imaging, typically running a more benign course than large duct PSC.

Frequently, PSC either is associated with other immune-mediated disorders or overlaps with other autoimmune liver conditions. Up to 83% of patients with PSC have inflammatory bowel disease (IBD)³ and about 8% of patients with IBD are affected by PSC.⁴ The most common overlap syndrome is PSC with features of autoimmune hepatitis (AIH), which is reported to be present in up to 17.0% of the patients.⁵ During follow-up, surveillance for other associated disorders and overlap features is recommended.

Natural history

The natural history of PSC is often variable and unpredictable. Men are more frequently affected than women in a 2:1 ratio, with a mean age of diagnosis in the fourth decade. In the early phases, the disease is usually asymptomatic, but latterly pruritus and fatigue are the most common symptoms. The majority of the patients, however, develop symptoms when complications occur and/or the disease progresses to cirrhosis.

Approximately 45% of patients with PSC experience the development of so-called dominant biliary strictures.⁶ The term refers to a common bile duct stricture <1.5 mm or a stricture <1 mm in diameter of the hepatic ducts on ERCP, which usually manifests as biliary obstruction with worsening liver biochemistry and/or proximal biliary dilatation or symptoms of cholestasis and are associated with an adverse prognosis.¹ The development of dominant strictures correlates with the presence of symptoms and duration of the disease but not with alkaline phosphatase levels.⁷ The advent of cholangioscopy has led to a better knowledge of dominant strictures. The Edmonton classification identifies three subclasses of strictures: the inflammatory type, the fibrostenotic type and the nodular or mass-forming type, which is the most concerning for evolution to cholangiocarcinoma (CCA).⁸

The occurrence of CCA and the progression to liver failure are the most feared clinical consequences of the disease. In historical cohorts series, liver failure and cirrhosis complications were the most common drivers for fatal outcome (64% of all deaths).⁹ Nowadays, the wide availability of transplantation has reduced the rate of deaths related to cirrhosis and its complications. As a consequence, death from CCA has relatively increased, accounting for 58% of all deaths.¹⁰ Recent International PSC Study Group data showed that 36.7% of patients progressed to liver transplantation or death during a median follow-up of 14.5 years.¹¹

Personalised management

General approach

Once the diagnosis of PSC is established, the new guidelines highlight the importance of an accurate follow-up and a personalised approach. Although no pharmacological treatment is available to prevent the progression of PSC, all patients should be provided with a lifelong structured follow-up. Risk stratification, disease staging, active management of symptoms and clinical events, surveillance for progression, cancer and other complications are the cornerstones of follow-up. Clinical assessment (eg, symptoms and comorbidities), biochemical markers, fibrosis staging and imaging in combination provide a complete evaluation of the disease and guide the planning of further investigations and follow-up. At least an annual clinical assessment with updated blood tests is recommended, but the frequency of clinical evaluation and diagnostic tests should be increased along with the evolution of the disease. Non-invasive tools, such as elastography, should be used to assess fibrosis, providing useful information about prognosis. Although numerous risk prediction scores have been developed, the use of clinical prognostic score is not routinely recommended due to a lack of external validation between cohorts. All patients should be screened for colitis using colonoscopy and colonic biopsies at diagnosis and then annually if a diagnosis of colitis is confirmed.

In case of symptomatic, advanced or complex disease, an early referral to expert centres is recommended. Such an approach could avoid the use of ineffective and potentially harmful treatments, promptly identify complications, diagnose overlap syndromes that require specific pharmacological treatments, ensure access to liver transplantation and offer the chance to enter into clinical trials.

The development of symptoms and/or changes in liver blood tests may reflect the occurrence of disease complications. This clinical suspicion requires further investigations, including an evaluation with cross sectional imaging (MRCP, dynamic liver MRI and/or contrast CT). Complications, indeed, affect the quality of life (QoL) of the patients and drive the evolution of the disease. Therefore, symptoms and clinical events should be actively managed (table 2). In particular, acute cholangitis, cirrhosis complications, dominant strictures and cancer deserve particular attention, as these clinical events require prompt and specific treatments and sometimes hospitalisation. Ongoing surveillance for the development of IBD, cirrhosis and its complications, CCA and gallbladder cancer should be provided to all patients. No particular biochemical or imaging surveillance is indicated for biliary cancers; however, an annual transabdominal ultrasound scan for gallbladder surveillance is recommended. This strategy could also help to detect CCA in early phases, although new guidelines do not recommend surveillance for CCA in PSC.¹² In patients with cirrhosis, hepatocellular carcinoma surveillance and endoscopic screening for varices should be performed according to international guidelines. All the patients should be screened for IBD using colonoscopy and colonic biopsies at diagnosis. If negative, IBD should be sought only in case of symptoms or clinical suspicion. Patients with PSC and IBD should be screened annually for colon cancer, those without IBD may benefit from less frequent 5-year colonoscopy or earlier in the advent of new symptoms. In the absence of clear evidence on some clinical situations, a multidisciplinary decision-making is highly advised.¹

Table 2.

Treatment of symptoms and clinical events

Concern	Importance	Recommendations
Pruritus	Significantly affect QoL. Frequent symptom but often related to complications.	Non-invasive imaging assessment to exclude complications. Cholestyramine is the first-line therapy; rifampicin and naltrexone are second-line treatments.
Fat soluble vitamin deficiency	Related to advanced cholestasis.	Screening according to the stage of the disease. Replacement therapy when diagnosed.
Metabolic bone disease	Common complication.	Risk assessment and lifestyle advice. Bone densitometry every 2 years in patients with cirrhosis or advanced cholestasis. Treat and monitor according to guidelines.
Cholangitis	Potentially serious complication. Previous ERCP is a risk factor.	Choose antibiotic according to clinical features and local microbiological ecology. Consider hospitalisation. When infection is secondary to dominant strictures, endotherapy is highly recommended.
Dominant strictures	The prevalence is up to 50% of patients with PSC. Associated with worse prognosis.	Cross-sectional contrast-enhanced imaging to investigate the presence of malignancies. Review cases in HPB meetings. In any clinical suspicion of malignancy, ERCP-guided histopathology is indicated. Once excluded cancer, consider endotherapy.
Cirrhosis	Higher risk for complications and association with poorer outcomes. Liver failure is a leading cause of death and liver transplantation in PSC.	Intensify follow-up. Regular screening for HCC and oesophageal varices in line with international guidelines. Consider referral to expert centres for liver transplantation.
Cholangiocarcinoma	Common cause of death of patients with PSC (lifetime risk up to 20%). Contraindication to liver transplantation.	Contrast enhanced imaging is the initial investigation. CA 19–9 supports the diagnosis. ERCP and/or US-guided histopathology confirms diagnosis. Referral to HPB multidisciplinary meeting to decide possible treatments.
Other HPB cancers	Increased risk compared with general population.	Annual abdominal US scan. Follow-up and manage gallbladder polyps in line with international guidelines.

ERCP, endoscopic retrograde cholangiopancreatography; HCC, hepatocellular carcinoma; HPB, hepatopancreatobiliary; PSC, primary sclerosing cholangitis; QoL, quality of life; US, ultrasound.

Psychological consequences of PSC are common and significantly impair the QoL of patients with PSC. Support groups provide information to patients and help to prevent isolation and other psychological conditions.¹³ Thus, access to and participation in the activities of support groups should be encouraged.

Pharmacotherapy

Several drugs have been evaluated for the treatment of PSC. Unfortunately, none has showed a real benefit in the prevention of disease progression. The absence of effective pharmacological treatments has led clinicians to treat patients with drugs that have showed efficacy in other chronic immune-mediated liver diseases. However, increasing evidence has demonstrated a lack of therapeutic benefit from ursodeoxycholic acid (UDCA), steroids (prednisolone and budesonide), and immunosuppressant agents (colchicine, penicillamine, azathioprine, ciclosporin, methotrexate, mycophenolate and antitumour necrosis factor monoclonal antibodies) in either disease activity or outcome.¹⁴

Several studies suggested that UDCA might improve liver biochemistry; nevertheless, it appears not to influence outcomes measured by death or liver transplantation.¹⁵ Moreover, high-dose treatments (28–30 mg/kg) have resulted in higher rates of serious adverse events.¹⁶ Hence, UDCA is not indicated for the treatment of newly diagnosed PSC nor prevention of CCA and colorectal cancer.

Similarly, steroids and immunosuppressant drugs are not recommended for the treatment of PSC. There is some evidence to support the use of corticosteroids in PSC/AIH and PSC/IgG4 overlap syndromes.^{17 18}

In the absence of licensed drugs, there are several ongoing phase 2 and 3 pharmacological trials. Coordinated by national UK-PSC project, several centres can recruit patients into clinical trials, with the potential to develop new therapies and provide early access to them. Patients should be informed about this opportunity and a referral to such centres should be offered.

Endoscopic therapy

ERCP is an important diagnostic and therapeutic tool in the management of PSC. The differentiation between malignant and benign strictures is crucial but often difficult with non-invasive imaging (eg, MRCP, dynamic liver MRI and/or contrast CT). Hence, all patients with suspicion of malignancy should be discussed in a specialist multidisciplinary meeting to decide further investigation and possible treatments.¹ In particular, the need for ERCP should be evaluated with a multidisciplinary approach to confirm appropriateness and minimise risks. ERCP should only be considered for the sampling or treatment of strictures. During ERCP, biliary brush cytology, fluoroscopically guided intraductal biopsy and cholangioscopy could improve the diagnostic accuracy in order to establish the nature of the strictures.

The best use of endoscopic therapy for dominant strictures is still debated. The development of strictures can cause symptoms and an elevation in the liver blood tests. There is some evidence that biliary decompression improves these parameters and may reduce the risk of cholangitis.¹⁹ The indication for this procedure must be assessed in multidisciplinary meetings, evaluating benefits and risks on a case by case basis. Furthermore, sampling of dominant stenosis is required to exclude the presence of malignancies as early as possible and to initiate treatment if biliary tract cancer is confirmed. In general, balloon dilatation should be preferred to the insertion of stents, due to a lower incidence of complications.¹⁹ Since a high incidence of cholangitis has been described, prophylactic antibiotic treatments are recommended in patients with PSC undergoing ERCP. The antibiotic regimens should be selected according to local microbial ecology.¹

Liver transplantation

At present, liver transplantation is the only treatment able to modify the natural history of the disease. PSC is a well-recognised indication for liver transplantation and is associated with excellent outcomes.^{20 21} However, the optimal timing for liver transplantation is uncertain. In fact, jaundice is often caused by the development of dominant strictures rather than liver failure. Hence, referral should be performed in line with national guidelines and eligibility should be assessed with a multidisciplinary approach. PSC recurs in 10%–40% of transplanted patients,^{22 23} and although intact colon and/or active colitis are risk factors for recurrent disease,²² colectomy at the time of liver transplantation is not routinely recommended. IBD remission prior to liver transplantation should be the objective, since better outcomes are observed.²⁴

Conclusion

New guidelines thoroughly outline current management of PSC, providing physicians with a useful tool for the clinical practice. Concurrently, experts identify pending question about this complex disease, tracing the route for future studies.