The course of the disease varies from person to person. When symptomatic, most of the patients present with pain in the upper right quadrant, jaundice, fatigue and pruritus. Symptoms undergo remission and exacerbations. Symptoms resemble acute cases of hepatitis in some. Some not so common symptoms include hyperpigmentation, xanthomas, and xantelasma [7]. Around 10-15% of the patients show febrile episodes that disappear spontaneously without any specific treatment, a typical symptom of bacterial cholangitis. Those with portal hypertension and cirrhosis present with esophageal varices, encephalopathy and ascites.

Fever, gallbladder and biliary stones, abdominal pain, biliary tract strictures and cholangiocarcinoma are some of the complications associated with PSC. About one third of the patients with PSC have gallstones [8]. About 15%-20% of the patients present with dominant strictures in common bile duct or common hepatic duct [9]. Acute onset of jaundice, fever and pruritus are the clinical manifestations of strictures. PSC also increases the risk of cholangiocarcinoma [10].

• Fatigue

  Early symptoms of primary sclerosing cholangitis include fatigue and bodily itching (pruritus). As the disease progresses, individuals may develop jaundice (yellowing of skin and darkening of urine). [emedicinehealth.com]

  Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of bile ducts..Patients with PSC usually presents with fatigue, jaundice and pruritus. Ultimately it leads to cirrhosis of liver and portal hypertension. [ncbi.nlm.nih.gov]

• Fever

  As primary sclerosing cholangitis progresses, individuals typically develop right upper abdominal pain, fever, fatigue, pruritus, and jaundice. These individuals also are at risk of developing primary sclerosing cholangitis complications. [emedicinehealth.com]

  […] disease The diagnosis of primary sclerosing cholangitis should be suspected in a patient with ulcerative colitis who has abnormal LFTs, especially a raised alkaline phosphatase pruritus and fatigue are early symptoms - patients may also present with fevers [gpnotebook.co.uk]

  […] appears in young adults but may develop at any age Gender : PSC is more common in men than women Symptoms of primary sclerosing cholangitis Symptoms of advanced primary sclerosing cholangitis (PSC) may include: Unexplained fatigue Itchiness Abdominal pain Fever [henryford.com]

  Symptoms of PSC include intermittent malaise, pruritus, fever, chills, night sweats, and right upper abdominal quadrant pain. [e-guide.ecco-ibd.eu]

• Chills

  […] young adults but may develop at any age Gender : PSC is more common in men than women Symptoms of primary sclerosing cholangitis Symptoms of advanced primary sclerosing cholangitis (PSC) may include: Unexplained fatigue Itchiness Abdominal pain Fever Chills [henryford.com]

  Symptoms of PSC include intermittent malaise, pruritus, fever, chills, night sweats, and right upper abdominal quadrant pain. [e-guide.ecco-ibd.eu]

  […] liver transplant; 75% of Pts have IBD; 70% of Pts are ♂, average age 39 Clinical Often asymptomatic until end-stage liver disease; as albumin ↓ and BR ↑, pruritus, fatigue, jaundice, and weight loss dominate clinical picture, ± accompanied by fever, chills [medical-dictionary.thefreedictionary.com]

  […] colitis (UC) 5% of all patients with UC have PSC 75% of all patients with PSC will have UC Most often between 30-60 years of age with a mean of 40 More common in men (70%) Clinical Findings Asymptomatic; onset of symptoms is insidious Diarrhea Fever, chills [learningradiology.com]

  The ducts may become infected, resulting in fever, chills and tenderness in the upper abdomen. If bile leaks into the bloodstream, itchiness may develop. Disease progression can cause chronic fatigue, loss of appetite, weight loss and jaundice. [livestrong.com]

• Sepsis

  Center, Oslo University Hospital Rikshospitalet, Oslo, Norway. 4 National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway. 5 Department of Internal Medicine IV, University Hospital Jena, Germany. 6 Center for Sepsis [ncbi.nlm.nih.gov]

  Cholangitis can result in bacterial infection spreading to the blood stream (a condition called sepsis ). Sepsis can cause damage to kidneys and lungs and even cause shock. [emedicinehealth.com]

  Sepsis Intrahepatic cholestasis is often seen in patients who have sepsis. 33 Circulatory endotoxins associated with sepsis induce cytokine production, including tumor necrosis factor α, interleukin-1, and interleukin 6, which results in impaired bile [clevelandclinicmeded.com]

• Malaise

  Symptoms of PSC include intermittent malaise, pruritus, fever, chills, night sweats, and right upper abdominal quadrant pain. [e-guide.ecco-ibd.eu]

  In early stages, unspecific manifestations such as fever, fatigue, pruritus, malaise, abdominal pain, and weight loss are reported, however about 40-50% of patients may be asymptomatic at time of diagnosis. [orpha.net]

  Additional symptoms include a general feeling of ill health (malaise); abdominal pain, especially the upper right portion of the abdomen; nausea; dark urine; light-colored stools; unintended weight loss, and/or abnormal enlargement of the liver (hepatomegaly [rarediseases.org]

  Dark urine, as a result of excretion of bile by-products into urine Anorexia, fatigue, malaise (general discomfort or unease), and abdominal pain Nutritional deficiencies, especially in vitamins A, D, E, and K, due to the lack of bile in the intestine [dovemed.com]

• Abdominal Pain

  Obstruction of the ducts can lead to abdominal pain, itching, jaundice, infection in the bile ducts (cholangitis), and liver scarring that leads to liver cirrhosis and liver failure. [emedicinehealth.com]

  A 39-year-old man presented with diarrhea and abdominal pain. At 26 years of age, he was found to have eosinophilia and abnormal liver function parameters, for which prednisolone therapy was started. [ncbi.nlm.nih.gov]

• Loss of Appetite

  Other symptoms may include: Enlarged liver Enlarged spleen Loss of appetite and weight loss Repeat episodes of cholangitis Medicines that may be used include: Cholestyramine (such as Prevalite) to treat itching Ursodeoxycholic acid (ursodiol) to improve [medlineplus.gov]

  Disease progression can cause chronic fatigue, loss of appetite, weight loss and jaundice. Long-term liver cell damage can lead to cirrhosis, a hardening of the liver that prevents it from functioning properly. [livestrong.com]

  Signs & symptoms The disease may take years to produce symptoms but once they begin to develop, patients experience: fatigue; loss of appetite; weight loss; and jaundice. [ariahealth.org]

• Nausea

  Affected individuals may also have dark urine, light-colored stools, abdominal pain, and/or nausea. In some cases, the liver may also become abnormally enlarged (hepatomegaly). [rarediseases.org]

  Symptoms of cholangitis can include any combination of the following: pain in the right upper quarter of the abdomen (pain may also occur in the chest, in the upper back, or the right shoulder) tenderness in the upper abdomen nausea and vomiting belching [psc-literature.org]

  There may also be nausea. If this occurs, it may help to reduce the amount of fat in the diet but only under the supervision of a dietician. Some people may need energy supplements and injections of fat-soluble vitamins. [britishlivertrust.org.uk]

  I started developing abdominal pains, convulsions at night, drench sweating, nausea and to some extent vomiting. This went for the whole of 2011 with everyday growing worse than the previous. [venasnews.co.ke]

• Upper Abdominal Pain

  As primary sclerosing cholangitis progresses, individuals typically develop right upper abdominal pain, fever, fatigue, pruritus, and jaundice. These individuals also are at risk of developing primary sclerosing cholangitis complications. [emedicinehealth.com]

  If there are early symptoms, they usually include: Itchy skin Feeling tired The disease can be present for many years, but as the disease advances the symptoms range from: Fevers and chills Night sweats Unexplained weight loss Right upper abdominal pain [newhealthguide.org]

• Clay-Colored Stool

  Symptoms may include: Pain in the upper right part of your belly (abdomen) Fever Chills Yellowing of the skin and eyes (jaundice) Nausea and vomiting Clay-colored stools Dark urine Low blood pressure Lethargy Not as alert The symptoms of cholangitis may [hopkinsmedicine.org]

• Jaundice

  As the disease progresses, individuals may develop jaundice (yellowing of skin and darkening of urine). Jaundice is due to the accumulation of bilirubin in the body. [emedicinehealth.com]

  Sclerosing cholangitis may also be caused by: Choledocholithiasis (gallstones in the bile duct) Infections in the liver, gallbladder, and bile ducts The first symptoms are usually: Fatigue Itching Yellowing of the skin and eyes (jaundice) However, some [medlineplus.gov]

  Jaundice (yellowish discoloration of the skin and whites of the eyes) tends to develop later. Inflammation and recurring infection of the bile ducts (bacterial cholangitis) sometimes occur. [merckmanuals.com]

• Hepatomegaly

  Primary Sclerosing Cholangitis – SC404 Primary Sclerosing Cholangitis (PSC) is characterized by progressive inflammatory fibrotic destruction of the biliary ducts and patients with PSC often have chronic jaundice, hepatomegaly and pruritus. [sancilio.com]

  Hepatomegaly, splenomegaly, jaundice, portal hypertension and, in more advanced cases, spider angiomata, ascites and muscle atrophy are observed. [orpha.net]

  Hepatomegaly (may also have splenomegaly at presentation). Later stages: signs of cirrhosis, portal hypertension or hepatic failure. [patient.info]

  Liver disease other than PSC was defined as autoimmune hepatitis, hepatitis, hepatomegaly, liver failure, cirrhosis, portal hypertension, cholangiocarcinoma, or hepatobiliary cancer.The age-standardized incidence of PSC was 0.68 (95% confidence interval [ncbi.nlm.nih.gov]

• Osteoporosis

  Osteoporosis Osteoporosis or bone thinning is another complication of PSC. The cause of osteoporosis in PSC is unclear. [patients.gi.org]

  Rarer complications of PSC include: cholestasis, cholangitis, cholecystolithiasis, cholangiocarcinoma, colorectal carcinoma, osteoporosis, vitamin deficiency and steatorrhea. [e-guide.ecco-ibd.eu]

  Affected individuals can eventually develop osteoporosis, a condition in which the bones become brittle and fragile. Individuals with osteoporosis are prone to repeated fractures. [rarediseases.org]

  The risk of osteoporosis increased with greater age, low body mass index, and longstanding IBD; three quarters of patients with all three of these risk factors had osteoporosis. [gi.org]

• Pruritus

  Medical management of pruritus is directed by the severity of the underlying pruritus. Mild pruritus may be treated with skin emollients and possibly antihistamines. [gi.org]

  Symptoms of PSC include intermittent malaise, pruritus, fever, chills, night sweats, and right upper abdominal quadrant pain. [e-guide.ecco-ibd.eu]

  Jaundice and pruritus. Right upper quadrant abdominal pain. Fatigue, weight loss, fevers and sweats. May present with complications (see 'Complications and their management', below). Signs Jaundice. [patient.info]

  The Cleveland Clinic has published an excellent article entitled "Pruritus" which describes the various types and causes of itching. A comprehensive article on pruritus is as follows: "Pruritus" (American Family Physician). [psc-literature.org]

  The reason for the pruritus is not entirely known. It may be due to accumulation of bile salts in the body, also as a result of obstruction of the bile ducts. [emedicinehealth.com]

• Excoriation

  It is often worse at night, in warm, humid climates, and may lead to excoriations from scratching, as well as other dermatologic complications (123). [gi.org]

  It is often worse at night, in warm, humid climates, and may lead to excoriations from scratching, as well as other dermatologic complications ( 123 ). [nature.com]

• Yellow Discoloration of the Skin

  Affected individuals may have no symptoms or may experience signs and symptoms of liver disease such as yellow discoloration of the skin and eyes, itching, and abdominal pain. [en.wikipedia.org]

• Tremor

  […] of tacrolimus (0.05 mg/kg twice daily) in 16 patients with PSC over a 1-year period. [53] Only 50% of patients completed the 1 year of treatment, while 31% stopped therapy secondary to drug-related adverse events such as diarrhea, nausea, vomiting, tremor [ncbi.nlm.nih.gov]

• Dark Urine

  Affected individuals may also have dark urine, light-colored stools, abdominal pain, and/or nausea. In some cases, the liver may also become abnormally enlarged (hepatomegaly). [rarediseases.org]

  Dark urine, as a result of excretion of bile by-products into urine Anorexia, fatigue, malaise (general discomfort or unease), and abdominal pain Nutritional deficiencies, especially in vitamins A, D, E, and K, due to the lack of bile in the intestine [dovemed.com]

  When the disease has progressed to the point that symptoms develop, they may include: Fatigue Abdominal pain Chills Diarrhea Fever Intense itching of the skin Unintentional weight loss Jaundice (yellowing of the eyes and skin) Enlargement of the liver Dark [disability-benefits-help.org]

Liver function tests are the most important diagnostic tests for PSC. Levels of serum alkaline phosphatase, serum aminotransferase, and hypergammaglobulinemia are confirmatory measures in this condition. Serum alkaline phosphatase levels tend to increase 3-5 times than normal. Gamma-glutamyl transpeptidase levels also rise simultaneously and help to differentiate PSC from bone disease. Patients with IBD present with hypoalbuminemia. About half of the patients with this disease have elevated levels of IgM. Antinuetrophil cytoplasmic antibodies and anticardiolipin measures also show an increase in most of them.

Endoscopic retrograde cholangiopancreatography (ERCP) is the imaging technique used in confirmatory diagnosis of PSC. Strictures and hepatic duct dilations can also be located and defined through ERCP. When ERCP is unsuccessful in diagnosis, transhepatic cholangiography is recommended. Magnetic resonance cholangiopancreatography is also being used in the diagnosis of PSC.

Histological features of liver are not always diagnostic for PSC. Some of the early histological features are ‘onion skin’ fibrosis, portal edema and expansion of portal ducts. Necrosis and portal phlebitis may also be seen in some.

• HLA-B8

  Thus, "A HLA association in PSC was first identified for HLA-B8 (i.e. HLA-B*0801) and DR3 (i.e. DRB1*0301)[24,50]. [psc-literature.org]

  Etiology O Immune mediated O Infection O Genetic predisposition HLA-B8, DR3, DR2, and DR4 O Environmental Factors 34. Pathophysiology 35. Pathophysiology 36. Clinical Presentation O Asymptomatic 50% 37. [slideshare.net]

  HLA-B8, HLA-DR3, and HLA-Drw52a alleles have an increased prevalence in patients with PSC, suggesting a genetic predisposition. A number of susceptible loci have been identified that increases the risk of this disease. [symptoma.com]

  HLA-DR3, and HLA-Drw52a. [emedicine.medscape.com]

There is no effective, standard cure for PSC. Treatment methods normally used aim at improving the symptoms and to manage complications associated with the condition. Any treatment modality used depends on the stage of the disease. Patient often needs to be monitored frequently for complications. Pruritus is controlled by cholestyramine with gradual increase in the dose until the symptoms are relieved. Rifampicin and naltrexone are used as next line treatment. Those with jaundice should be given replenishment of fat soluble vitamins, calcium, and vitamin D3.

For acute cholangitis, broad spectrum antibiotics are suggested. Endoscopic dilation of the duct is considered when well defined obstruction is located. For prominent strictures, stenting may be helpful. Biliary stones and biliary sludge are two complications often associated with PSC. Endoscopic sphincterotomy with duct extraction leads to improvement in the symptoms.

Ursodeoxycholic acid when used in combination with endoscopic stenting or dilation has shown to improve the survival rate [11]. Patients with variceal bleeding and portal gastropathy are considered for liver transplantation. Other indications include hepatic encephalopathy, recurrent cholangitis, and ascites. Survival rate for liver transplantation ranges from 69.8% to 93.7%, with the highest for transplantation done within a year. Recurrence is noted in 20% patients after one year of transplantation. But recurrence has not been found to cause liver decompensation to the extent of going for another transplantation. Patients with ulcerative colitis may opt for proctocolectomy. Good outcome is also seen for resection of extrahepatic biliary tree followed by stenting. Patients with PSC and ulcerative colitis are at an increased risk of developing colon cancer and hence should undergo colonoscopy every year.

PSC is a progressive disease that results in portal hypertension and liver cirrhosis. Median length of survival from diagnosis is reported to be 12 years. Liver transplantation is a treatment modality that has a good prognosis. If symptoms are present at the time of diagnosis, prognosis is poor. Factors that affect prognosis in a patient include age, serum bilirubin and albumin, and history of variceal bleeding [5]. Severity of disease is based on levels of bilirubin and albumin and prothrombin time. Presence of ascites, and grade of encephalopathy also influence outcome of the disease [6].

The actual etiology of the disease is not defined yet, but many factors are presumed to be responsible for the development of PSC. Some of the causative factors include absorption of toxins from the colon, ischemic injury, portal bacteremia, viral infections, and genetic predisposition. Autoimmunity is the accepted factor as the most common underlying cause of PSC. This is supported by the fact that about 75%-80% of the patients with PSC have IBD. Most of the patients present with hypergammaglobulinemia, while smooth muscle antibodies and antinuclear factors are also elevated, but at low titers.

Theories suggest that recurrent bacterial infection in the portal circulation and exposure to toxic components trigger an inflammatory response [2]. HLA-B8, HLA-DR3, and HLA-Drw52a alleles have an increased prevalence in patients with PSC, suggesting a genetic predisposition [3]. A number of susceptible loci have been identified that increases the risk of this disease. Exposure of genetically susceptible individuals to environmental triggers like infection and toxins, elicits an autoimmune reaction that leads to the development of this chronic condition.

Prevalence of PSC in many countries is not known. The condition is found to be closely associated with another inflammatory disease, IBD. The prevalence of PSC in patients with IBD is found to vary in different studies. Prevalence of IBD in patients with PSC ranges from 23% to 100% in different countries [4]. Onset of the disease happens usually around the age of 20-30 years, but reports of childhood occurrence are also present. It is a progressive disease and may remain undiagnosed for a long period of time.

One of the studies shows that the prevalence of PSC is 2 to 4 times higher among Jewish population. About 70% of the patients with PSC are men with mean age of onset or diagnosis as 40 years. But, PSC without IBD is found to be more common in women with the mean age of diagnosis higher than that of men.

PSC is characterized by thickening and induration of the bile duct. As the disease progresses, the liver may become nodular in appearance. In the first stage of pathogenesis, epithelial cells of the bile duct degenerate forming the primary lesion. This is followed by infiltration of bile duct by lymphocytes and neutrophils. This progresses into inflammation, scarring and enlargement of the portal triad. In the next stage, inflammation and fibrosis spread to the periportal parenchyma resulting in destruction of periportal hepatocytes and necrosis of liver. Enlargement of portal triads is characteristic in this phase of the disease. Portal to portal fibrous septa formation ensues enlargement and bile ducts undergo degenerative changes. In the last stage cirrhosis is prominent.

Patients with PSC show a significant increase in the circulating immune complexes in the serum and bile. These complexes are associated with activation of complement system resulting in autoimmune response. T-suppressor cells reduce in the serum leading to altered T-helper to T-suppressor ratio. Activated-lymphocytes leads the infiltration into portal ducts. Immune complex increase may result from any of the environmental triggers in a genetically susceptible person.

Bacterial infection, as per another theory, leads to production of tumor necrosis factors and endotoxins through reaction with bacterial cell wall products. IBD is presumed to increase the risk of this reaction. Increased levels of cytokines activate neutrophils, fibroblasts, T cells and macrophages. Fibrosis result in atrophy of biliary epithelial cells leading to cholestasis, fibrosis and secondary biliary cirrhosis.

As the etiology of the disease is not defined, preventive measures are not known.

Primary sclerosing cholangitis (PSC) is a chronic, progressive, cholestatic liver disease characterized by fibrosis and inflammation of intra- and extrahepatic biliary ducts. The course of the disease varies and it may lead to liver cirrhosis and other complications. It is commonly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis.

The etiology of the disease is not clearly defined, but autoimmune responses are presumed to be an important factor. Diagnosis of PSC is based on clinical, biochemical and radiological features. Beaded appearance of the bile ducts on cholangiography is indicative of PSC [1]. It is more commonly seen among men and the mean age at diagnosis is around 40 years. It is less common than alcoholic liver disease, but is one of the leading cause for liver transplantation in the US. As an effective treatment modality is yet to be worked out, symptomatic treatment and management of complications are the steps in therapy now. Liver transplantation is the only method that gives a good prognosis.

Primary sclerosing cholangitis (PSC) is a chronic liver disease in which the bile ducts progressively undergo scarring and inflammation, narrowing the lumen. It may be seen alone or in association with ulcerative colitis. The disease progresses gradually and may lead to liver failure, infections of the liver, and tumors in the organ. The actual cause of PSC is not known yet. It is presumed that in people who are susceptible to the disease, infections or exposure to toxins trigger PSC. Some factors like age, gender, and inflammatory bowel disease, increase the risk of developing this disease. It is more prevalent in the age group of 30 to 50 years and occurs more frequently in men when compared to women. A major proportion of people with inflammatory bowel disease also have PSC.

Many patients remain asymptomatic for several years. Sometime it is diagnosed during a laboratory test or imaging indicated for the diagnosis of some other condition. Some of the early symptoms of the disease include fatigue, pain in the upper right part of the abdomen. Enlarged liver, weight loss and jaundice are also commonly seen. Some of the complications of PSC include liver failure, repeated infections, hypertension in portal veins, thinning of bones, cancer of bile duct, and colon cancer.

Liver function tests are the major tests used in the diagnosis of PSC. Magnetic resonance cholangiopancreatography is used to obtain images of the bile ducts and liver. This non-invasive procedure helps in identifying and defining the problem. Endoscopic retrograde cholangiopancreatography is the imaging method of choice to get an image of the ducts and liver. Biopsy of liver tissue is used to assess the extent of damage to the liver.

There are no known standard, effective treatments for PSC. Any method suggested aims at monitoring the health of liver and to control the complications. As the bile duct narrows due to fibrosis and inflammation, bile backs up and this may result in repeated infections. Antibiotics are recommended in case of repeated infections. Absorption of vitamins are affected in this condition and hence replenishing vitamins through supplementation is very important. If bone thinning is one of the symptoms, vitamin D and calcium supplementation are also needed. Block in the bile ducts can be cleared by balloon dilation or stenting. The only treatment known to cure and give a good prognosis is liver transplantation. This is usually recommended for people with liver failure or other severe complications. In some rare cases, PSC may recur in patients after liver transplantation.

1. Chapman RWG, Arborgh BAM, Rhodes JM, et al. Primary sclerosing cholangitis; a review of its clinical features, cholangiography and hepatic histology. Gut. 1980;21:870-877.
2. Trottier J, Bialek A, Caron P, Straka RJ, Heathcote J, Milkiewicz P, et al. Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: A pilot study. Dig Liver Dis. 2011;44(4):303-310.
3. Gotthardt D, Chahoud F, Sauer P. Primary sclerosing cholangitis: diagnostic and therapeutic problems. Dig Dis. 2011;29 Suppl 1:41-5.
4. Okada H, Mizuno M, Yamamoto K, Tsuji T. Primary sclerosing cholangitis in Japanese patients: association with inflammatory bowel disease. Acta Med Okayama. 1996;50(5):227-35.
5. Kim WR, Therneau TM, Wiesner RH, et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc. 2000;75(7):688-94.
6. Shetty K, Rybicki L, Carey WD. The Child-Pugh classification as a prognostic indicator for survival in primary sclerosing cholangitis. Hepatology. 1997;25(5):1049-53.
7. Wiesner RH, LaRusso NF, Ludwig J, ER D. Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology. 1985;88:108-114. 
8. Brandt DJ, Mac Carty RL, Charboneau JW, et al. Gall bladder disease in patients with primary sclerosing cholangitis. Am J Roentgenol. 1988; 150:571-574.
9. Lee J, Schutz S, England R, et al. Endoscopic therapy of sclerosing cholangitis. Hepatology. 1995;21:661-667.
10. Jesudian AB, Jacobson IM. Screening and diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis. Rev Gastroenterol Disord. 2009;9(2):E41-7.
11. Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009; 50(3):808-814.