Primary sclerosing cholangitis

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Primary sclerosing cholangitis
Cholangiogram of primary sclerosing cholangitis.jpg
Cholangiogram of primary sclerosing cholangitis
Specialty Gastroenterology
DurationLong term and progressive
CausesUnknown

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. 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.

Contents

The bile duct scarring that occurs in PSC narrows the ducts of the biliary tree and impedes the flow of bile to the intestines. Eventually, it can lead to cirrhosis of the liver and liver failure. PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer, and cholangiocarcinoma. [1] [2] The underlying cause of PSC is unknown. Genetic susceptibility, immune system dysfunction, and abnormal composition of the gut flora may play a role. [3] [4] This is further suggested by the observation that around 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. [5]

No effective medical treatment for primary sclerosing cholangitis is known. Its most definitive treatment is a liver transplant, [1] but disease recurrence can occur in 25-30% of cases. [6]

PSC is a rare disease and most commonly affects people with IBD. [2] About 3.0 to 7.5% of people with ulcerative colitis have PSC, and 80% of people with PSC have some form of IBD. [3] Diagnosis usually occurs in people in their 30s or 40s. [3] Individuals of Northern European ancestry are affected more often than people of Southern European or Asian descent. [2] Men are affected more often than women. [7] The disease was initially described in the mid-1800s, but was not fully characterized until the 1970s with the advent of improved medical-imaging techniques such as endoscopic retrograde cholangiopancreatography. [7]

Signs and symptoms

Nearly half of people with PSC do not have symptoms, and are often incidentally discovered to have PSC due to abnormal liver function tests; [1] however, a substantial proportion have debilitating signs and symptoms of the disease. [8] Signs and symptoms of PSC may include severe itching and nonspecific fatigue. Yellowing of the skin and white portion of the eyes may also be seen. Enlargement of the liver and spleen are seen in roughly 40% of affected individuals. Abdominal pain affects about 20% of people with PSC.[ citation needed ]

Multiple episodes of life-threatening acute cholangitis (infection within the bile ducts) can be seen due to impaired drainage of the bile ducts, which increases the risk of infection. [9]

Cause

The exact cause of primary sclerosing cholangitis is unknown, and its pathogenesis is improperly understood. [1] Although PSC is thought to be caused by autoimmune disease, it does not demonstrate a clear response to immunosuppressants. Thus, many experts believe it to be a complex, multifactorial (including immune-mediated) disorder and perhaps one that encompasses several different hepatobiliary diseases. [11] [12]

Data have provided novel insights suggesting:

  1. an important association between the intestinal microbiota and PSC [13] [14] [15] and
  2. a process referred to as cellular senescence and the senescence-associated secretory phenotype in the pathogenesis of PSC. [16] [17]

In addition, longstanding, well-recognized associations are seen between PSC and human leukocyte antigen alleles (A1, B8, and DR3). [4]

Pathophysiology

PSC is characterized by inflammation of the bile ducts (cholangitis) with consequent stricturing (i.e., narrowing) and hardening (sclerosis) of these ducts due to scar formation, be it inside and/or outside the liver. [18] The resulting scarring of the bile ducts obstructs the flow of bile, which further perpetuates bile duct and liver injury. Chronic impairment of bile flow due to blockage and dysfunctional bile transport (cholestasis) causes progressive biliary fibrosis and ultimately biliary cirrhosis and liver failure. [19]

The primary physiological function of bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K). [20]

Liver enlargement is seen due to portal hypertension caused by compression of portal veins by the proximate sclerosed intrahepatic bile ducts, and leads to right upper quadrant abdominal pain.[ citation needed ]

Diagnosis

CT scan findings in a case of primary sclerosing cholangitis CT of primary sclerosing cholangitis.jpg
CT scan findings in a case of primary sclerosing cholangitis
Ultrasound of sclerosing cholangitis in the common bile duct Sclerosing cholangitis 0001.jpg
Ultrasound of sclerosing cholangitis in the common bile duct

PSC is generally diagnosed on the basis of having at least two of three clinical criteria after secondary causes of sclerosing cholangitis have been ruled out:[ citation needed ]

Historically, a cholangiogram would be obtained via endoscopic retrograde cholangiopancreatography (ERCP), which typically reveals "beading" (alternating strictures and dilation) of the bile ducts inside and/or outside the liver. Currently, the preferred option for diagnostic cholangiography, given its noninvasive yet highly accurate nature, is magnetic resonance cholangiopancreatography (MRCP), a magnetic resonance imaging technique. MRCP has unique strengths, including high spatial resolution, and can even be used to visualize the biliary tract of small animal models of PSC. [21]

Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels. [22] For example, approximately 80% of people with PSC have perinuclear antineutrophil cytoplasmic antibodies (P-ANCA); however, this and other immunoglobulin findings are not specific to those with PSC and are of unclear clinical significance/consequence. Antinuclear antibodies and anti-smooth muscle antibody are found in 20-50% of PSC patients, and likewise are not specific for the disease, but may identify a subgroup of PSC patients who also have autoimmune hepatitis (i.e. PSC-AIH overlap syndrome). [4]

The differential diagnosis can include primary biliary cholangitis (formerly referred to as primary biliary cirrhosis), drug-induced cholestasis, cholangiocarcinoma, IgG4-related disease, post-liver transplantation nonanastomotic biliary strictures, [23] and HIV-associated cholangiopathy. [24] Primary sclerosing cholangitis and primary biliary cholangitis are distinct entities and exhibit important differences, including the site of tissue damage within the liver, associations with IBD, which includes ulcerative colitis and Crohn's disease, response to treatment, and risks of disease progression. [25]

Classification

Primary sclerosing cholangitis is typically classified into three subgroups based on whether the small and/or large bile ducts are affected. The subgroups of PSC include: [1]

Management

No pharmacologic treatment has been approved by the U.S. Food and Drug Administration for PSC. Some experts recommend a trial of ursodeoxycholic acid (UDCA), a bile acid occurring naturally in small quantities in humans, as it has been shown to lower elevated liver enzyme numbers in patients with PSC and has proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clearly lead to improved liver histology and survival. [8] [26] Guidelines from the American Association for the Study of Liver Diseases and the American College of Gastroenterology do not support the use of UDCA but guidelines from the European Association for the Study of the Liver do endorse the use of moderate doses (13-15 milligrams per kilogram) of UDCA for PSC. [1] [27] [28] [29]

Supportive treatment for PSC symptoms is the cornerstone of management. These therapies are aimed at relieving symptoms such as itching with antipruritics (e.g. bile acid sequestrants such as cholestyramine); antibiotics to treat episodes of ascending cholangitis; and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (A, D, E, and K). [30]

ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile-duct cancer (cholangiocarcinoma). [31]

Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial ascending cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. Not all patients are candidates for liver transplantation, and some experience disease recurrence afterward. [11] The reasons why some patients develop recurrent PSC remains largely obscure, but surprisingly, those without recurrence of disease (hence protected from recurrence) are characterized by an increased presence of the potentially pathogenic Shigella species. [32]

Prognosis

Estimated median survival from diagnosis until liver transplant or PSC-related death is 21.3 years. [33] Various models have been developed to help predict survival, [34] but their use is generally best suited for research and not clinical purposes. A serum alkaline phosphatase less than 1.5 times the upper limit of normal has been associated with better outcomes, but its use in predicting long-term outcomes is unclear. [1] An IgA isotype autoantibody to the pancreatic GP2 protein (anti-GP2 IgA antibody) is the first verified prognostic biomarker in PSC. [35] The role of anti-GP2 IgA in PSC was simultaneously investigated and reported by two research groups, [36] [37] and later confirmed by others. [38] [39] Association was demonstrated between anti-GP2 IgA and progressive liver fibrosis, cholangiocarcinoma development and shorter transplantation free survival in PSC patients. [35]

Other markers which may be measured and monitored are a complete blood count, serum liver enzymes, bilirubin levels (usually grossly elevated), kidney function, and electrolytes. Fecal fat measurement is occasionally ordered when symptoms of malabsorption (e.g., gross steatorrhea) are prominent.[ citation needed ]

The development of any of the cancers associated with PSC predicts a poor prognosis. Complications from PSC-associated cancers account for 40% of deaths from PSC. [2] Primary sclerosing cholangitis is one of the major known risk factors for cholangiocarcinoma, [40] a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%. [3] This represents a 400-fold greater risk of developing cholangiocarcinoma compared to the general population. [1] Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance with a specialized imaging study and serum markers, [41] although consensus regarding the modality and interval has yet to be established.[ citation needed ] Similarly, a screening colonoscopy is recommended in people who receive a new diagnosis of primary sclerosing cholangitis since their risk of colorectal cancer is 10 times higher than that of the general population. [1]

PSC is strongly associated with IBD, in particular ulcerative colitis (UC) and to a lesser extent Crohn's disease. As many as 5% of patients with IBD are co-diagnosed with PSC, [42] and approximately 70% of people with PSC have IBD. [19] Of note, the presence of colitis appears to be associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma) development, although this relationship remains poorly understood. [43] Close monitoring of PSC patients is vital.

Various forms of gallbladder disease such as gallstones and gallbladder polyps are also common in those with PSC. [1] Approximately 25% of people with PSC have gallstones. [1] Ultrasound surveillance of the gallbladder every year is recommended for people with PSC. [1] Any person with PSC who is found to have a mass in the gallbladder should undergo surgical removal of the gallbladder due to the high risk of cholangiocarcinoma. [1] Osteoporosis (hepatic osteodystrophy) and hypothyroidism are also associated with PSC.[ citation needed ]

A 2–3:1 male-to-female predilection occurs in primary sclerosing cholangitis. [19] PSC can affect men and women at any age, although it is commonly diagnosed in the fourth decade of life, most often in the presence of IBD. [18] PSC progresses slowly and is often asymptomatic, so it can be present for years before it is diagnosed and before it causes clinically significant consequences. Relatively few data are available on the prevalence and incidence of PSC, with studies in different countries showing annual incidence of 0.068–1.3 per 100,000 people and prevalence 0.22–8.5 per 100,000; given that PSC is closely linked with ulcerative colitis, the risk is likely higher in populations where UC is more common. [44] In the United States, an estimated 29,000 individuals have PSC. [1]

Research

Although no curative treatment is known, several clinical trials are underway that aim to slow progression of this liver disease. [45] Obeticholic acid is being investigated as a possible treatment for PSC due to its antifibrotic effects. Simtuzumab is a monoclonal antibody against the profibrotic enzyme LOXL2 that is being developed as a possible therapy for PSC. [1]

Notable cases

Related Research Articles

<span class="mw-page-title-main">Gallstone</span> Disease where stones form in the gallbladder

A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of migrated gallstones within bile ducts.

<span class="mw-page-title-main">Caroli disease</span> Medical condition

Caroli disease is a rare inherited disorder characterized by cystic dilatation of the bile ducts within the liver. There are two patterns of Caroli disease: focal or simple Caroli disease consists of abnormally widened bile ducts affecting an isolated portion of liver. The second form is more diffuse, and when associated with portal hypertension and congenital hepatic fibrosis, is often referred to as "Caroli syndrome". The underlying differences between the two types are not well understood. Caroli disease is also associated with liver failure and polycystic kidney disease. The disease affects about one in 1,000,000 people, with more reported cases of Caroli syndrome than of Caroli disease.

<span class="mw-page-title-main">Autoimmune hepatitis</span> Chronic, autoimmune disease of the liver

Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the liver to be inflamed. Common initial symptoms may include fatigue, nausea, muscle aches, or weight loss or signs of acute liver inflammation including fever, jaundice, and right upper quadrant abdominal pain. Individuals with autoimmune hepatitis often have no initial symptoms and the disease may be detected by abnormal liver function tests and increased protein levels during routine bloodwork or the observation of an abnormal-looking liver during abdominal surgery.

<span class="mw-page-title-main">Primary biliary cholangitis</span> Autoimmune disease of the liver

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

<span class="mw-page-title-main">Klatskin tumor</span> Medical condition

A Klatskin tumor is a cholangiocarcinoma occurring at the confluence of the right and left hepatic bile ducts. The disease was named after Gerald Klatskin, who in 1965 described 15 cases and found some characteristics for this type of cholangiocarcinoma

<span class="mw-page-title-main">Endoscopic retrograde cholangiopancreatography</span> Use of endoscopy and fluoroscopy to treat and diagnose digestive issues.

Endoscopic retrograde cholangiopancreatography (ERCP) is a technique that combines the use of endoscopy and fluoroscopy to diagnose and treat certain problems of the biliary or pancreatic ductal systems. It is primarily performed by highly skilled and specialty trained gastroenterologists. Through the endoscope, the physician can see the inside of the stomach and duodenum, and inject a contrast medium into the ducts in the biliary tree and pancreas so they can be seen on radiographs.

<span class="mw-page-title-main">Cholangiocarcinoma</span> Cancer of the bile ducts

Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.

Courvoisier's principle states that a painless palpably enlarged gallbladder accompanied with mild jaundice is unlikely to be caused by gallstones. Usually, the term is used to describe the physical examination finding of the right-upper quadrant of the abdomen. This sign implicates possible malignancy of the gallbladder or pancreas and the swelling is unlikely due to gallstones.

<span class="mw-page-title-main">Ursodeoxycholic acid</span> Medication and metabolite of cholesterol

Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived. In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:

<span class="mw-page-title-main">Magnetic resonance cholangiopancreatography</span> Medical imaging technique

Magnetic resonance cholangiopancreatography (MRCP) is a medical imaging technique. It uses magnetic resonance imaging to visualize the biliary and pancreatic ducts non-invasively. This procedure can be used to determine whether gallstones are lodged in any of the ducts surrounding the gallbladder.

<span class="mw-page-title-main">Ascending cholangitis</span> Medical condition

Ascending cholangitis, also known as acute cholangitis or simply cholangitis, is inflammation of the bile duct, usually caused by bacteria ascending from its junction with the duodenum. It tends to occur if the bile duct is already partially obstructed by gallstones.

Neonatal cholestasis refers to elevated levels of conjugated bilirubin identified in newborn infants within the first few months of life. Conjugated hyperbilirubinemia is clinically defined as >20% of total serum bilirubin or conjugated bilirubin concentration greater than 1.0 mg/dL regardless of total serum bilirubin concentration. The differential diagnosis for neonatal cholestasis can vary extensively. However, the underlying disease pathology is caused by improper transport and/or defects in excretion of bile from hepatocytes leading to an accumulation of conjugated bilirubin in the body. Generally, symptoms associated with neonatal cholestasis can vary based on the underlying cause of the disease. However, most infants affected will present with jaundice, scleral icterus, failure to thrive, acholic or pale stools, and dark urine.

<span class="mw-page-title-main">Biliary tract</span> Organ system which creates, stores, and transports bile

The biliary tract refers to the liver, gallbladder and bile ducts, and how they work together to make, store and secrete bile. Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin. Some components are synthesized by hepatocytes ; the rest are extracted from the blood by the liver.

<span class="mw-page-title-main">Liver cancer</span> Medical condition

Liver cancer, also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy, is cancer that starts in the liver. Liver cancer can be primary in which the cancer starts in the liver, or it can be liver metastasis, or secondary, in which the cancer spreads from elsewhere in the body to the liver. Liver metastasis is the more common of the two liver cancers. Instances of liver cancer are increasing globally.

<span class="mw-page-title-main">Recurrent pyogenic cholangitis</span> Medical condition

Recurrent pyogenic cholangitis (RPC), also known as Hong Kong disease, Oriental cholangitis, and Oriental infestational cholangitis, is a chronic infection characterized by recurrent bouts of bacterial cholangitis with primary hepatolithiasis. It is exclusive to people who live or have lived in southeast Asia.

Secondary sclerosing cholangitis (SSC) is a chronic cholestatic liver disease. SSC is a sclerosing cholangitis with a known cause. Alternatively, if no cause can be identified, then primary sclerosing cholangitis is diagnosed. SSC is an aggressive and rare disease with complex and multiple causes. It is characterized by inflammation, fibrosis, destruction of the biliary tree and biliary cirrhosis. It can be treated with minor interventions such as continued antibiotic use and monitoring, or in more serious cases, laparoscopic surgery intervention, and possibly a liver transplant.

<span class="mw-page-title-main">Obeticholic acid</span> Chemical compound

Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.

<span class="mw-page-title-main">Biliary endoscopic sphincterotomy</span> Use of endoscopy and fluoroscopy to treat and diagnose digestive issues.

Biliary endoscopic sphincterotomy is a procedure where the sphincter of Oddi and the segment of the common bile duct where it enters the duodenum are cannulated and then cut with a sphincterotome, a device that includes a wire which cuts with an electric current (electrocautery).

References

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