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Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is an inflammatory disease that causes fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans and strictures of the bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy ducts. The exact etiology is unknown, but there is a strong association with inflammatory bowel disease (IBD). Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship typically present with an insidious onset of fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema), and jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, which can progress to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis and complications related to biliary obstruction. The diagnosis is established with magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). Liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases is the only definitive treatment and is indicated in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with advanced liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease.

Last updated: Sep 1, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Epidemiology

  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency is approximately 6.3 cases per 100,000
  • Higher rate in Scandinavian countries
  • 70% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are men.
  • Age at diagnosis is around 30–50 years.
  • Predominantly seen in non-smokers

Etiology

The cause of primary sclerosing cholangitis (PSC) is unknown, but the disease is associated with:

  • Inflammatory bowel disease (IBD):
    • Approximately 80% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Ulcerative colitis Ulcerative colitis Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn’s disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis > Crohn’s disease
  • Genetic predisposition:
    • PSC is increased among 1st-degree relatives of effected individuals.
    • Increased prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of:
      • HLA-B8
      • HLA-DR3
      • HLA-Drw52a
  • Ischemic damage to the biliary ducts
  • Bacterial infection leading to chronic or recurrent cholangitis

Pathophysiology

  • Environmental insult in susceptible individuals → cholangiocyte activation → cytokine production → perpetual inflammatory response
  • Chronic periductal inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation leads to:
    • Cholangiocyte damage → peribiliary gland proliferation (accessory glands containing biliary stem cells) 
    • Portal myofibroblast activation → periductal fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (“onion skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions”) → biliary strictures and interlobular duct loss
    • Hepatic stellate cell activation → hepatic fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
    • Potential malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology of cholangiocytes
Pathophysio of primary sclerosing cholangitis

Progression of cholangiocyte activation, inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, and fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans in PSC. This starts with a predisposed phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics, and may be triggered by a stressor.

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Clinical Presentation

Though many patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are asymptomatic, others may present with:

  • Insidious onset of:
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema)
    • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice (later in the course)
  • Later development of:
    • Hepatomegaly
    • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly 
    • Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Evidence of biliary obstruction (approximately 75% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship):
    • Acute cholangitis Acute Cholangitis Acute cholangitis is a life-threatening condition characterized by fever, jaundice, and abdominal pain which develops as a result of stasis and infection of the biliary tract. Septic shock, liver abscess, and multi-organ dysfunction are potential serious complications. Acute Cholangitis (15%–20% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship):
      • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever 
      • Right upper quadrant Right upper quadrant Anterior Abdominal Wall: Anatomy abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways 
    • Gallstones Gallstones Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis
    • Choledocholithiasis Choledocholithiasis Presence or formation of gallstones in the common bile duct. Cholelithiasis
  • Associated IBD:
    • Chronic diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Colicky abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Tenesmus
Psc symptoms and related diseases

Common presentations in PSC are fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, pruritis, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, and cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may have concurrent IBD, and PSC is associated with an increased risk of cholangiocarcinoma Cholangiocarcinoma A malignant tumor arising from the epithelium of the bile ducts. Rare Malignant Liver Tumors.

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Diagnosis

  • Laboratory testing: 
    • Usually the 1st step in the workup
    • Evidence of cholestasis:
      • Alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma
      • ↑ Gamma-glutamyl transferase ( GGT GGT An enzyme, sometimes called ggt, with a key role in the synthesis and degradation of glutathione; (gsh, a tripeptide that protects cells from many toxins). It catalyzes the transfer of the gamma-glutamyl moiety to an acceptor amino acid. Alcoholic Liver Disease)
      • ↑ Conjugated bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism
    • Aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids aminotransferase ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests) and alanine Alanine A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. Synthesis of Nonessential Amino Acids aminotransferase ( ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests) may be slightly ↑ (typically < 300 IU/L).
    • Perinuclear anti-neutrophil cytoplasmic antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions ( P-ANCA p-ANCA Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis) are positive in about 75% of cases.
    • Antimitochondrial antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions (AMAs) are negative (testing helps to rule out primary biliary cholangitis Primary Biliary Cholangitis Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis).
    • Immunoglobulin G4 (IgG4) elevation has been seen in effected individuals.
    • Immunoglobulin M ( IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions) levels may be ↑.
  • Magnetic resonance cholangiopancreatography (MRCP):
    • Investigation of choice
      • Noninvasive
      • No risk of pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
    • Findings:
  • Endoscopic retrograde cholangiopancreatography (ERCP): 
    • 2nd choice for diagnosis in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who cannot undergo MRCP ( patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with implanted devices, such as a pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias)
    • Unlike MRCP, ERCP allows:
      • Brush cytology or biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
      • Therapeutic intervention (in cases of obstruction)
    • Similar findings to MRCP
  • Ultrasonography (US):
    • Not diagnostic
    • Usually performed during the initial workup to exclude biliary obstruction
    • Thickening of the wall of the common bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy and hepatic ducts are potential findings.
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
    • Rarely required for the diagnosis
    • Will show:
      • Peribiliary duct proliferation
      • Periductal fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (“onion skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions”)
      • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
      • Loss of bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy ducts
      • Potential biliary cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
    • Indicated if presentation has overlap features with autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis

Complications and Management

Complications

Primary sclerosing cholangitis is a progressive and chronic disease that causes inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation in the bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy ducts, which can lead to several complications:

  • Biliary cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis → portal hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension:
    • Varices
    • Ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
    • Hepatic encephalopathy Hepatic Encephalopathy Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. Hepatic Encephalopathy
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of malignancy Malignancy Hemothorax:
  • Cholelithiasis Cholelithiasis Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis, choledocholithiasis Choledocholithiasis Presence or formation of gallstones in the common bile duct. Cholelithiasis, and acute cholangitis Acute Cholangitis Acute cholangitis is a life-threatening condition characterized by fever, jaundice, and abdominal pain which develops as a result of stasis and infection of the biliary tract. Septic shock, liver abscess, and multi-organ dysfunction are potential serious complications. Acute Cholangitis
  • Fat-soluble vitamin Fat-soluble Vitamin Fat-soluble vitamins are absorbed and stored in adipose tissue (fat) and the liver. These vitamins can be released from storage and used when necessary. The 4 important fat-soluble vitamins are A, D, E, and K. Fat-soluble Vitamins and their Deficiencies deficiencies (A, D, E, K):
    • Rare, generally seen in advanced disease
    • Due to ↓ secretion Secretion Coagulation Studies of conjugated bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance
  • Osteopenia Osteopenia Osteoporosis or osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis: Mechanism is unclear.

Management

  • Medical management:
    • Ursodeoxycholic acid Ursodeoxycholic acid An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. Primary Biliary Cholangitis:
      • Improves biochemical tests but provides no definite benefit in terms of need for transplantation
      • Does not improve survival
      • Still under investigation
    • Other immunosuppressive and anti-inflammatory agents have not shown a benefit.
  • ERCP:
  • Liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases
    • The only definitive treatment
    • Indications:
      • Recurrent acute cholangitis Acute Cholangitis Acute cholangitis is a life-threatening condition characterized by fever, jaundice, and abdominal pain which develops as a result of stasis and infection of the biliary tract. Septic shock, liver abscess, and multi-organ dysfunction are potential serious complications. Acute Cholangitis
      • End-stage liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease complications (intractable ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites, hepatic encephalopathy Hepatic Encephalopathy Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. Hepatic Encephalopathy, esophageal varices)
  • Cancer screening Screening Preoperative Care:
    • Gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract: Anatomy cancer and cholangiocarcinoma Cholangiocarcinoma A malignant tumor arising from the epithelium of the bile ducts. Rare Malignant Liver Tumors:
      • Serial imaging (US, abdominal computed tomography (CT), or MRCP) every 6–12 months
      • Periodic cancer antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination 19-9 ( CA CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) 19-9)
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer:
    • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases:
      • Performed in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
      • Abdominal US and alpha-fetoprotein Alpha-fetoprotein The first alpha-globulins to appear in mammalian sera during fetal development and the dominant serum proteins in early embryonic life. Hepatocellular Carcinoma (HCC) and Liver Metastases ( AFP AFP The first alpha-globulins to appear in mammalian sera during fetal development and the dominant serum proteins in early embryonic life. Hepatocellular Carcinoma (HCC) and Liver Metastases) every 6 months
  • General health maintenance:
    • Screening Screening Preoperative Care and treatment for osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
    • Screening Screening Preoperative Care and supplementation for fat-soluble vitamin Fat-soluble Vitamin Fat-soluble vitamins are absorbed and stored in adipose tissue (fat) and the liver. These vitamins can be released from storage and used when necessary. The 4 important fat-soluble vitamins are A, D, E, and K. Fat-soluble Vitamins and their Deficiencies deficiencies in advanced disease

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

Differential Diagnosis

Primary sclerosing cholangitis should be differentiated from primary biliary cholangitis Primary Biliary Cholangitis Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis ( PBC PBC Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis), because the 2 conditions are similar in presentation:

Table: Primary sclerosing cholangitis compared to primary biliary cholangitis Primary Biliary Cholangitis Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis
PBC PBC Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis PSC
Predominantly women Predominantly men
Associated with autoimmune diseases Autoimmune diseases Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides. Selective IgA Deficiency Associated with IBD
Intrahepatic involvement only Intra- and extrahepatic involvement
Absence of bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy duct narrowing on MRCP MRCP shows narrowing and dilation of bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy ducts.
AMA AMA Primary Biliary Cholangitis positive in 95% of cases.
IBD: inflammatory bowel disease
MRCP: magnetic resonance cholangiopancreatography
P-ANCA p-ANCA Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: perinuclear anti-neutrophil cytoplasmic antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions
AMA AMA Primary Biliary Cholangitis: antimitochondrial antibody
  • PBC PBC Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis: autoimmune destruction of the intrahepatic bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy ducts. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are typically women, and may present with pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema), fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, and evidence of cholestasis or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis. Diagnosis is made with elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, AMAs, and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma, which will differentiate PBC PBC Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis from PSC. Management includes ursodeoxycholic acid Ursodeoxycholic acid An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. Primary Biliary Cholangitis, vitamin supplementation, and liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases for advanced disease.
  • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy duct obstruction: an obstruction of the biliary system that may be due to gallstones Gallstones Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis, malignancy Malignancy Hemothorax, or trauma. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with acute jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice and right upper abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways. Diagnosis will show elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, and imaging (US or MRCP) will differentiate bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy duct obstruction from PSC. Treatment is based on the etiology. 
  • Autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis: an autoimmune disease causing chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy. The clinical presentation ranges from asymptomatic, to symptoms of acute liver failure Liver failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis. Serum anti-smooth muscle antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma will determine the diagnosis and differentiate autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis from PSC. Treatment is with corticosteroids Corticosteroids Chorioretinitis and azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants. With early treatment, the prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is favorable.
  • Acute cholangitis Acute Cholangitis Acute cholangitis is a life-threatening condition characterized by fever, jaundice, and abdominal pain which develops as a result of stasis and infection of the biliary tract. Septic shock, liver abscess, and multi-organ dysfunction are potential serious complications. Acute Cholangitis: a life-threatening condition characterized by fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, and abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways that develops as a result of stasis and infection of the biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the “corners” of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract: Anatomy. Biliary strictures from PSC may precipitate acute cholangitis Acute Cholangitis Acute cholangitis is a life-threatening condition characterized by fever, jaundice, and abdominal pain which develops as a result of stasis and infection of the biliary tract. Septic shock, liver abscess, and multi-organ dysfunction are potential serious complications. Acute Cholangitis. The diagnosis is confirmed with elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy tests, leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus, and an US showing dilation of the common bile duct common bile duct The largest bile duct. It is formed by the junction of the cystic duct and the common hepatic duct. Gallbladder and Biliary Tract: Anatomy or gallstones Gallstones Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis. Treatment includes hemodynamic stabilization, broad-spectrum Broad-Spectrum Fluoroquinolones antibiotics, urgent biliary drainage, and cholecystectomy Cholecystectomy Cholecystectomy is a surgical procedure performed with the goal of resecting and extracting the gallbladder. It is one of the most common abdominal surgeries performed in the Western world. Cholecystectomy is performed for symptomatic cholelithiasis, cholecystitis, gallbladder polyps > 0.5 cm, porcelain gallbladder, choledocholithiasis and gallstone pancreatitis, and rarely, for gallbladder cancer. Cholecystectomy to prevent recurrence.

References

  1. Longo, D.L., Fauci, A.S., Kasper, D.L., Hauser, S.L., Jameson, J., & Loscalzo, J. (Eds.) (2018). Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill. 2060-2062. 
  2. Kowdley, K. (2020). Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis. UpToDate. Retrieved November 10, 2020, from: https://www.uptodate.com/contents/primary-sclerosing-cholangitis-in-adults-clinical-manifestations-and-diagnosis
  3. Kowdley, K.V. (2020). Primary sclerosing cholangitis in adults: Management. In Grover, S. (Ed.), Uptodate. Retrieved December 5, 2020, from https://www.uptodate.com/contents/primary-sclerosing-cholangitis-in-adults-management
  4. Mendes, F., & Lindor, K.D. (2010). Primary sclerosing cholangitis: overview and update. Nat Rev Gastroenterol Hepatol. Nov; 7(11):611-9. 
  5. Lindor, K.D., Kowdley, K.V., & Harrison, M.E. (2015). American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol; 110:646.
  6. Khurana, V., Singh, T., & Roy, P.K. (2019). Primary sclerosing cholangitis. In Kapoor, V.K. (Ed.), Medscape. Retrieved December 5, 2020, from https://emedicine.medscape.com/article/187724-overview
  7. Lindenmeyer, C.C. (2020). Primary sclerosing cholangitis (PSC). [online] MSD Manual Professional Version. Retrieved December 5, 2020, from https://www.msdmanuals.com/professional/hepatic-and-biliary-disorders/gallbladder-and-bile-duct-disorders/primary-sclerosing-cholangitis-psc

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