Pathophysiology
Summary
Gallbladder and biliary tract diseases encompass a broad range of pathologies, including autoimmune cholangitis and cancer. Autoimmune cholangitis most commonly manifests as either primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC).
Primary biliary cholangitis (PBC) affects the small intrahepatic bile ducts, particularly the interlobular bile ducts, and shows a predominance in cis-gendered women and a strong familial association. Genetically, it is associated with MHC type II DR & DQ alleles, and is associated with other autoimmune inflammatory disorders such as Sjogren’s syndrome & RA. PBC arises from a combination of genetic susceptibility & environmental exposure. Its pathogenesis involves T-cell mediated destruction of the small bile ducts, facilitated by anti-mitochondrial antibodies and CD8+ T-cells targeting bile duct epithelial cells. The hallmark pathology of PBC is a granulomatous reaction around the interlobular bile duct, known as a florid duct lesion.
Clinically, PBC manifests as a cholestatic pattern of liver dysfunction, evidenced by lab findings such as hyperbilirubinemia, increased alkaline phosphatase and GGT, as well as symptoms such as pruritus and fatigue. If PBC progresses, hyperlipidemia, elevated IgM, and visible signs such as jaundice, hyperpigmentations, and xanthomas can occur. Complications can be severe, including liver cirrhosis, hepatocellular carcinoma, and metabolic bone disease. Ursodeoxycholic acid is the mainstay of treatment for PBC, known for its beneficial effects on liver function and disease progression.
Primary sclerosing cholangitis (PSC) targets the medium and large intrahepatic and extrahepatic bile ducts. PSC is predominant in cis-gendered males, and is frequently associated with ulcerative colitis. It is associated with MHC type II DR haplotypes. Onset is often initiated by bacterial exposure due to increased gut permeability. PSC is associated with elevated IgM and p-ANCA antibodies, and is caused by T-cell mediated destruction of bile duct epithelial cells. Its hallmark histopathology a fibro-obliterative lesion known as ’onion skin’ fibrosis.
PSC naturally progresses towards liver cirrhosis, and is associated with complications such as cholangiocarcinoma and nutritional deficiencies like steatorrhea and fat-soluble vitamin deficiencies. Diagnosis involves endoscopic assessment or imaging via magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). Imaging in PSC displays a 'beads on a string’ appearance due to alternating areas of segmental fibrosis and areas of saccular dilation.
Lesson Outline
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FAQs
PBC and PSC are both immune-mediated inflammatory disorders of the liver, but they target different parts of the biliary tract and have distinct associations. PBC primarily affects the small intrahepatic bile ducts and is often linked with other autoimmune disorders like Sjogren's syndrome and rheumatoid arthritis. Its hallmark feature is the presence of anti-mitochondrial antibodies. On the other hand, PSC affects both medium and large intrahepatic and extrahepatic bile ducts. It is commonly associated with ulcerative colitis and is characterized by bile ducts with a 'beads on a string' appearance.
Genetic susceptibility plays a significant role in the onset of PBC, particularly the presence of MHC type II DR and DQ alleles. The disease also exhibits a strong familial association. Environmental factors, such as exposure to toxins, viruses, and bacteria, are also implicated in the development of PBC. Thus, the condition arises from a combination of genetic predisposition and environmental exposure.
Anti-mitochondrial antibodies are a key diagnostic marker for PBC. These antibodies target antigens on the inner mitochondrial membrane, such as pyruvate dehydrogenase. Their presence indicates an immune-mediated attack against the bile duct epithelial cells in the liver, which is a characteristic feature of PBC.
Untreated PBC can lead to severe complications like liver cirrhosis, hepatocellular carcinoma, and metabolic bone diseases like osteoporosis and osteopenia. PSC, if not managed, can also progress to liver cirrhosis and is specifically linked to an elevated risk of cholangiocarcinoma and gallbladder cancers. Both conditions can result in malabsorption, leading to deficiencies in fat-soluble vitamins such as A, D, E, and K.
The cornerstone of PBC treatment is Ursodeoxycholic acid, which is effective in improving liver function, slowing the progression of the disease, and extending transplant-free survival. In contrast, the benefits of Ursodeoxycholic acid in PSC are not clearly established. PSC is generally managed through endoscopic assessment or imaging via MRCP for disease monitoring and to prevent complications.
