Tight junctions, which normally maintain the integrity of the intestinal epithelium, may become disrupted in inflammation. Leaky tight junctions could allow commensal bacteria and toxins to enter portal circulation and reach the liver, where they can trigger inflammation and fibrosis.The intestinal dysbiosis theory hypothesizes that yet unidentified environmental triggers (e.g., diet, medication, inflammation) reduce microbiota diversity and/or alter the population of specific species. The resulting imbalance between primary and secondary bile acids may lead to PSC via the gut-liver axis. The primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized in the liver and undergo conjugation before being released into the small intestine to aid digestion. In the distal ileum, 95% of these conjugated BAs are actively reabsorbed via ASBT but 5% enter the colon and are converted by gut microbes into deconjugated secondary bile acids, predominantly deoxycholic acid (DCA) and lithocholic acid (LCA). DCA and LCA are then reabsorbed into portal circulation and reach the liver, where they serve as signaling molecules that maintain bile acid homeostasis. Specifically, DCA and LCA and potent agonists of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), both of which mediate anti-inflammatory and cholangioprotective effects upon activation. On cholangiocytes, TGR5 activation induces CFTR to secrete chloride into bile ducts, which then drives anion exchanger 2 to secrete bicarbonate into bile canaliculi. Bicarbonate serves to protect the apical surface of cholangiocytes from damage by bile acids. On macrophages, activation of FXR and TGR5 inhibits NF-κB, thereby reducing production of proinflammatory cytokines.
Peripheral neuropathic pain is often described as "burning", "tingling", "electrical", "stabbing", or "pins and needles". Causes
Pathophysiology
Under persistent activation, the transmission of pain signals to the dorsal horn may produce a pain wind-up phenomenon. This triggers changes that lower the threshold for pain signals to be transmitted. In addition, it may cause nonnociceptive nerve fibers to respond to, generate, and transmit pain signals. The type of nerve fibers that are believed to generate the pain signals are the C-fibers, since they have a slow conductivity and give rise to a painful sensation that persists over a long time. In chronic pain, this process is difficult to reverse or stop once established. In some cases, chronic pain can be caused by genetic factors which interfere with neuronal differentiation, leading to a permanently lowered threshold for pain.Chronic pain of different causes has been characterized as a disease that affects brain structure and function. MRI studies have shown abnormal anatomical and functional connectivity, even during rest involving areas related to the processing of pain. Also, persistent pain has been shown to cause grey matter loss, which is reversible once the pain has resolved.These structural changes can be explained by neuroplasticity. In the case of chronic pain, the somatotopic representation of the body is inappropriately reorganized following peripheral and central sensitization. This can cause allodynia or hyperalgesia. In individuals with chronic pain, EEGs showed altered brain activity, suggesting pain-induced neuroplastic changes.