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The physiologic bile acid ursodeoxycholic acid (UDCA) has potent anticholestatic and weak litholytic properties and has been used for centuries as a remedy for cholestatic liver diseases. Today, UDCA at 13-15 mg/kg/day is the standard first line medication for all people with primary biliary cholangitis (PBC), the most frequent chronic cholestatic liver disease where UDCA clearly improves long-term survival. For many other chronic cholestatic conditions, anticholestatic effects are described, but long-term data are incomplete. While UDCA's litholytic properties can be explained by lowering biliary cholesterol hypersaturation, its beneficial effects in cholestatic diseases build on different mechanisms of action, namely: (i) stimulation of hepatobiliary secretion by post-transcriptional mechanisms including membrane targeting and insertion of key transporters and ion channels, (ii) stabilization of a biliary bicarbonate umbrella by stimulation of biliary chloride/bicarbonate secretion, and (iii) inhibition of hepatocyte and cholangiocyte apoptosis and reduction of endoplasmic reticulum stress induced by toxic endogenous bile acids.

Immunoglobulin G4-related disease (IgG4-RD) is a newly recognised immune-mediated disease of unknown origin. IgG4-related disease predominantly affects the pancreas (autoimmune pancreatitis type 1), biliary tract (IgG4-associated cholangitis) and salivary glands. However, based on distinct histopathological findings, IgG4-RD has also been described in nearly every organ of the human body. Patient characteristics include elevated IgG4 serum levels, massive infiltration of lymphocytes - in particular IgG4-positive B and plasma cells - in affected tissues and a good response to immunosuppressive treatment. If left untreated, the chronic inflammation associated with IgG4-RD may lead to fibrosis and organ failure. Here, we discuss diagnostic challenges in two patients who were ultimately diagnosed with IgG4-RD. Additionally, we make suggestions on when to consider a possible diagnosis of IgG4-RD and how to approach the patient, thus enabling early diagnosis and treatment.

Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus during pregnancy in the absence of primary skin lesions, combined with an increase in serum total bile salts and/or abnormal serum liver tests. This article provides an insight into the diagnostic and therapeutic considerations by presenting two cases. ICP usually presents around 34 weeks of gestation, but can be present early in pregnancy as described in a 32-year-old patient pregnant after in-vitro fertilization. DNA analysis showed a mutation in the ABCB4 gene, causing MDR3 deficiency. Ursodeoxycholic acid treatment seems to alleviate maternal pruritus and possibly reduces perinatal risks related to the severe form of ICP, defined as fasted serum bile salt levels of ≥ 40 μmol/l at any point during the pregnancy. Short-term rifampicin treatment can be considered in patients with persistent pruritus. Induction of labour is advised only after 37 weeks of gestation in patients with severe ICP.

The diagnosis IgG4-related disease (IgG4-RD) is often difficult to make. The clinical spectrum is diverse, with a variety of organ systems that may be affected simultaneously or sequentially. Patients often present with symptoms that mimic a malignant disease, for example, symptoms compatible with a pancreatic tumour. The lack of reliable tests often prolongs the diagnostic process. Limited insight into the causative disease mechanisms has confined the therapeutic options to the empirical use of immunosuppression. During the past year, the first papers on the fundamental aspects of the disease have resulted in the emergence of a new disease model for IgG4-RD. Recently published clinical and experimental findings support the hypothesis that antigenic stimulation plays a pivotal role in the aetiology of IgG4-RD. These new insights may pave the way for more sensitive diagnostic tests and more evidence-based strategies to cope with the many manifestations of IgG4-related disease.

Pruritus is a severe symptom in patients with cholestatic hepatobiliary disease; it can greatly reduce the quality of life. Cholestatic itching often peaks in the evening and early night. It mainly occurs on the palms of the hands and soles of the feet but can also occur more generalised. The pathogenesis of cholestatic pruritus has not yet been completely clarified. Possible contributors are bile salts, histamine, progesterone metabolites and opioids. A relationship between these elements and the intensity of the itch has not, however, been demonstrated. Autotaxin, an enzyme that produces lysophosphatidic acid, has recently been identified as a possible pruritogen caused by cholestasis. Treatment is aimed at eliminating pruritogens with bile acid sequestrants (cholestyramine), managing the metabolism of pruritogens (rifampicin), and influencing the perception of itch by the central nervous system with µ-opioid antagonists or SSRIs. In cases of unbearable, treatment-resistant itching, consideration may be given to experimental therapies such as UV light therapy or nasobiliary drainage.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown cause, with genetic predisposition in combination with environmental factors possibly playing a role. The diagnosis is made on the basis of a liver enzyme profile indicating cholestasis and characteristic bile duct abnormalities in cholangiography or the liver biopsy after excluding other causes. Approximately 80% of patients have concurrent inflammatory bowel disease (IBD), specifically ulcerative colitis in most patients. PSC predisposes to hepatobiliary malignancies such as cholangiocarcinoma, gallbladder carcinoma and hepatocellular carcinoma, as well as to colorectal carcinoma in patients with concurrent IBD.- UDCA and endoscopic bile duct dilatation relieve symptoms and improve the liver enzyme profile. Orthotopic liver transplantation is the only potentially curative therapy available.