Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory bile duct disease leading to fibrotic strictures and beading-like dilatations of the bile ducts.1 The disease might be diagnosed in individuals of all ages; however, the mean age at diagnosis is about 40 years and the incidence is twice as high in men when compared with women. A typical patient is a young male with symptoms or biochemical signs of cholestasis and a history of ulcerative colitis.2 Moreover, 60% to 80% of PSC patients also have inflammatory bowel disease, mainly ulcerative colitis, and although the exact link between both diseases is not completely understood, this striking association is the paradigm of the concept of the gut-liver axis. The course of the disease is highly variable, with more or less pronounced symptoms of cholestasis (jaundice, pruritus), and recurrent episodes of septic cholangitis. Another burden for the patients is the significantly increased risk of cholangiocarcinoma (about 1% per year),2 which are frequently diagnosed in an advanced inoperable stage, and of colorectal carcinoma. With an incidence around 1 / 100 000 / year and a prevalence around 10 / 100 000 in central Europe,3,4 PSC is a rare disease. However, due to lack of effective medical or interventional therapies, it is one of the leading indications for liver transplantation in northern and central Europe, and given frequent hospital admissions of young patients, this disease represents a significant healthcare burden, nonetheless.

Without exaggeration, PSC can still be seen as one of the most enigmatic and challenging diseases in hepatology today5: the etiopathogenesis is only fragmentarily elucidated and is obviously complex as well as multifactorial, involving genetic susceptibility, immune dysregulation of the gut-liver axis and bile ducts but also disturbed biliary homeostasis. Thus, a causal and effective medical therapy is not available. The rarity of the disease as well as its slow course limit the feasibility of clinical trials to evaluate new therapeutic strategies.

In this issue of Polish Archives of Internal Medicine (Pol Arch Intern Med), Wronka et al6 draw our attention to another, less investigated, aspect of the complex pathogenetic mechanisms of PSC. The authors investigated the role of impaired liver sulfation capacity in the development and clinical course of PSC in a large cohort of 233 patients with PSC from Warsaw and Szczecin, Poland. Primary sclerosing cholangitis, together with primary biliary cholangitis, secondary sclerosing cholangitis, and IgG4-associated cholangitis, are all fibrosing cholangiopathies.7,8 According to the so-called toxic bile hypothesis, the accumulation of certain bile acids, due to impaired biliary excretion but also due to disturbed enterohepatic recirculation and dysregulated protective mechanisms against toxic bile components, plays a crucial role in cholestatic liver injury. Although these mechanisms are not the primary trigger of cholangiopathy, they may promote disease progression through initiating or maintaining a chemokine and cytokine response. During enterohepatic recirculation, bile acids that were reabsorbed in the ileum undergo intrahepatic conjugation by hydroxylation, glucuronidation, or sulfation reactions. There is some evidence that genetic variants of the glucuronidation enzyme, UDP-glucuronosyltransferases 1A,9 are associated with the clinical phenotype and the disease course of PSC and that the expression of the hepatoprotective sulfation enzyme, sulfotransferase 2A1, is impaired in PSC.10 In the present study, Wronka et al6 compared the sulfation capacity of noncirrhotic patients with PSC with a control cohort of patients with other noncirrhotic liver diseases and with healthy controls. They analyzed the serum concentration of dehydroepiandrosterone sulfate (DHEA-S) as a surrogate parameter for sulfation capacity since this endogenous steroid hormone is mainly metabolized by hepatic sulfotransferase 2A1. They found decreased DHEA-S levels (adjusted for gender and age) in 21% of patients with PSC as compared with 3% of diseased controls and 2% of healthy individuals and reported that decreased DHEA-S levels were associated with younger age, female gender, and lower serum albumin. Since patients with PSC were more frequently male (69% vs 58%) and since they were younger (mean age, 32 years vs 47 years) than controls, a multivariable analysis to exclude a possible bias of age and gender would have been recommendable. Furthermore, patients with PSC with low DHEA-S reported significantly lower health-related quality of life scores and more severe fatigue. Those findings confirm previous evidence10 that hepatic sulfation capacity is specifically impaired in PSC. Although based on the findings of the study, it is not possible to differentiate whether lack of sulfation of toxic metabolites might be the cause of reported symptoms or if lower levels of DHEA-S are directly associated with fatigue.

Nonetheless, the study represents an important contribution both to our knowledge about the complex pathogenesis of PSC and the development of future therapeutic strategies. With the current6 and previous studies,9,10 evidence is accumulating that conjugation mechanisms are involved in the disturbed bile acid homeostasis and could modify disease progression of patients with PSC. There is little doubt that immune mechanisms are the primary trigger of PSC. Nevertheless, this initial “first hit” is usually asymptomatic and therefore unnoticed, so that a therapeutic intervention is almost impossible. Therefore, almost all studies that investigated immunosuppressive or immunomodulatory11 approaches for treatment of PSC were not able to prove effectiveness of these therapeutic strategies.12 On the other hand, the most promising therapeutic approaches are based on the modification of the composition and homeostasis of bile. Although controversial, ursodeoxycholic acid has been used for decades in the treatment of PSC and a large part of new drugs that are currently under investigation for PSC are targeting the regulation and modification of bile acid metabolism.13,14 Future analyses should investigate the extent to which the subgroup of patients with PSC with decreased sulfation capacity might show a different response to these new therapeutic approaches. The supplementation of DHEA is currently discussed rather uncritically as a miracle cure for a number of diseases, especially in the popular press. Fatigue is a severe health burden for a significant part of patients with PSC. However, the observed association of low DHEA-S levels with fatigue is certainly not sufficient for a specific recommendation. Whether patients with PSC and low levels of DHEA-S will benefit from supplementation can only be answered by a randomized controlled trial.