Sulfated progesterone metabolites in the pathogenesis of intrahepatic cholestasis of pregnancy: Another loop in the ascending spiral of medical knowledge
Authors: Humberto Reyes
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article on Page 1287 Progress in medical knowledge can be represented by an ascending spiral in which every loop stands over previous data, adds new findings that deepen our understanding of a disease, and helps to design further research and therapeutic strategies. New loops are frequently inspired by novel approaches to accepted hypotheses and usually supported by the use of more advanced technologies, as seems to be the case in the article by Abu‐Hayyeh et al.1 Intrahepatic cholestasis of pregnancy (ICP), a frequent liver disorder of pregnancy, implies an unpredictable risk of fetal distress, with premature deliveries and stillbirths. Its pathogenesis has been linked to effects of sex hormones during pregnancy, and in recent decades successive reports have revealed a role for progesterone derivatives. In this regard, the spiral started in 1970 when Sjövall and Sjövall reported increased sulfated metabolites of progesterone in serum and urine of Swedish patients with ICP, in contrast to normal pregnancies.2 Furthermore, this biochemical peculiarity was identified in two patients during an early stage of pregnancy, before the onset of pruritus and abnormalities in serum liver tests, suggesting that it could have predicted the development of ICP. In 1979, Giusti et al. reported that an increase in sulfated progesterone metabolites in plasma from Italian patients with ICP did not occur in patients with viral hepatitis in pregnancy, giving further support to its specificity in ICP.3 In the 1990s, a series of reports centered in Sjövall's laboratory, in Stockholm, Sweden, using now more sophisticated and precise techniques applied to serum and urine from Chilean patients with ICP and their controls, clarified that a distinctive biochemical feature in ICP was the switch of progesterone metabolism toward a four‐fold to 10‐fold increase in serum and urine concentration of sulfated metabolites, with an increased ratio of 3α‐hydroxysteroid sulfates to 3β‐hydroxysteroid sulfates, changes that were reversed after treatment with ursodeoxycholic acid.4 Among other important steps in this research line, Glantz et al., in Sweden, reported similar changes in the pattern of progesterone metabolites in urine of ICP patients, with a reversal after ursodeoxycholic acid administration, correlating with an improvement in maternal pruritus5; and Abu‐Hayyeh et al. also reported increased levels of progesterone sulfates in ICP patients studied in the United Kingdom.6 Therefore, this metabolic pattern has been detected in ICP patients from different geographic locations and ethnic origins. The present study1 identified three sulfated progesterone metabolites, 5α‐pregnan‐3α,‐20α‐diol‐3,20‐disulfate, 5β‐pregnan‐3α‐20α‐diol‐3‐sulfate, and 5β‐pregnan‐3α‐20α‐diol‐3,20‐disulfate, that were present in ICP patients in serum samples obtained even at 9‐15 weeks of gestation, before the onset of pruritus, and that increased during pregnancy and rapidly decreased after delivery. Adding an experimental study in mice, 5β‐pregnan‐3α‐20α‐diol‐3‐sulfate and autotaxin activity appeared as a combined pruritogen. The authors propose that these sulfated progesterone metabolites participate in the pathogenesis of ICP, may predict the onset of the disease, and are involved in the pathogenesis of maternal pruritus. One key question is whether these characteristics in molecular structures retained in blood depend only or mainly upon the maternal liver. Progesterone metabolism occurs both in the liver and in extrahepatic sites: it has been estimated that half of the daily synthesis of progesterone may occur outside of the maternal liver.4 Maternal ovaries and adrenals, the placenta, the fetus, the intestinal microflora, and the enterohepatic circulation of hormone metabolites should also be considered.7 In 2008, Marin et al. provided a stimulating review of studies in humans and in rodents, exploring the roles of the fetal liver, the placenta, and the maternal liver in the metabolism of cholephilic compounds8; but a specific approach to progesterone metabolism in pregnant women and in patients with ICP, considering the maternal liver and extrahepatic sites, is still needed. Another relevant question is whether the pattern of progesterone metabolites described in patients with ICP has a genetic background, which would imply an etiologic role in this disease. A single causal role for a constitutional metabolic abnormality would be difficult to sustain in multiparous women who develop ICP in pregnancies preceded or followed by pregnancies without ICP. Furthermore, it would not help to explain the seasonal variations in the prevalence of ICP and why this prevalence has changed so strikingly in only a few decades, as observed in Chile. An important observation in the present study is that the distinctive pattern of serum progesterone metabolites was not found in pregnant women who developed skin pruritus similar to ICP but did not show increased serum levels of total bile salts, considered a hallmark for the diagnosis of ICP. Patients with these characteristics have been identified in several studies, being usually labeled as having pruritus gravidarum (PG), an enigmatic entity that does not carry the fetal risks of a genuine ICP.5 Table 1 summarizes clinical and biochemical data previously reported in patients with ICP and in normal pregnancies,7 comparing them with a concurrent unreported cohort of patients with PG in whom pruritus appeared at the same gestational age but was slightly less severe than in patients with ICP. In three of these patients with PG, pruritus diminished spontaneously 1 week prior to delivery; and in another patient, pruritus disappeared in the final week of pregnancy, a phenomenon that was not observed in patients with a genuine ICP. We do not know whether PG is a mild form of ICP or conceals a different morbid entity. The pathogenesis of pruritus in PG seems to be unrelated to combined effects of 5β‐pregnan‐3α‐20α‐diol‐3‐sulfate and autotaxin activity. Table 1 - Data in Patients With ICP or PG and in Normal Pregnancies ICP PGa Normal Pregnancy (n = 21) (n = 13) (n = 29) Onset of pruritus (week) 30 ± 4 31 ± 5 — Pruritus score, median (range) 3.7 (3‐4) 3.0 (2‐4) — ALT (IU/L, mean ± SD) 100 ± 127b 12 ± 4 13 ± 5 AST (IU/L) 85 ± 126b 18 ± 5 20 ± 5 Bile salts (μmol/L) 36.0 ± 32.8b 5.1 ± 3.0 6.7 ± 3.6 Bilirubin (mg/dL) 0.9 ± 0.3 0.5 ± 0.1 0.4 ± 0.1 Alkaline phosphatases (U/L) 825 ± 380b 365 ± 103 385 ± 142 GGT (U/L) 47 ± 36b 12 ± 5 15 ± 7 Cholesterol (mg/dL) 310 ± 64b 237 ± 50 265 ± 66 Triglycerides (mg/dL) 348 ± 92b 212 ± 28 248 ± 63 Main data taken from Reyes et al.7aPreviously unpublished data.bP < 0.05 compared to PG and normal pregnancy.Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltranspeptidase; SD, standard deviation. In clinical practice it would be desirable to have a test that could predict the development of ICP at an early stage of pregnancy, being unequivocally positive before the onset of pruritus and serum abnormalities. This test should then be performed routinely in the first trimester of pregnancy in multiparous women with a history of ICP in previous pregnancies, mainly if they have had a severe ICP (e.g., early onset in pregnancy, high serum total bile salts, hyperbilirubinemia, spontaneous premature delivery, or stillbirth). The test should also be applied to pregnant women with a family history of ICP. A positive result would identify a high‐risk pregnancy requiring special obstetric care. But such a test should be adaptable to clinical laboratories, should use standardized techniques, and should be available at reasonable cost. The current data open a promising road to this expectation, provided that they fulfill the classical reproducibility in new studies extended to different populations and a simplification of chemical techniques. Nevertheless, this meritorious group of multinational investigators has provided a new loop in the ascending spiral of medical knowledge. Author names in bold designate shared co‐first authorship.