Intrahepatic cholestasis of pregnancy — A heterogeneous group of pregnancy-related disorders?
Authors: Ulrich Beuers, Thomas Pusl
Journal: Hepatology (2006)

Physicians, confronted with signs and symptoms of newly developing liver disease in pregnant women, should be careful not to overlook one of several pregnancy-related liver disorders. These may start mildly, but could end in a catastrophe for mother or child. Intrahepatic cholestasis of pregnancy (ICP) is the most frequent of the pregnancy-related liver diseases.1 ICP was responsible for 21% of cases of jaundice evolving during pregnancy in a series from Switzerland in which viral hepatitis (42%) and bile duct obstruction by gallstones (6%) represented the major causes of jaundice not specific to pregnancy.2 ICP increases the risk of preterm delivery (19%-60%), fetal distress (22%-41%)3-7 and fetal loss (0.4%-1.6%),3-8 particularly when associated with fasting serum bile acid levels >40 μmol/L.8 ICP is observed in <0.2% of pregnancies in most areas of Central and Western Europe and North America. In contrast, Chile and Bolivia as well as Scandinavia and the Baltic states are regarded as "hot spots" for ICP: roughly 5%-15% and 1%-2%, respectively, of pregnancies are associated with ICP in these areas.1 ICP, intrahepatic cholestasis of pregnancy; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. ICP is characterized by (1) pruritus of cholestasis, (2) elevated fasting serum bile acids >10 μmol/L (and elevated serum transaminases), and (3) spontaneous relief of signs and symptoms within 2 to 3 weeks after delivery. These criteria are indispensable to make a diagnosis of ICP. A number of other liver disorders may erroneously be interpreted as ICP during pregnancy under the high systemic and hepatic load of estrogens and gestagens. In particular, patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hepatitis C, or drug-induced hepatitis may develop pruritus independently of pregnancy, and the hormone load in the second half of pregnancy may enhance the risk to develop pruritus for some of these patients. Thus, complete disappearance of pruritus and of biochemical signs of liver disease after delivery appears crucial for the diagnosis of ICP. In this issue of the journal, Ropponen et al. report the largest retrospective population-based cohort study in ICP (n = 10,504, identical number of controls matched for age, site and time of delivery). The aim of the study was to assess the occurrence of liver, biliary and pancreatic diseases in women from Finland with a history of ICP for the years 1972-2000.9 The results of the study confirm previous observations and suggest a higher incidence of (1) gallstone formation and cholecystitis (rate ratio 3.7), (2) non-alcoholic pancreatitis (3.2), (3) hepatitis C (3.5), (4) non-alcoholic liver cirrhosis (8.2), (5) miscellaneous liver disorders (6.1), and (6) biliary system disorders (2.9) in women with a history of ICP. These findings deserve some comments. 1. An association of ICP and gallstone disease was expected and both, at least to some extent, have a common genetic background. Mutations in the hepatocellular phospholipid transporter, ABCB4 (MDR3), that flips the major human phospholipid, phosphatidylcholine (lecithine), from the inner to the outer leaflet of the canalicular membrane, and, thereby, mediates its secretion into bile, have been estimated to account for up to 15% of all ICP cases.10-12 ABCB4 (MDR3) gene mutations also represent a major genetic risk factor in a symptomatic and recurring form of cholesterol gallstone disease in young adults, the LPAC syndrome (LPAC, low phospholipid-associated cholelithiasis).13 One single gene defect of ABCB4 (MDR3) has been associated with both early gallstone disease and ICP.14 In two Finnish ICP families with dominant inheritance, however, molecular genetic analysis did not support either an involvement of ABCB4 (MDR3) nor that of other major ABC transporters of liver cells, the bile salt export pump, ABCB11 (BSEP), and the aminophospholipid transporter, ATP8B1 (FIC1), in the pathogenesis of ICP.15 It remains to be shown which genetic factors in addition to ABCB4 (MDR3) gene mutations may contribute to an enhanced risk for both, ICP and cholelithiasis. 2. A higher incidence of non-alcoholic pancreatitis in ICP patients may be expected as gallstones are the major risk factor of non-alcoholic pancreatitis. It deserves to be studied in future analyses whether additional genetic factors like mutations in genes of the aminophospholipid transporter, ATP8B1 (FIC1), or the cystic fibrosis transmembrane conductance regulator, ABCC7 (CFTR), which are associated both with cholestatic syndromes and chronic pancreatitis, may contribute to an ICP-like disorder in single cases. 3. The present study showed that hepatitis C infection was more often observed in patients with a history of ICP than in controls (rate ratio: 3.5) confirming previous findings.16 However, HCV testing in contrast to HAV and HBV testing was not available in the 1970s and early 1980s when a considerable part of data of this retrospective analysis were collected. It can not be excluded that signs (elevated serum bile acids and serum transaminases) and symptoms (pruritus) suggestive of ICP mirrored hepatitis C under high loads of estrogens and gestagens. The function of major hepatocellular ABC transporters like the bile salt export pump, ABCB11 (BSEP), or the phospholipid translocator, ABCB4 (MDR3), has been shown to be impaired at the posttranscriptional level in vitro by high loads of estrogen glucuronides17, 18 and progesterone,19 respectively. Basolateral as well as canalicular bile acid transporter expression of the liver cell have also been shown to be impaired by estrogens in vitro at the transcriptional level. Interestingly, the conjugate export pump, ABCC2 (MRP2), a key transport protein for biliary elimination of endo- and xenobiotics, is sensitive at the transcriptional level to numerous stimuli including cytokines.20 Significant reduction of ABCC2 (MRP2) expression to <30 % in the virus-infected liver was shown.21 Thus, hormone- and cytokine-induced reduction of expression and function of the principal sinusoidal or canalicular bile acid transporters in late pregnancy could result in the development of symptomatic cholestasis in a previously asymptomatic pregnant woman with hepatitis C. 4-6. Non-alcoholic cirrhosis as well as miscellaneous liver disorders and biliary system disorders were reported at markedly higher rates (but comparably small numbers of cases) in women with a putative history of ICP. This finding is worrisome at first glance, but may be questioned at a closer look. In this retrospective analysis, a diagnosis of ICP was accepted when the diagnosis code of the Finnish national register indicated hepatosis gravidarum, icterus gravis gravidarum, or necrosis acuta et subacuta hepatis gravidarum between 1972 and 1986, hepatosis gravidarum or hepatopathia allia gravidarum between 1987 and 1995, and ICP between 1996 and 2000. Thus, diagnostic criteria of ICP, as previously mentioned, were probably not applied. Also, the data analysis did not provide any information about exclusion of chronic liver diseases associated with pruritus like PBC, PSC, or hepatitis C, when the diagnosis of ICP was made. Thus, misdiagnosis of ICP in patients with asymptomatic chronic liver diseases who developed pruritus during pregnancy may have contributed to the high rate of cirrhosis during follow-up in the present study as admitted by the authors—although genetic factors may explain subsequent occurrence of ICP and adult cirrhosis in single cases.22 The reader is left with some uncertainty about which percentage of ICP patients in this retrospective analysis represent "true ICP" as defined today. It has long been speculated that not only genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP.1 The seasonal variation, the incomplete recurrence (<70%) at subsequent pregnancies, as well as the decrease in the prevalence of ICP in "hot spots" like Chile in association with improved nutritional supply had led experts in the field like Dr. Reyes and coworkers from Chile to speculate on nutritional factors like selenium deficiency as pathophysiologic cofactors for ICP.23 In the present issue of the journal, Reyes et al. address a pathophysiological factor which had so far escaped the attention of hepatologists.24 Enhanced intestinal permeability and endotoxemia are discussed as pathogenetic factors for the development of liver disease when associated with Crohn's disease, ulcerative colitis, celiac disease, or intestinal infections25 and have also been observed in advanced cirrhosis with portal hypertension. The current study investigated the frequency of a "leaky gut" in patients with ICP in comparison to healthy pregnant and non-pregnant women. Gastroduodenal permeability was assessed by measurement of urinary excretion of sucrose and intestinal permeability by measurement of urinary lactulose and mannitol after their oral administration. Urinary lactulose/mannitol ratio was significantly higher in ICP than in pregnant and non-pregnant controls, and a "leaky gut" was identified in 5/20 ICP patients. No differences were found in anti-LPS or cytokine plasma levels between ICP patients and controls. The pathophysiological background of these findings is unclear, but the findings may reflect a genetic factor affecting both intestinal and hepatic function in a subgroup of patients with ICP. A potential cause-and-effect relationship between a "leaky gut" and ICP remains open to debate. It should, however, be noted that liver histology in ICP, in contrast to cytokine-induced liver injury, is typically characterized by lack of (or minimal) inflammatory changes. Could cytokines be the missing link between "leaky gut" and ICP? Certainly, the findings need to be confirmed in a second larger group of ICP patients before firm conclusions can be drawn, but Reyes and colleagues have again challenged the community to reconsider theoretical concepts of the pathogenesis and treatment of ICP. The presence of additional genetic and environmental factors contributing to ICP further challenges studies attempting to unravel the molecular mechanisms leading to hepatocyte secretory failure under a high hepatic hormone load. They also may assist in the development of more effective therapeutic strategies than those currently available.26 The studies by Ropponen et al. and Reyes et al. support the notion that ICP represents a pregnancy-related cholestatic syndrome with a heterogeneous pathogenetic background.