Significance of Serum Delta-Bilirubin in Patients with Obstructive Jaundice

Kozaki, Naoto; Shimizu, Shuji; Higashijima, Hidetaka; Kuroki, Shin-Ichiro; Yamashita, Hiroyuki; Yamaguchi, Koji; Chijiiwa, Kazuo; Tanaka, Masao

doi:10.1006/jsre.1998.5357

Cited by 14 publications

(8 citation statements)

References 22 publications

(29 reference statements)

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“…Several lines of evidence support this contention: the predominance of "white bile" in the obstructed biliary tree of IL-6 ϩ/ϩ mice and "black bile" in the IL-6 Ϫ/Ϫ mice, 29 higher serum TB and delta fraction in the IL-6 Ϫ/Ϫ mice, 28 and the ability of exogenous rhIL-6 to quickly lower the serum bilirubin in the IL-6 Ϫ/Ϫ mice. Previous studies have shown that "white bile" is a result of total obstruction of an intact biliary tree.…”

Section: Discussionmentioning

confidence: 94%

“…28 Both the absolute level of delta bilirubin (1.4 Ϯ 0.3 versus 3.9 Ϯ 1.2 mg/dl; P Ͻ 0.0007) and the ratio of delta bilirubin to total bilirubin (9.2 Ϯ 1.8% versus 16.7 Ϯ 4.0%; P Ͻ 0.002) were higher in the IL-6 Ϫ/Ϫ mice at 12 weeks. This indicates that more conjugated bilirubin was in contact with blood for a longer period of time in the IL-6 Ϫ/Ϫ mice, which, in conjunction with the gross appearance of the bile (below), is suggestive of impaired biliary tree integrity in this group.…”

Section: Morbidity Liver Injury Tests Mortality and Bile Colormentioning

confidence: 90%

“…Delta bilirubin is a measure of conjugated bilirubin covalently bound to albumin 28 and is 1) proportional to the length of time conjugated bilirubin is in contact with Figure 1. Measures of morbidity, liver injury, and function and mortality after bile duct ligation (BDL).…”

Section: Morbidity Liver Injury Tests Mortality and Bile Colormentioning

confidence: 99%

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The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Ezure

Sakamoto

Tsuji

et al. 2000

The American Journal of Pathology

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In an effort to understand the role of IL-6/gp130 signaling in chronic liver injury, IL-6 deficient (IL-6 ؊/؊ ) and wild-type control (IL-6 ؉/؉ ) mice were subjected to bile duct ligation (BDL) for 12 weeks. This maneuver causes chronic biomechanical stress and liver injury, fueling sustained biliary epithelial and hepatocyte proliferation. By 12 weeks after BDL, IL-6 ؊/؊ mice develop significantly higher total serum bilirubin levels (23.2 ؎ 2.3 versus 14.9 ؎ 2.1 mg/dl, P < 0.0001; delta bilirubin subfraction 16.7 ؎ 4.0% versus 9.2 ؎ 1.8%; P < 0.002), and the majority (15/18) show "black" gallbladder bile, compared to IL-6 ؉/؉ mice (5/16; P < 0.003). The IL-6 ؊/؊ mice also cannot sustain the compensatory liver mass increase commonly seen with chronic obstructive cholangiopathy, because of less hepatocyte proliferation, despite a rate of hepatocyte apoptosis similar to that of IL-6 ؉/؉ mice. Moreover, IL-6 ؊/؊ mice show a more advanced stage of biliary fibrosis and a higher mortality rate than the IL-6 ؉/؉ controls (51% versus 23%; P < 0.02). These phenotypic changes in the IL-6 ؊/؊ mice are associated with decreased expression and phosphorylation of gp130 and the transcription factor STAT3, compared to IL-6 ؉/؉ mice. Daily treatment with exogenous recombinant IL-6 for 3-6 weeks starting at 6 weeks after BDL significantly lowers the serum total bilirubin in both groups. In the IL-6 ؊/؊ mice, exogenous IL-6 treatment also increases the level of gp130 protein expression and completely reverses the loss of liver mass by increasing the hepatocyte proliferation. In conclusion, IL-6 appears to contribute to biliary tree integrity and maintenance of hepatocyte mass during chronic injury. Interleukin-6 (IL-6)/gp-130 signaling is involved acutely in hepatocyte 1,2 and biliary epithelial cell (BEC) growth control and pathobiology. For example, liver regeneration after partial hepatectomy (PH) is delayed in IL-6 Ϫ/Ϫ mice, 1,2 whereas IL-6/sIL-6R double transgenic mice develop hepatocellular hyperplasia and adenomas. 3 Although data on the in vitro effects of IL-6 on hepatocyte proliferation are conflicting, 4,5 there are at least two mechanisms by which IL-6/gp-130 promotes BEC growth in vitro. IL-6 is able to directly stimulate BEC DNA synthesis 6 and inhibit apoptosis, via an increase of the bcl-2/ bax ratio. 7 When stimulated by other proinflammatory cytokines or phorbol esters, nonneoplastic BEC can also produce and secrete IL-6, which can then act as an autocrine growth factor under conditions of BEC stress. 6,8,9 Serum and liver IL-6 levels are also elevated in patients with chronic inflammatory liver diseases. 10 -13 In this setting, IL-6 has traditionally been considered to exert a profibrogenic and mitoinhibitory influence on the development of cirrhosis. 10,14 -17 However, in other "chronic inflammatory proliferative disorders," such as psoriasis and rheumatoid arthritis, IL-6 has been linked with keratinocyte and synovial cell proliferation, respectively. 18 In addition, recent studies have shown that gp130 sign...

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Section: Discussionmentioning

confidence: 94%

Section: Morbidity Liver Injury Tests Mortality and Bile Colormentioning

confidence: 90%

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The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Ezure

Sakamoto

Tsuji

et al. 2000

The American Journal of Pathology

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“…In isolated genetic hyperbilirubinemias, few – if any – other organic metabolites are elevated. In contrast, several other metabolites are elevated in addition to bilirubin in cholestasis, many of which may alter the equilibrium between bilirubin and albumin (Alemi et al, 2013; Jacobsen and Brodersen, 1983; Kalir et al, 1990; Kozaki et al, 1998). Moreover, bilirubin’s affinity for albumin and other lipoproteins is disrupted by numerous agents in bile that are upregulated specifically in cholestasis.…”

Section: Discussionmentioning

confidence: 99%

Identification of a bilirubin receptor that may mediate a component of cholestatic itch

Meixiong

Vasavda

Green

et al. 2019

eLife

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Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.

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“…Kovalent bağ ile irreversibl bağlı bulunduğu albüminin yarı ömrünün uzunluğuna bağlı olarak, delta-bilirubinemide kanda uzun süre direkt bilirubin düzeyi yüksek ölçülürken idrarla atılmaması sonucu idrar incelemesinde bilirubinin negatif saptanır. [2] Kaşıntı kolestatik karaciğer hastalıklarının ortak bir semptomudur. Kolestazda meydana gelen kaşıntının nedeni olarak önceleri artmış safra asitleri sorumlu tutulurken son yıllarda özellikle ototaksin enziminin rolü üzerinde durulmaktadır.…”

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Delta-Bilirubinemia and Persistent Itching in a Child Patient with Hepatitis A Infection

Emiroğlu¹,

Emiroğlu²

2020

Journal of Contemporary Medicine

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Significance of Serum Delta-Bilirubin in Patients with Obstructive Jaundice

Cited by 14 publications

References 22 publications

The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Identification of a bilirubin receptor that may mediate a component of cholestatic itch

Delta-Bilirubinemia and Persistent Itching in a Child Patient with Hepatitis A Infection

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