Impact of higher-order heme degradation products on hepatic function and hemodynamics

Seidel, Raphael A.; Claudel, Thierry; Schleser, Franziska; Ojha, Navin K.; Westerhausen, Matthias; Nietzsche, Sándor; Sponholz, Christoph; Cuperus, Frans J. C.; Coldewey, Sina M.; Heinemann, Stefan H.; Pohnert, Georg; Trauner, Michael; Bauer, Michael

doi:10.1016/j.jhep.2017.03.037

Cited by 17 publications

(45 citation statements)

References 40 publications

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“…Chronic cholangiopathy has been associated with hepatic fibrosis in other clinical settings, whereas more recent data suggest that B T and/or higher‐order heme degradation products might be cytotoxic to certain nonneuronal cells . Two oxidation products (Z‐BOX A and Z‐BOX B) produced during heme degradation are about 20‐fold elevated in serum of both hyperbilirubinemic Gunn rats and humans with cholestasis . In cultured hepatocytes, high concentrations of Z‐BOX A and B differentially modulate two nuclear receptor transcription factors (NR1D1 and NR1D2), deplete cells of reduced glutathione, and activate cytoskeletal remodeling, indicating a potential role in the hepatopathy of CN1.…”

Section: Discussionmentioning

confidence: 99%

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

et al. 2020

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Background and Aims We describe the pathophysiology, treatment, and outcome of Crigler‐Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient‐years. Approach and Results Unbound (“free”) bilirubin (Bf) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT) to albumin (A) and validate their molar concentration ratio (BT/A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT/A at least 30% below intravascular BT binding capacity (i.e., BT/A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (Lf) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to BT (R2 = 0.71) and BT/A (R2 = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin–albumin equilibrium association binding constant (R2 = 0.69), which varied 10‐fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak BT ≥ 30 mg/dL and BT/A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5‐fold. Consistent phototherapy with 33‐103 µW/cm2•nm for 9.2 ± 1.1 hours/day kept BT and BT/A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. Conclusion Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.

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Section: Discussionmentioning

confidence: 99%

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

et al. 2020

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“…(25) Heme degradation products Z-BOX A and B, which are elevated in cholestatic liver injury, show dose-dependent intrahepatic and extrahepatic cytotoxicity. (26) Collectively, impaired hepatobiliary transport and BA signaling contributes to cholestasis and may have widespread implications for control of metabolism, inflammation, gut integrity, and microbiota. Detailed information on pathophysiology of cholestatic dysfunction and impact of serum bile acids is shown in the Supporting Information.…”

Section: Figmentioning

confidence: 99%

Liver Injury and Failure in Critical Illness

et al. 2019

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The frequency of acquired liver injury and failure in critical illness has been significantly increasing over recent decades. Currently, liver injury and failure are observed in up to 20% of patients in intensive care units and are associated with significantly increased morbidity and mortality. Secondary forms of liver injury in critical illness are divided primarily into cholestatic, hypoxic, or mixed forms. Therefore, sufficient knowledge of underlying alterations (e.g., hemodynamic, inflammatory, or drug induced) is key to a better understanding of clinical manifestations, prognostic implications, as well as diagnostic and therapeutic options of acquired liver injury and failure. This review provides a structured approach for the evaluation and treatment of acquired liver injury and failure in critically ill patients.

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“…Both isomers of each group are in an equilibrium and are proven intermediates to BOXes . Those oxidative heme degradation products were quantified in nano‐ to micromolar concentrations with a 20–80 times higher abundance for PDPs compared to BOXes in bile, gallstones and the cerebrospinal fluid of stroke patients . Heme degradation products are involved in vessel constrictions as stroke complication and act as effectors in the liver …”

Section: Introductionmentioning

confidence: 99%

Pyrrolic and Dipyrrolic Chlorophyll Degradation Products in Plants and Herbivores

Ritter

Oetama

Schulze

et al. 2020

Chemistry A European J

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The degradation of chlorophyll,t he omnipresent green pigment, has been investigatedi ntensively over the last 30 years resulting in manye lucidated tetrapyrrolic degradationp roducts. With ac omparison to the degradation of the structurally similarh eme, we hereby propose an ovel additionalc hlorophyll degradation mechanism to mono-and dipyrrolic products.T his is the first proof of the occurrence of af amilyo fm ono-and dipyrrols in leaves that are previously only known as heme degradationp roducts.T his prod-uct familyi sa lso found in spit and feces of herbivores with specific metabolomic patterns reflecting the origin of the samples. Based on chromatographica nd mass spectrometric evidencea swell as on mechanistic considerations we also suggest severalt entative new degradation products.O ne of them,d ihydro BOX A, was fully confirmed as an ovel natural product by synthesis andc omparison of its spectroscopic data.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.org/10. Scheme1.Enzymatic chlorophyll degradation in plants.Scheme2.Enzymatic (top) andoxidativeheme degradation by reactive oxygen species (ROS) to PDPs and BOXes.

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Impact of higher-order heme degradation products on hepatic function and hemodynamics

Cited by 17 publications

References 40 publications

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

Liver Injury and Failure in Critical Illness

Pyrrolic and Dipyrrolic Chlorophyll Degradation Products in Plants and Herbivores

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