RESUMEN
This is the case of a 25-year-old patient, with the notion of unprotected sexual relations with multiple partners consulted for cholestatic icterus with pruritus evolving for 2 months. The general examination found an intense mucocutaneous icterus. The examination of the lymph nodes revealed multiple lymph nodes. A thoracic-abdominal-pelvic scanner showed peri-portal edema and adenopathies above and below the diaphragm without suspicious lesions. Biologically, there was acute cytolysis with ASAT at 1612IU/L, ALAT at 1506IU/L, and icteric cholestasis, the acute viral serologies and other autoantibodies were all negative. Given the presence of adenopathy and sexual risk factors, a syphilis serology was requested and was positive: a TPHA at 2560UI/L, and a VDRL at 1/32 UI/L. A liver biopsy was performed, which showed the presence, on immunohistochemistry, of anti-treponemal-pallidum antibodies. After eliminating all etiologies of cytolytic hepatitis, we retained the diagnosis of syphilitic hepatitis. Therapeutically, we started a treatment based on ceftriaxone 2g/dl with spectacular biological improvement at H48 of the beginning of treatment.
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Antibacterianos , Hepatitis , Sífilis , Humanos , Adulto , Sífilis/diagnóstico , Sífilis/complicaciones , Masculino , Hepatitis/etiología , Hepatitis/diagnóstico , Hepatitis/microbiología , Antibacterianos/administración & dosificación , Enfermedad Aguda , Ceftriaxona/administración & dosificación , Biopsia , Colestasis/etiología , Colestasis/diagnósticoRESUMEN
Human adenovirus (HAdV) type F41 has been identified as a possible cause of the non-A-to-E hepatitis outbreak. This study uses wastewater monitoring to track HAdV F40 and F41, supporting clinical investigations and providing insights into the pathogen's role in the outbreak. Given the limited clinical monitoring in Sweden of HAdV-F40/41, this approach also helps estimate the true infection burden of this pathogen during the outbreak. This study developed three qPCR assays for the hexon, penton, and fiber genes of HAdV F40 and F41. The hexon assay was F41-specific, while the fiber assay detected multiple HAdV-F strains. Comprehensive monitoring of HAdV-F40/41 levels in Stockholm's wastewater was conducted over 1.5 years, capturing the period before, during, and after the outbreak. A significant infection wave was observed in spring 2022, with strains beyond lineage 2 contributing to the outbreak. Moreover, simultaneous SARS-CoV-2 surveillance revealed that HAdV-F infections peaked at different times from COVID-19, but the HAdV-F wave aligned with the relaxation of pandemic restrictions. These findings offer valuable insights for future HAdV-F investigations and confirm its role in the non-A-to-E hepatitis outbreak.
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Adenovirus Humanos , Brotes de Enfermedades , Aguas Residuales , Suecia/epidemiología , Adenovirus Humanos/genética , Adenovirus Humanos/aislamiento & purificación , Humanos , Aguas Residuales/virología , Hepatitis/epidemiología , Hepatitis/virología , Infecciones por Adenovirus Humanos/epidemiología , Infecciones por Adenovirus Humanos/virología , SARS-CoV-2/genéticaRESUMEN
The paper presents an approach for overcoming modeling problems of typical life science applications with partly unknown mechanisms and lacking quantitative data: A model family of reaction-diffusion equations is built up on a mesoscopic scale and uses classes of feasible functions for reaction and taxis terms. The classes are found by translating biological knowledge into mathematical conditions and the analysis of the models further constrains the classes. Numerical simulations allow comparing single models out of the model family with available qualitative information on the solutions from observations. The method provides insight into a hierarchical order of the mechanisms. The method is applied to the clinics for liver inflammation such as metabolic dysfunction-associated steatohepatitis or viral hepatitis where reasons for the chronification of disease are still unclear and time- and space-dependent data is unavailable.
Asunto(s)
Simulación por Computador , Modelos Biológicos , Humanos , Hígado Graso , Inflamación/inmunología , Conceptos Matemáticos , Hepatitis Viral Humana , HepatitisRESUMEN
BACKGROUND: Spermine oxidase (SMOX), an inducible enzyme involved in the catabolic pathway of polyamine, was found to be upregulated in hepatocellular carcinoma and might be an important oncogene of it in our previous studies. This study attempted to further investigate its relationship with liver inflammation and fibrosis both in vitro and in vivo. METHODS: The effect of SMOX inhibition on LPS-induced inflammatory response in mouse liver cell line AML12 was validated by using small interfering RNA or SMOX inhibitor MDL72527. Western blotting and immunofluorescence were utilized to verify whether LPS could induce ß-catenin to transfer into the nucleus and whether it could be reversed by interfering with the expression of SMOX or using SMOX inhibitor. Then, the SMOX inhibitor MDL72527 and SMOX knockout mice were used to verify the hypothesis above in vivo. RESULTS: The expression of SMOX could be induced by LPS in AML12 cells. The inhibition of SMOX could inhibit LPS-induced inflammatory response in AML12 cells. LPS could induce ß-catenin transfer from cytoplasm to nucleus, while SMOX downregulation or inhibition could partially reverse this process. In vivo intervention with SMOX inhibitor MDL72527 or SMOX knockout mice could significantly improve the damage of liver function, reduce intrahepatic inflammation, inhibit the nuclear transfer of ß-catenin in liver tissue, and alleviate carbon tetrachloride-induced liver fibrosis in mice. CONCLUSION: SMOX can promote the inflammatory response and fibrosis of hepatocytes. It provides a new therapeutic strategy for hepatitis and liver fibrosis, inhibiting early liver cancer.
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Cirrosis Hepática , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH , Poliamino Oxidasa , beta Catenina , Animales , Masculino , Ratones , beta Catenina/metabolismo , Hepatitis/etiología , Hepatitis/metabolismo , Lipopolisacáridos , Cirrosis Hepática/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Putrescina/análogos & derivados , Transducción de SeñalRESUMEN
BACKGROUND: Immune-related hepatitis (irHepatitis) is a relatively common immune-related adverse event (irAE) of checkpoint inhibitors. Often, it responds well to steroids; however, in refractory cases, further therapy is needed. Anti-tumor necrosis factor (TNF) antibodies are used for management of multiple irAEs, but there are little data in irHepatitis. Here, we report on safety and efficacy of infliximab in 10 cases of steroid-refractory irHepatitis. METHODS: We retrospectively reviewed patients treated with infliximab for steroid-refractory grade ≥3 irHepatitis at the Department of Dermatology, University Hospital Zurich. The positive response to infliximab was defined as no further increase in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) above 50% than at the time of first infliximab infusion and control of irHepatitis without therapies other than steroids and infliximab. RESULTS: 10 patients with steroid-resistant irHepatitis grade ≥3 were treated with infliximab 5 mg/kg, of whom 7 (70%) responded positively. In two cases, the liver values increased over 50% before the irHepatitis could be controlled. In another case, therapies other than infliximab and steroids were given. At the median follow-up of 487 days, 90% of the patients demonstrated resolved irHepatitis without AST/ALT elevation following infliximab infusions. CONCLUSIONS: Treatment of irHepatitis with infliximab did not result in hepatotoxicity and led to long-lasting positive response in 9 of 10 of the cases. Further research is needed to evaluate the role of anti-TNF antibodies in management of irHepatitis.
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Infliximab , Esteroides , Humanos , Infliximab/uso terapéutico , Infliximab/efectos adversos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Esteroides/uso terapéutico , Hepatitis/tratamiento farmacológico , Hepatitis/etiología , Adulto , Enfermedad Hepática Inducida por Sustancias y Drogas/etiologíaAsunto(s)
Dengue , Hepatitis E , Hepatitis , Coronavirus del Síndrome Respiratorio de Oriente Medio , CóleraRESUMEN
OBJECTIVE: To evaluate the efficacy of rituximab (RTX)-containing therapy as first-line as well as rescue treatment for giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA). METHODS: This retrospective study recruited patients diagnosed with GCH-AHA and treated with conventional immunosuppressor regimens consisting of prednisone or RTX-containing regimes consisting of RTX and prednisone, with or without another immunosuppressor. The primary outcomes were the complete remission (CR) rate and time-period required for CR. The secondary outcomes included relapses and adverse events. RESULTS: Twenty patients (8 females and 12 males; age range 1-26 months), 15 receiving conventional regimens and 5 receiving RTX-containing regimens, were included. The CR rates were 73.3 % (11/15) and 100 % (5/5) in the conventional and RTX-containing groups, respectively. The time-period required for CR was significantly shorter in the RTX-containing group than in the conventional group (6 (3-8) versus 14 (5-25) months, P = 0.015). Relapses occurred in 30.8 % (4/13) of patients in the conventional group; all achieved CR after adding RTX. Relapses occurred in 40.0 % (2/5) of patients in the RTX-containing group; both achieved CR after adding intravenous immune globulins or tacrolimus. Transient low immunoglobulin and infections were recorded in both groups. Treatment withdrawal was achieved in 73.3 % (11/15) and 60.0 % (3/5) of patients receiving conventional and RTX-containing regimens after 36 (2-101) and 22 (4-41) months, respectively. Two patients in conventional group died of disease progression and infection. CONCLUSIONS: RTX-containing first-line therapy achieves CR of GCH-AHA more quickly than the conventional therapy. RTX is efficacious when added to rescue therapy.
Asunto(s)
Anemia Hemolítica Autoinmune , Rituximab , Humanos , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Estudios Retrospectivos , Masculino , Femenino , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Lactante , Preescolar , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Quimioterapia Combinada , Resultado del Tratamiento , Factores Inmunológicos/uso terapéutico , Factores Inmunológicos/administración & dosificación , Recurrencia , Inducción de Remisión , Hepatitis/tratamiento farmacológico , Hepatitis/complicacionesRESUMEN
BACKGROUND AND AIMS: The majority of indeterminate pediatric acute liver failure (PALF) cases are secondary to immune dysregulation, labeled activated T-cell hepatitis (TCHep). We aimed to describe a cohort of children with acute severe hepatitis and PALF and define how clinical immune labs may help identify the TCHep group. METHODS: Retrospective review of children with acute hepatitis and PALF between March 2020 and August 2022. Patients were classified as known diagnosis, indeterminate hepatitis (IND-Hep), or TCHep (defined by liver biopsy with predominant CD8 T-cell inflammation or development of aplastic anemia). RESULTS: 124 patients were identified: 83 with known diagnoses, 16 with TCHep, and 25 with IND-Hep. Patients with TCHep had significantly increased median total bilirubin levels (7.5 mg/dL (IQR 6.8-8.9) vs 1.5 mg/dL (IQR 1.0-3.6), p < 0.0001), soluble interleukin-2 receptor levels (4512 IU/mL (IQR 4073-5771) vs 2997 IU/mL (IQR 1957-3237), p = 0.02), and percent of CD8+ T-cells expressing perforin (14.5 % (IQR 8.0-20.0) vs 1.0 % (IQR 0.8-1.0), p = 0.004) and granzyme (37.5 % (IQR 15.8-54.8) vs 4.0 % (IQR 2.5-5.5), p = 0.004) compared to IND-Hep patients. Clinical flow cytometry showed that TCHep patients had significantly increased percent CD8+ T cells (29.0 % (IQR 24.5-33.5) vs 23.6 % (IQR 19.8-25.8), p = 0.04) and HLA-DR+ (16.0 % (IQR 14.5-24.5) vs 2.7 (1.8-5.3), p < 0.001) compared to IND-Hep patients indicative of increase in CD8+ T cells that are activated. CONCLUSIONS: Peripheral blood clinical immune studies demonstrate increased markers of CD8 T-cell activation, proliferation, and cytotoxic function for TCHep patients. These readily available immune function labs can be used to help distinguish patients with TCHep from those with other causes. This provides a non-invasive tool for early detection of potential TCHep before progression to liver failure.
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Linfocitos T CD8-positivos , Humanos , Estudios Retrospectivos , Niño , Masculino , Femenino , Preescolar , Linfocitos T CD8-positivos/inmunología , Fallo Hepático Agudo/inmunología , Fallo Hepático Agudo/sangre , Adolescente , Hepatitis/inmunología , Hepatitis/sangre , Activación de Linfocitos , Lactante , Receptores de Interleucina-2/sangre , Granzimas/sangreRESUMEN
SummaryUlcerative colitis (UC), a chronic inflammatory bowel disease, can cause extraintestinal manifestations (EIMs) in approximately 40% of individuals. This case report discusses the diagnostic procedure of a woman in her 20s who initially had non-specific symptoms. The patient underwent a thorough evaluation, which initially pointed towards tuberculosis (TB) due to necrotic lymphadenopathy and granulomatous hepatitis. However, no microbiological evidence of TB was found, and her symptoms worsened despite antitubercular therapy. The patient developed painful nodular-ulcerative skin lesions consistent with cutaneous polyarteritis nodosa (cPAN) on biopsy. Eventually, a definitive diagnosis of UC was made, revealing the true nature of her multisystemic manifestations. Cutaneous vasculitis, including leucocytoclastic vasculitis and cPAN, is a rare EIM of UC, with only five reported cases in the literature. This case report highlights the clinical implications of EIMs and contributes to the expanding knowledge of rare EIMs such as cPAN and granulomatous hepatitis.
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Colitis Ulcerosa , Hepatitis , Poliarteritis Nudosa , Humanos , Poliarteritis Nudosa/diagnóstico , Poliarteritis Nudosa/tratamiento farmacológico , Poliarteritis Nudosa/complicaciones , Femenino , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/tratamiento farmacológico , Hepatitis/diagnóstico , Diagnóstico Diferencial , Granuloma/diagnóstico , Adulto , Antituberculosos/uso terapéuticoRESUMEN
Syphilitic hepatitis is a very rare presentation of syphilis infection, characterized by inflammation of the liver due to the invasion of hepatic tissue by the bacterium Treponema pallidum. This review article provides an in-depth analysis of the existing body of information pertaining to syphilitic hepatitis. The article primarily concentrates on key aspects such as the epidemiology, clinical manifestations, diagnostic methods, and therapeutic approaches associated with this condition. Despite its rarity, awareness of syphilitic hepatitis is vital for accurate diagnosis and appropriate intervention. The clinical presentations frequently exhibit similarities with many liver illnesses, hence presenting difficulties in making an accurate diagnosis. Common symptoms include fatigue, stomach pain, and jaundice. Diagnostic procedures encompass the use of serological assays, including rapid plasma reagin (RPR) and fluorescent treponemal antibody absorption (FTA-ABS), in conjunction with imaging modalities to evaluate hepatic engagement. The primary therapeutic approach is the prompt initiation of antibiotic therapy, with a particular emphasis on penicillin, to eradicate the causative bacterial infection and facilitate the restoration of liver function. Failure to swiftly manage this condition may result in substantial morbidity. In summary, syphilitic hepatitis is a very uncommon but medically relevant manifestation of syphilis infection. The significance of increased clinical suspicion, precise diagnostic techniques, and prompt antibiotic administration is emphasized in this review since these are crucial in reducing the potentially severe outcomes associated with this illness.
Asunto(s)
Antibacterianos , Hepatitis , Sífilis , Treponema pallidum , Humanos , Sífilis/diagnóstico , Sífilis/tratamiento farmacológico , Antibacterianos/uso terapéutico , Treponema pallidum/inmunología , Treponema pallidum/aislamiento & purificación , Hepatitis/diagnóstico , Hepatitis/microbiología , Hepatitis/tratamiento farmacológicoRESUMEN
OBJECTIVES: Vibrio cholerae non-O1/non-O139 (NOVC) bacteremia is infrequently reported in Western countries and is associated with unfavorable outcome. PATIENT/METHOD: We describe here the case of a diabetic patient with hepatic cytolysis and NOVC bacteremia following an episode of diarrhea. RESULT: The patient was paucisymptomatic and had a favorable resolution with oral ciprofloxacin. CONCLUSION: NOVC should be systematically sought in stool samples, particularly in immunocompromised patients, due to an increased risk of infection occurrence.
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Antibacterianos , Bacteriemia , Vibrio cholerae no O1 , Humanos , Bacteriemia/microbiología , Bacteriemia/tratamiento farmacológico , Francia/epidemiología , Vibrio cholerae no O1/aislamiento & purificación , Vibrio cholerae no O1/genética , Vibrio cholerae no O1/clasificación , Antibacterianos/uso terapéutico , Masculino , Ciprofloxacina/uso terapéutico , Hepatitis/microbiología , Hepatitis/complicaciones , Vibriosis/microbiología , Vibriosis/diagnóstico , Vibriosis/tratamiento farmacológico , Diarrea/microbiología , Cólera/microbiología , Cólera/complicaciones , Persona de Mediana Edad , Heces/microbiología , Anciano , FemeninoRESUMEN
Boletim com o objetivo de demonstrar o perfil epidemiológico dos casos que foram notificados entre 2019 a 2023, apresentando os indicadores epidemiológicos e operacionais de relevância do estado, para fins de tomada de decisão em relação às ações do Programa para Eliminação das Hepatites Virais até 2030. Trata-se de uma análise de dados secundários obtidos do Sistema de Informação de Agravos de Notificações (SINAN), referentes aos casos diagnosticados e notificados, por município de residência entre 2019 e 2023 pelos serviços de saúde do Estado de Goiás
Bulletin with the aim of demonstrating the epidemiological profile of cases that were reported between 2019 and 2023, presenting epidemiological and operational indicators of relevance to the state, for decision-making purposes in relation to the actions of the Program for the Elimination of Viral Hepatitis by 2030. This is an analysis of secondary data obtained from the Notifiable Diseases Information System (SINAN), referring to cases diagnosed and notified, by municipality of residence between 2019 and 2023 by the health services of the State of Goiás
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Humanos , Hepatitis/epidemiología , Hepatitis C/diagnóstico , Hepatitis C/mortalidad , Hepatitis C/epidemiología , Hepatitis B/diagnóstico , Hepatitis B/mortalidad , Hepatitis B/epidemiologíaRESUMEN
Glycyrrhizin (GL) has immunoregulatory effects on various inflammatory diseases including hepatitis and nephritis. However, the mechanisms underlying the anti-inflammatory effect of GL on renal inflammation are not fully understood. Hepatorenal syndrome (HRS) is a functional acute renal impairment that occurs in severe liver disease, and we found that kidney injury also occurs in Con A-induced experimental hepatitis in mice. We previously found that GL can alleviate Con A-induced hepatitis by regulating the expression of IL-25 in the liver. We wanted to investigate whether GL can alleviate Con A-induced nephritis by regulating IL-25. IL-25 regulates inflammation by modulating type 2 immune responses, but the mechanism by which IL-25 affects kidney disease remains unclear. In this study, we found that the administration of GL enhanced the expression of IL-25 in renal tissues; the latter promoted the generation of type 2 macrophages (M2), which inhibited inflammation in the kidney caused by Con A challenge. IL-25 promoted the secretion of the inhibitory cytokine IL-10 by macrophages but inhibited the expression of the inflammatory cytokine IL-1ß by macrophages. Moreover, IL-25 downregulated the Con A-mediated expression of Toll-like receptor (TLR) 4 on macrophages. By comparing the roles of TLR2 and TLR4, we found that TLR4 is required for the immunoregulatory effect of IL-25 on macrophages. Our data revealed that GL has anti-inflammatory effects on Con A-induced kidney injury and that the GL/IL-25/M2 axis participates in the anti-inflammatory process. This study suggested that GL is a potential therapeutic for protecting against acute kidney injury.
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Modelos Animales de Enfermedad , Ácido Glicirrínico , Síndrome Hepatorrenal , Interleucinas , Riñón , Macrófagos , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/uso terapéutico , Síndrome Hepatorrenal/inducido químicamente , Síndrome Hepatorrenal/tratamiento farmacológico , Síndrome Hepatorrenal/metabolismo , Inflamación/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucinas/metabolismo , Riñón/patología , Riñón/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Nefritis/tratamiento farmacológico , Nefritis/metabolismo , Nefritis/etiología , Nefritis/prevención & control , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Concanavalina A , Hepatitis , Enfermedad Hepática Inducida por Sustancias y Drogas/complicaciones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismoAsunto(s)
Células Gigantes , Hepatitis , Humanos , Masculino , Células Gigantes/patología , Hepatitis/etiología , Hepatitis/diagnóstico , Adulto JovenRESUMEN
Inflammation plays a critical role in conditions such as acute liver failure, acute-on-chronic liver failure, and ischemia-reperfusion-induced liver injury. Various pathogenic pathways contribute to liver inflammation, involving inflammatory polarization of macrophages and Küpffer cells, neutrophil infiltration, dysregulation of T cell subsets, oxidative stress, and activation of hepatic stellate cells. While mesenchymal stromal cells (MSCs) have demonstrated beneficial properties, their clinical translation is limited by their cellular nature. However, MSC-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach for immunomodulation. MSC-EVs naturally mirror their parental cell properties, overcoming the limitations associated with the use of MSCs. In vitro and in vivo preclinical studies have demonstrated that MSC-EVs replicate the beneficial effects of MSCs in liver injury. This includes the reduction of cell death and oxidative stress, improvement of hepatocyte function, induction of immunomodulatory effects, and mitigation of cytokine storm. Nevertheless, MSC-EVs face challenges regarding the necessity of defining consistent isolation methods, optimizing MSCs culture conditions, and establishing quality control measures for EV characterization and functional assessment. By establishing standardized protocols, guidelines, and affordable cost mass production, clinicians and researchers will have a solid foundation to conduct further studies, validate the therapeutic efficacy of MSC-EVs, and ultimately pave the way for their clinical implementation in acute liver injury.
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Vesículas Extracelulares , Inmunomodulación , Células Madre Mesenquimatosas , Investigación Biomédica Traslacional , Vesículas Extracelulares/metabolismo , Humanos , Animales , Enfermedad Aguda , Inflamación/patología , Hepatitis/inmunología , Hepatitis/terapiaRESUMEN
Sepsis is understood as the result of initiating systemic inflammation derived from an inadequate host response against pathogens. In its acute phase, sepsis is marked by an exacerbated reaction to infection, tissue damage, organ failure, and metabolic dysfunction. Among these, hypoglycemia, characterized by disorders of the gluconeogenesis pathway, is related to one of the leading causes of mortality in septic patients. Recent research has investigated the involvement of sympathetic efferent neuroimmune pathways during systemic inflammation. These pathways can be stimulated by several centrally administered drugs, including Angiotensin-(1-7) (Ang-(1-7)). Therefore, the present study aims to evaluate the effects of central treatment with Ang-(1-7) on hypoglycemia during endotoxemia. For this, male Wistar Hannover rats underwent stereotaxic surgery for intracerebroventricular (i.c.v.) administration of Ang-(1-7) and cannulation of the jugular vein for lipopolysaccharide (LPS) injection. Our results demonstrate that LPS was capable of inducing hypoglycemia and that prior central treatment with Ang-(1-7) attenuated this effect. Our data also show that Ang-(1-7) reduced plasma concentrations of TNF-α, IL-1ß, IL-6, and nitric oxide, in addition to the decrease and increase of hepatic IL-6 and IL-10 respectively, in animals subjected to systemic inflammation by LPS, resulting in the reduction of systemic and hepatic inflammation, thus attenuating the deleterious effects of LPS on phosphoenolpyruvate carboxykinase protein content. In summary, the data suggest that central treatment with Ang-(1-7) attenuates hypoglycemia induced by endotoxemia, probably through anti-inflammatory action, leading to reestablishing hepatic gluconeogenesis.