Colestasis intrahepática drepanocítica a propósito de un casoy revisión de la literatura / Sickle cell intrahepatic cholestasis regarding a case and reviewof the literature

La enfermedad de células falciformes (ECF) o anemia drepanocítica, es el trastorno hereditario más frecuente en los glóbulos rojos, y la enfermedad con más complicaciones en diferentes órganos, lo que provoca múltiples presentaciones de una misma enfermedad., se hace revisión literatura sobre ECF y colestasis intrahepática drepanocítica, y se describe un caso presentado en el Hospital General y de Especialidades Nuestra Señora de la Altagracia de Higüey Republica Dominicana en el año 2022. Es un varón de 24 años, con diagnóstico de ECF, que se complicó con una colestasis intrahepática drepanocítica muy severa que se manejó con hemodiálisis. El objetivo de publicar este caso es revisar la información respecto a la incidencia y la morbimortalidad de esta complicación, teniendo en cuenta que fue tratado por un equipo multidisciplinario usando la hemodiálisis como alternativa terapéutica(AU)

Sickle cell disease (SCD) or sickle cell anemia is the most common hereditary disorder in red blood cells, and the disease with the most complications in different organs, which causes multiple presentations of the same disease. Literature review on SCD is made and sickle cell intrahepatic cholestasis,and a case presented at the Hospital General y de Especialidades Nuestra Señora de la Altagracia de Higüey in the Dominican Republic in 2022 is described. Very severe sickle cell intrahepatic disease that was managed with hemodialysis. The purpose of publishing this case is to review the information regarding the incidence and morbidity and mortality of this complication,taking into account that it was treated by a multidisciplinary team using hemodialysis as a therapeutic alternative(AU)

Assessment of intrahepatic cholestasis in pregnancy and the effect of disease severity on transient tachypnea in the newborn in uncomplicated fetuses.

OBJECTIVES: Considering the effects of bile-acid levels on fetal lungs and pulmonary surfactants, we hypothesized that in the presence of intrahepatic pregnancy cholestasis (ICP), poor neonatal respiratory problems are observed in relation to the severity of the disease. Delivery timing with the presence of ICP is scheduled during late-preterm and early term gestational weeks. The aim of this study was to assess ICP and disease severity effects on transient tachypnea of the newborn (TTN) in uncomplicated fetuses. METHODS: This study comprised 1,097 singleton pregnant women who were separated into three groups-control, mild ICP, and severe ICP. The pregnant women diagnosed with ICP between January 2010 and September 2020 was investigated using the hospital's database. For the control group, healthy pregnant women who met the same exclusion criteria and were similar in terms of maternal age, gestational age at delivery, and mode of delivery were analyzed. RESULTS: The TTN rate was 14.5% in the severe ICP group, 6.5% in the mild ICP group, and 6.2% in the control group. The TTN rate in the severe ICP group was significantly higher than that in the other groups (p<0.001). Similarly, the rate of admission to the neonatal intensive care unit was significantly higher in the severe ICP group than in the other groups (p<0.001). According to Pearson correlation analyses, maternal serum bile-acid levels were positively correlated with TTN (r=0.082; p=0.002). CONCLUSIONS: Severe ICP, but not mild ICP, and serum bile-acid levels were positively correlated with increased TTN risk and reduced pulmonary surfactant levels.

Odevixibat para prurito debido a colestasis intrahepática familiar progresiva / Odevixibat for pruritus due to cholestasis progressive familial intrahepatic

INTRODUCCIÓN: Las condiciones que causan hiperbilirrubinemia pueden clasificarse en aquellas que resultan en una hiperbilirrubinemia predominantemente no conjugada, y aquellas que están asociadas con una elevación de las formas conjugadas y no conjugadas de bilirrubina. La eliminación de la bilirrubina conjugada en la bilis se ve afectada en varios trastornos hereditarios a través de diferentes mecanismos, aunque en todas estas situaciones se comparte con el defecto excretor de todos o algunos otros aniones orgánicos. Entre los genes que sus mutaciones usualmente conllevan a síndromes hereditarios de colestasis intrahepática se encuentran el SERPINAI (alfa 1-antitripsina), JAG1 (que causa el síndrome de Alagille), ATP8B1 (también conocido como FIC1), ABCB11 (bomba de exportación de sales biliares [BSEP]), MDR3 (ABCB4) y MRP2 (que causa el síndrome de Dubin-Johnson); mientras que no se ha identificado el gen del síndrome de Rotor. Otras enfermedades hereditarias, como la colestasis intrahepática familiar progresiva y la colestasis intrahepática recurrente benigna, provocan hiperbilirrubinemia conjugada como consecuencia de la reducción del flujo biliar. La colestasis intrahepática familiar progresiva es un grupo heterogéneo de trastornos, caracterizado por una secreción defectuosa de ácidos biliares u otros componentes de la bilis. Se clasifica en cuatro tipos según la mutación genética predominante identificada; donde el tipo I es conocida como enfermedad de Byler o colestasis familiar de Groenlandia, la tipo II se asemeja clínicamente a la enfermedad de Byler, pero ocurre principalmente en Oriente Medio y Europa, la tipo III que involucra el gen ABCB4 (también conocido como proteína 3 Pglicoproteína de resistencia a múltiples fármacos) y tipo IV que es una enfermedad hepática colestásica crónica grave. TECNOLOGÍA: Odevixibat es un inhibidor no absorbible del transportador de ácidos biliares ileal reversible, que disminuye la reabsorción de ácidos biliares (principalmente formas de sal) del íleon terminal. Se desconoce el mecanismo exacto por el cual odevixibat mejora el prurito en pacientes con colestasis intrahepática familiar progresiva, pero puede implicar la inhibición de del transportador de ácidos biliares ileal reversible. Se administra una vez por día por vía oral a 40 mcg/kg/día, donde según la respuesta clínica a los tres meses puede a incrementarse en 40 mcg/kg/día hasta 120 mcg/kg/día. Cuando se lo coadministra con colestiramina debe tomarse al menos con cuatro horas de diferencia entre fármacos, y también interacciona con la absorción de vitaminas liposolubles. Las formulaciones disponibles son en cápsula para espolvorear de 200 mcg y 600 mcg, y cápsulas de 400 mcg y 1200 mcg. Entre los eventos adversos graves más frecuentemente identificados se destacan la deficiencia de vitamina, dolor abdominal, diarrea persistente, esplenomegalia e incremento de las enzimas hepáticas. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de odevixibat para el tratamiento del prurito debido a colestasis intrahepática familiar progresiva. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. CONCLUSIONES: No se hallaron ensayos clínicos aleatorizados publicados con revisión de pares que hayan evaluado la eficacia y seguridad de odevixibat para el tratamiento del prurito debido a colestasis intrahepática familiar progresiva. Las agencias regulatorias de Estados Unidos y Europa han autorizado su comercialización en la indicación evaluada de forma acelerada, a la espera de ensayos clínicos confirmatorios, brindando la designación de medicamento huérfano. El tratamiento consistente en odevixibat es de alto costo para Argentina. No se hallaron recomendaciones actualizadas en Argentina y en el Mundo que mencionen la tecnología en la indicación evaluada.

Current understanding of autophagy in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy. Manifested with pruritus and elevation in bile acids, the etiology of ICP is still poorly understood. Although ICP is considered relatively benign for the mother, increased rates of adverse fetal outcomes including sudden fetal demise are possible devastating outcomes associated with ICP. Limited understanding of the underlying mechanisms restricted treatment options and managements of ICP. In recent decades, evolving evidence indicated the significance of autophagy in pregnancy and pregnancy complications. Autophagy is an ancient self-defense mechanism which is essential for cell survival, differentiation and development. Autophagy has pivotal roles in embryogenesis, implantation, and maintenance of pregnancy, and is involved in the orchestration of diverse physiological and pathological cellular responses in patients with pregnancy complications. Recent advances in these research fields provide tantalizing targets on autophagy to improve the care of pregnant women. This review summarizes recent advances in understanding autophagy in ICP and its possible roles in the causation and prevention of ICP.

The Role of Vitamin K in Cholestatic Liver Disease.

Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.

Burden of Future Liver Abnormalities in Patients With Intrahepatic Cholestasis of Pregnancy.

INTRODUCTION: There are limited data on the incidence, predictors, and time to future liver abnormalities in patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: Single-center retrospective study of pregnant women with and without ICP who delivered from 2005 to 2009 evaluating incidence and time to future liver abnormalities. Women returning for care with liver function tests at a minimum of 6 months postpartum were included. Liver disease diagnoses and liver functions test abnormalities were compared. Time to development of alanine aminotransferase (ALT) >25 U/L, alkaline phosphatase (ALP) >140 U/L, and diagnosis of liver disease (through imaging or clinical evaluation) were compared between women with and without ICP using Kaplan-Meier methods and Cox regression models. RESULTS: A total of 255 women with ICP and 131 age-matched control subjects with delivery during the same period were identified. Subjects in both groups were similar in follow-up time, age at pregnancy, prepregnancy body mass index, and ethnicity (≥75% were Hispanic in both groups). On univariate analyses, ICP was associated with increased incidence of ALT >25 U/L P < 0.01 ALP >140 U/L (P < 0.01) and liver disease (P = 0.03). Adjusting for metabolic factors, ICP diagnosis was associated with risk of future liver abnormalities: postpartum ALT >25 U/L (hazard ratio [HR] 1.9, P < 0.01), ALP >140 U/L (HR 3.4, P < 0.01), and liver disease (HR 1.5, P = 0.05). DISCUSSION: In our cohort of urban women, ICP diagnosis predicted risk of future liver disease and abnormal liver tests. Women with pregnancies complicated by ICP may benefit from surveillance for postpartum liver abnormalities.

Reduced spontaneous itch in mouse models of cholestasis.

Pruritus is one of the most distressing symptoms in cholestatic patients. Plasma autotaxin (ATX) activity correlates with the severity of pruritus in cholestatic patients, but the pathophysiology is unclear. To study pruritus in mice, we measured scratch activity in cholestatic Atp8b1 mutant mice, a model for Progressive Familial Intrahepatic Cholestasis type 1, and wild type mice (WT) with alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. To induce cholestasis, Atp8b1 mutant mice received a diet containing 0.1% cholic acid (CA) and WT mice were treated with ANIT. In these mice ATX was also overexpressed by transduction with AAV-ATX. Scratch activity was measured using an unbiased, electronic assay. Marked cholestasis was accomplished in both Atp8b1 mutant mice on a CA-supplemented diet and in ANIT-treatment in WT mice, but scratch activity was decreased rather than increased while plasma ATX activity was increased. Plasma ATX activity was further increased up to fivefold with AAV-ATX, but this did not induce scratch activity. In contrast to several reports two cholestatic mouse models did not display increased scratch activity as a measure of itch perception. Increasing plasma ATX activity by overexpression also did not lead to increased scratch activity in mice. This questions whether mice are suitable to study cholestatic itch.

Severe intrahepatic cholestasis as the initial manifestation of light chain amyloidosis / Colestasis intrahepática grave como manifestación inicial de la amiloidosis por depósito de cadenas ligeras

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Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a secondary analysis of the PITCHES trial.

OBJECTIVE: To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ursodeoxycholic acid (UDCA). DESIGN: Secondary analysis of the PITCHES trial (ISRCTN91918806). SETTING: United Kingdom. POPULATION OR SAMPLE: 527 women with ICP. METHODS: Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman's response to treatment with UDCA. MAIN OUTCOME MEASURES: Bile acid concentration and itch score. RESULTS: In women with baseline bile acid concentrations less than 40 µmol/l, treatment with UDCA resulted in increased post-randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.00-1.41, P = 0.048). A test of interaction showed no significance (P = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (-6.0 mm, 95% CI -11.80 to -0.21, P = 0.042), with a test of interaction not showing significance (P = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity. CONCLUSIONS: There was no subgroup of women with ICP in whom a beneficial effect of treatment with UDCA on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered. TWEETABLE ABSTRACT: PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy is a common disorder of pregnancy manifested by pruritus and elevated bile acids. The etiology of cholestasis is poorly understood and management is difficult due to the paucity of data regarding its diagnosis, treatment, and related adverse outcomes. In this article, we review the epidemiology, pathophysiology, risk factors, laboratory findings, complications, treatment, management, and current evidence surrounding intrahepatic cholestasis of pregnancy.

Assessment of selected parameters of placental microstructure in patients with intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder during pregnancy. Cholestasisis associated with increased risk of fetal complications: prematurity, perinatal hypoxia and meconium stained amnioticfluid, and sudden intrauterine fetal death. The exact mechanisms associated with cholestasis fetal sequelae are not fullyunderstood. The aim of the study was the histopathological evaluation of placentas from patients with cholestasis andhealthy pregnant women to establish whether cholestasis is accompanied by changes in placental microstructure. MATERIAL AND METHODS: The effect of cholestasis on placental microstructure was investigated using placental tissue frompatients with cholestatsis treated with ursodeoxycholic acid (UDCA) and from uncomplicated pregnancies. Five placentalhistopathological features were analyzed: number of syncytial knots, number of capillaries per villous, structure of stroma,presence of Hofbauer cells, and villitis of unknown etiology. RESULTS: There were no statistically significant differences in any of the studied parameters between cholestasis-affectedand healthy control groups. CONCLUSIONS: There are no diffrences in placental microstructure in cholestasis patients treated with UDCA and in patientswith uncomplicated pregnancy.

Association between intrahepatic cholestasis in pregnancy and gestational diabetes mellitus. A retrospective analysis.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is a liver specific disorder affecting 0.08%-27.6% pregnant women.It is characterized by reduced expression of the primary bile acid farnesoid receptor (FXR). In recent studies, it has beenshowed that FXR has an impact on normal glucose homeostasis. Based on that it was suggested that the level of bile acidscorrelates with glucose level. The aim of the study was to evaluate the association between ICP and gestational diabetesmellitus (GDM). MATERIAL AND METHODS: 102 singleton patients complicated by ICP were included to the study and divided into twogroups: non-GDM group (74 patients) and GDM group (28 patients). ICP was diagnosed based on the serum bile acidslevel > 10 µmol/L and GDM with the 75 g oral glucose tolerance test and FIGO guidelines. Demographic and clinical outcomedata (including maternal age, BMI and infant weight) and ICP and GDM biochemical markers were collected. RESULTS: The incidence of GDM in ICP patients was 27.45%. 73% of women included to the study developed mild cholestasis.Lower levels of serum bile acids were correlated with GDM group. When compared mean total bilirubin level wassignificantly higher in non-GDM group. Transaminases (ALT, AST) and neonate condition including mean birth weightrevealed no significant difference between the groups. On the other hand, prevalence of large for gestational age wassignificantly higher in non-GDM group (p < 0.00001). CONCLUSIONS: The incidence of ICP is higher in women with GDM.

Direct Amplification of Tissue Factor:Factor VIIa Procoagulant Activity by Bile Acids Drives Intrahepatic Coagulation.

OBJECTIVE: Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestatic patients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acid glycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone. CONCLUSIONS: The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.

Intrahepatic Cholestasis of Pregnancy: A Case Study of the Rare Onset in the First Trimester.

Intrahepatic cholestasis of pregnancy (ICP) is a gestation-specific liver disorder, defined most often as the onset of pruritus, usually from the third trimester of pregnancy, associated with abnormal liver test results and/or increased total serum bile acids and spontaneous relief after delivery. The 21-year-old patient was admitted to our ward in the 11th week of pregnancy due to raised liver enzymes. The first onset of pruritus and jaundice appeared a month before hospitalization. Immunology tests and Toxoplasma gondii were negative. We excluded viral etiology, while alpha-1-antitrypsin, serum and urine copper levels, and thyroid hormones were within the reference values. The patient denied she had taken any medicines and herbal preparations before and during pregnancy. Total bile acids in the serum were significantly elevated (242 µmol/L). The abdominal ultrasound revealed a regular finding. Liver biopsy suggested a cholestatic liver disorder. After a presentation of all risks, the patient decided to stop the pregnancy. After a month, the hepatogram was within the reference values. Very rarely an ICP can occur in early pregnancy (first trimester), which calls for close monitoring. The risk of serious adverse fetal outcomes and spontaneous preterm delivery is proportional with increased levels of maternal serum bile acid.

[The descending pathophysiology model of cholestatic liver disease].

Intrahepatic cholestasis is a pathological condition in which the synthesis, secretion, and excretion of bile are blocked, and thus the bile does not flow normally into the duodenum and bloodstream. According to cytological damage site, it can be divided into hepatocellular cholestasis, biliary duct cell cholestasis and mixed cell cholestasis. The two kinds of pathophysiological models [ascending or upstream (damage begins with cholangiocytes and then extends to the hepatocytes) and descending or downstream (the damage starts from the liver cells and then extends to the bile duct cells)] has distinct features in the process of disease occurrence and development. This article mainly elaborates the "descending" pathophysiological model of cholestatic liver disease (hepatocytic damage progresses to biliary duct cell), and further explores its etiology, pathogenesis and treatment methods.

Familial intrahepatic cholestasis: New and wide perspectives.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood. AIMS: To update the panel of single genes mutations involved in familial cholestasis. METHODS: PubMed search for "familial intrahepatic cholestasis" alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses. RESULTS: PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer. CONCLUSION: There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting.

Liver disease in pregnancy: Medical aspects and their implications for mother and child.

Liver disease during pregnancy is more common than expected and may require specialized intervention. It is important to determine if changes in liver physiology may develop into liver disease, to assure early diagnosis. For adequate surveillance of mother-fetus health outcome, liver disease during pregnancy might require intervention from a hepatologist. Liver diseases have a prevalence of at least 3% of all pregnancies in developed countries, and they are classified into two main categories: related to pregnancy; and those non- related that are present de novo or are preexisting chronic liver diseases. In this review we describe and discuss the main characteristics of those liver diseases associated with pregnancy and only some frequent pre-existing and co-incidental in pregnancy are considered. In addition to the literature review, we compiled the data of liver disease occurring during pregnancies attended at the National Institute of Perinatology in Mexico City in a three-year period. In our tertiary referral women hospital, liver disease was present in 11.24 % of all pregnancies. Associated liver disease was found in 10.8% of all pregnancies, mainly those related to pre-eclampsia (9.9% of pregnancies). Only 0.56% was due to liver disease that was co-incidental or preexisting; the acute or chronic hepatitis C virus was the most frequent in this group (0.12%). When managing pregnancy in referral hospitals in Latin America, it is important to discard liver alterations early for adequate follow up of the disease and to prevent adverse consequences for the mother and child.