Transitional pain services updates and a novel service for the obstetric population.

PURPOSE OF REVIEW: This paper is an update of the publications on Transitional Pain Services and explores the viability of a dedicated transitional pain service for women. RECENT FINDINGS: We address common pain pathologies establishing referral criteria, pathways, and effective strategies to decrease chronification of pain during pregnancy. SUMMARY: This review highlights the importance establishing transitional pain service models at every institution and in particular in obstetric population as pain is normalized by Society during pregnancy.

Monitoring the Shelf Life of Refined Vegetable Oils under Market Storage Conditions-A Kinetic Chemofoodmetric Approach.

Most physicochemical and sensory properties of edible vegetable oils are not stable over time. One of the main causes of quality depletion of vegetable oils is oxidation, which influences sensory acceptability and nutritional value, and could even lead to toxic compounds. That negative influence affects international refined oil prices and the variety of its culinary applications. Modelling quality depletion of vegetable oils and establishing the shelf life, generally accepted as the time until rancidity becomes evident, already remains a challenge for the industry. Hence, this paper will show a promising chemofoodmetric methodology, as an easy and straightforward tool to estimate the current shelf-life of refined vegetable oils, based on a comprehensive characterisation of quality depletion-related changes over storage time under real market conditions. The methodology for building a multivariate kinetic ageing-based model is described, taking into account all time-related physicochemical parameters and chemometric processing tools. From a particular ageing state, multiparametric models are able to reliably infer the expected storage time for each vegetable oil so that it remains consistent with acceptability requirements. The results of the study pointed out the accuracy of multivariate shelf-life modelling with regard to univariate modelling. Discrepancies were found in the oxidation rates of oils extracted from different plant seeds.

Osteoid osteoma in the ankle and foot. An overview of 50 years of experience.

BACKGROUND: The literature published about osteoid osteoma (OO) in the ankle-foot consists mainly on case reports. METHODS: We performed a retrospective study in which we analyzed demographic parameters, pain characteristics, treatment options and functional outcomes measured using the AOFAS and the SEFAS scales. RESULTS: We treated 17 patients with OO around the ankle-foot. Eighty-eight percent of patients had night pain that was relieved with NSAIDs. The bones most often affected were the talus and calcaneus. OO was diagnosed 21 months after the onset of symptoms. Mean follow-up was 17.3 years. The surgical techniques most used were curettage and curettage and bone grafting. There was a significant increase in AOFAS and SEFAS scores after surgery. CONCLUSIONS: Suspicion is the base of a prompt and a correct diagnosis of OO. The OO should be especially suspected in patients who present night pain that can be relieved with NSAIDs.

The efficacy of an intramedullary nitinol implant in the correction of claw toe or hammertoe deformities.

INTRODUCTION: A multitude of procedures has been described in the literature for the treatment of lesser toe deformities and there is currently no general consensus on the optimal method of fixation. The aim of this study is to assess the clinical and radiological outcomes of an intramedullary nitinol implant for the correction of lesser toe deformities, and to determine if the distal interphalangeal (DIP) joint and metatarsophalangeal (MTP) joint are modified during patient follow-up after correction of the PIP joint. MATERIALS AND METHODS: A prospective analysis of 36 patients with claw toe or hammertoe who were treated with an intramedullary nitinol implant. Clinical manifestations and angulation of the metatarsophalangeal, proximal and distal interphalangeal (MTP, PIP, DIP) joints were evaluated in radiographic studies preoperatively, at first medical revision post-surgery, and after a minimum of 1 year of follow-up. Complications such as non-union rate, implant rupture, and implant infection were also evaluated during follow-up. RESULTS: All patients were women with an average age of 65.5 (range 47-82) years. The average follow-up time was 2.4 (range 1-5.7) years. Fifty intramedullary nitinol implants were used. The MTP joint extension and PIP joint flexion decreased by 15.9° (95% CI - 19.11 to - 12.63) and 49.4° (95% CI - 55.29 to - 43.52), respectively, at the end of follow-up. Moreover, the DIP joint flexion increased progressively during follow-up (13.7° pre-surgery versus 35.6 in last medical check-up, 95% CI 13.24-30.57). There were four (8%) asymptomatic implant ruptures. The rate of fusion was 98%. CONCLUSION: The reduction of the PIP joint using an intramedullary nitinol implant is a good option in lesser toe deformities, with few complications and a high rate of arthrodesis. Moreover, the PIP joint reduction affects both the MTP and DIP joints.

Haplotype-based gene-gene interaction of bone morphogenetic protein 4 and interferon regulatory factor 6 in the etiology of non-syndromic cleft lip with or without cleft palate in a Chilean population.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans, the etiology of which can be dependent on the interactions of multiple genes. We previously reported haplotype associations for polymorphic variants of interferon regulatory factor 6 (IRF6), msh homeobox 1 (MSX1), bone morphogenetic protein 4 (BMP4), and transforming growth factor beta 3 (TGFB3) in Chile. Here, we analyzed the haplotype-based gene-gene interaction for markers of these genes and NSCL/P risk in the Chilean population. We genotyped 15 single nucleoptide polymorphisms (SNPs) in 152 Chilean patients and 164 controls. Linkage disequilibrium (LD) blocks were determined using the Haploview software, and phase reconstruction was performed by the Phase program. Haplotype-based interactions were evaluated using the multifactor dimensionality reduction (MDR) method. We detected two LD blocks composed of two SNPs from BMP4 (Block 1) and three SNPs from IRF6 (Block 2). Although MDR showed no statistical significance for the global interaction model involving these blocks, we found four combinations conferring a statistically significantly increased NSCL/P risk (Block 1-Block 2): T-T/T-G C-G-T/G-A-T; T-T/T-G C-G-C/C-G-C; T-T/T-G G-A-T/G-A-T; and T-T/C-G G-A-T/G-A-T. These findings may reflect the presence of a genomic region containing potential causal variants interacting in the etiology of NSCL/P and may contribute to disentangling the complex etiology of this birth defect.

Local and systemic diffusion of antineoplastic drugs following vertebroplasty using acrylic cement mixed with cisplatin or methotrexate: experimental study in pigs.

PURPOSE: To determine the efficacy of cisplatin- or methotrexate-containing acrylic cement for local and systemic antineoplastic drug diffusion. Among the uses of acrylic cement or Polymethylmethacrylate (PMMA), there is the possibility to employ it as vehicle for drug diffusion. This capability is of interest in the treatment of pathological fractures: The curative effects of the cement (cytotoxicity of the monomer and increased temperature) are added to the antineoplastic effect of the drugs. METHODS: In the experimental study, two groups of ten pigs underwent vertebroplasty using cement mixed with 500 mg of powder cisplatin or 1000 mg of powder methotrexate. Vertebroplasty was performed in two non-consecutive lumbar vertebrae with bipedicular cement injection. Transpedicular bone biopsy was performed weekly to measure levels of antineoplastic agent in bone tissue and blood plasma. Cisplatin was studied by atomic absorption spectrometry and methotrexate by fluorescence polarization immunoassay. Renal and hepatic function and blood analysis were performed weekly. RESULTS: Cisplatin and methotrexate levels were found in bone tissue at more than 5 weeks following surgery. The cisplatin peak occurred at week 3 (mean 1269 µg/g bone) and the methotrexate peak at week 1 (mean 862.76 µg/g bone). Plasma drug levels were found 72 h after surgery, with a peak at 24 h for cisplatin (mean 0.23 µmol/L) and at 30 min for methotrexate (mean 0.92 µmol/L). None of the animals died during the study. Animals with intracanal cement leaks showed no neurological involvement. Renal, hepatic and hemogram studies remained within normal limits. CONCLUSIONS: There is local diffusion of antineoplastic agents from the cement to bone and plasma. We found methotrexate and cisplatin levels in bone at up to 5 weeks, comparable to previous in vitro reports. At the doses administered, there were no cases of myelosuppression, hepatotoxicity, or nephrotoxicity.

Association of PALB2 sequence variants with the risk of familial and early-onset breast cancer in a South-American population.

BACKGROUND: Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer (BC) in several populations. Nevertheless its contribution in the South-American population is unknown. The goal of this study was to determine the prevalence of PALB2 mutations in the Chilean population. METHODS: 100 Chilean BRCA1/2-negatives familial BC cases were included for the PALB2 mutation analysis. We use conformational sensitive gel electrophoresis and direct sequencing. Using a case-control design, we studied the identified variants in 436 BC cases and 809 controls to evaluate their possible association with BC risk. RESULTS: No pathogenic mutations were detected. We identified three variants, the variant c.1861C > A not previously described was found in one of the 436 cases and none of the 809 controls. The bioinformatic analyses indicate that this variant probably is not pathogenic. PALB2 c.1676A > G (rs152451A/G) and c.2993C > T (rs45551636C/T) variants were significantly associated with increased BC risk only in cases with a strong family history of BC (OR = 1.9 [CI 95% 1.3-2.8] p < 0.01 and OR = 3.3 [CI 95% 1.4-7.3] p < 0.01, respectively). The rs152451A/G-rs45551636C/T composite genotype produce increase of the BC risk in cases with a strong family history of BC (OR = 3.6 [CI 95% 1.7-8.0] p = 0.003). The rs152451-G/rs45551636-C and rs152451-G/rs45551636-T haplotypes were associated with an increased BC risk only in cases with a strong family history of BC (OR = 1.6 [CI 95% 1.0-2.5] p = 0.05 and OR = 3.7 [CI 95% 1.8-7.5] p < 0.001, respectively). CONCLUSION: Our results suggest that PALB2 c.1676A > G and c.2993C > T play roles in BC risk in women with a strong family history of BC.

Hemorrhagic complications of dental extractions in 181 patients undergoing double antiplatelet therapy.

PURPOSE: There is limited information on hemorrhagic complications during invasive dental procedures in patients treated with double antiplatelet therapy. The objective of this study is to assess the frequency of hemorrhagic complications of patients taking dual antiplatelet medication undergoing dental extractions. PATIENTS AND METHODS: An observational, multicenter, prospective, cohort study was performed in 11 oral and dental care units of primary care. The study sample was derived from the population of patients aged 18 years or older who were undergoing double antiplatelet therapy and presented to the oral and dental care units requiring dental extraction. Double antiplatelet therapy is the combination of 100 mg per day of acetylsalicylic acid and a second antiplatelet agent. The predictor variables were type of extraction performed, number of extracted teeth, number of extracted roots, and presence of inflammation. The primary outcome variable was intraoperative hemorrhage, and the secondary outcome variables were hemorrhage at 24 hours and hemorrhage at 10 days. First, a univariate analysis that considered all studied variables was performed. All variables with P < .25 in the univariate analysis were included in a multivariate analysis. The association between hemorrhage severity and its relevant factors was evaluated using logistic regression analysis. RESULTS: The study included 181 patients. Light hemorrhage (<30 minutes) was observed in 165 patients (91.2%). Intraoperative hemorrhage lasted more than 30 minutes in 15 patients (8.3%) and more than 60 minutes in only 1 patient, whose hemorrhage was controlled by local hemostatic measures. The presence of inflammation and 3-root extractions increased the probability of hemorrhage persisting for more than 30 minutes by factors of 10 and 7.3, respectively. CONCLUSIONS: In 8.3% of patients treated with dual antiplatelet therapy, dental extractions cause hemorrhagic complications lasting more than 30 minutes are resolved using local hemostatic measures. The results of this study support the safety of dental extraction without withdrawal double antiplatelet therapy.

Quadratus lumborum block for postoperative pain after caesarean section: A randomised controlled trial.

BACKGROUND: Effective postoperative analgesia after caesarean section is important because it enables early ambulation and facilitates breast-feeding. Several case reports have shown that local anaesthetic injection around the quadratus lumborum muscle is effective in providing pain relief after various abdominal operations and in patients with chronic pain. The quadratus lumborum block (QLB) is performed in close proximity to the surface and uses a fascial compartment path to extend the distribution of local anaesthesia into the posterior abdominal wall and paravertebral space. This central effect can be of vital importance when managing the visceral pain after caesarean section. OBJECTIVE: We hypothesised that the QLB after caesarean section can provide adequate pain relief as part of a multimodal approach. DESIGN: Double-blind, randomised and controlled clinical trial. SETTING: A single centre between June 2014 and December 2014. PATIENTS: Fifty patients who were American Society of Anesthesiologists physical status 1 or 2, with normal singleton pregnancies with a gestation of at least 37 weeks, and scheduled for elective caesarean section under spinal anaesthesia, were enrolled into the study. They were randomly assigned to receive a QLB (n = 25) with 0.125% bupivacaine 0.2 ml kg⁻¹ (Group 1) or a QLB (n = 25) with 0.9% Normal saline 0.2 ml kg⁻¹ (Group 2). MAIN OUTCOME MEASURES: The primary outcome measure for the study was the morphine demands and doses delivered by a patient-controlled analgesia system at predetermined intervals (1, 2, 4, 6, 12, 24 and 48 h) after surgery. The secondary endpoints were visual analogue scale (VAS) for pain at rest and on movement (dynamic), heart rate, blood pressure, pruritus, itching, nausea, vomiting and sedation. RESULTS: The patients who received local anaesthetic used significantly less morphine than the control group (P < 0.001) at 6 and 12 h, but not at 24 and 48 hours after caesarean section. The local anaesthetic group had significantly less morphine demand than the control group (P < 0.001) 6, 12, 24 and 48 h after caesarean section. The VAS was significantly lower in the local anaesthetic group than the control group, including VAS for pain at rest at all times except 24 h after caesarean section, and VAS for pain on movement (dynamic) at all times. CONCLUSION: The QLB after caesarean section was effective and provided satisfactory analgesia in combination with a typical postoperative analgesic regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02328378.

Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population.

Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95%CI 1.02-13.84, P = 0.046) and 8.0 (95%CI 2.20-29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28-1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.

Reconstruction of the extensor mechanism with fresh-frozen tendon allograft in total knee arthroplasty.

PURPOSE: Patellar tendon rupture after total knee replacement is a rare and highly limiting injury with multifactorial aetiology. Many reconstruction techniques have been described with not very predictable results. The use of allografts has been accepted as a suitable solution. METHODS: A series of seven patients with patellar tendon rupture treated with fresh-frozen tendon allograft reconstruction after knee arthroplasty is presented. RESULTS: Median follow-up is 25 months (20-31). Functional assessment improved, and the knee society score and knee functional score improved from 26 and 16 to 82 and 55, respectively. Median extension lag was 5° (0°-20°), with a median range of motion of 95° (70-100). Radiological study showed a rise of the patella of 22.26 mm. CONCLUSION: The use of fresh-frozen allografts as a solution to patellar tendon ruptures after knee arthroplasty seems to provide acceptable results. Increased patellar height does not seem to affect functionality. LEVEL OF EVIDENCE: Case series, Level IV.

[Methylenetetrahydrofolate reductase polymorphisms as risk factors for myelomeningocele]. / Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile.

BACKGROUND: Mandatory fortification with folic acid (FA) was implemented in Chile in 2000. Thereafter, the rate of spina bifida decreased by 52 to 55%. Genetic abnormalities in folate metabolism may be involved in the etiology of spina bifida. AIM: To evaluate the association between myelomeningocele (MM) and c.A1298C and c.C677T polymorphisms within the coding gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) in the Chilean population. MATERIAL AND METHODS: These polymorphisms were genotyped in 105 patients showing isolated MM, born after the onset of FA fortification, and in their parents. The transmission disequilibrium test (TDT) was performed to evaluate alterations in the transmission of both alleles and haplotypes MTHFR polymorphism. We also evaluated the presence of parent-origin-effect (POE) of alleles using the Clayton's extension of the TDT. RESULTS: TDT analysis showed no significant distortions in the transmission of alleles or haplotypes. Moreover, although the POE showed increased risk for maternally derived allele, this risk was not statistically significant. CONCLUSIONS: The studied variants in the MTHFR gene (c.C677T and c.A1298C) do not constitute risk factors for MM in this sample of Chilean patients and their parents.

Simulating real-life scenarios to better understand the spread of diseases under different contexts.

Current statistical models to simulate pandemics miss the most relevant information about the close atomic interactions between individuals which is the key aspect of virus spread. Thus, they lack a proper visualization of such interactions and their impact on virus spread. In the field of computer graphics, and more specifically in computer animation, there have been many crowd simulation models to populate virtual environments. However, the focus has typically been to simulate reasonable paths between random or semi-random locations in a map, without any possibility of analyzing specific individual behavior. We propose a crowd simulation framework to accurately simulate the interactions in a city environment at the individual level, with the purpose of recording and analyzing the spread of human diseases. By simulating the whereabouts of agents throughout the day by mimicking the actual activities of a population in their daily routines, we can accurately predict the location and duration of interactions between individuals, thus having a model that can reproduce the spread of the virus due to human-to-human contact. Our results show the potential of our framework to closely simulate the virus spread based on real agent-to-agent contacts. We believe that this could become a powerful tool for policymakers to make informed decisions in future pandemics and to better communicate the impact of such decisions to the general public.

Factors to consider for fascial plane blocks' success in acute and chronic pain management.

The outcome of fascial plane blocks (FPBs) has a certain variability that may depend on many factors, which can be divided into three main categories: operator-related, patient-related and drug-related. Operator-related factors include personal skills, choice of needle and injection modalities. Patient variables include anthropometric features, the type of targeted fascia, anatomical variants, patient positioning, muscle tone and breathing. Ultimately, efficacy, onset, and duration of fascial blocks may be affected by characteristics of the injected solution, including the type of local anesthetic, volume, concentration, pH, temperature and the use of adjuvants. In this article, we investigated all the factors that may influence the outcome of FPBs from a generic perspective, without focusing on any specific technique. Also, we provided suggestions to optimize techniques for everyday practitioners and insights to researchers for future studies.

HDACi vorinostat protects muscle from degeneration after acute rotator cuff injury in mice.

Aims: Rotator cuff (RC) injuries are characterized by tendon rupture, muscle atrophy, retraction, and fatty infiltration, which increase injury severity and jeopardize adequate tendon repair. Epigenetic drugs, such as histone deacetylase inhibitors (HDACis), possess the capacity to redefine the molecular signature of cells, and they may have the potential to inhibit the transformation of the fibro-adipogenic progenitors (FAPs) within the skeletal muscle into adipocyte-like cells, concurrently enhancing the myogenic potential of the satellite cells. Methods: HDACis were added to FAPs and satellite cell cultures isolated from mice. The HDACi vorinostat was additionally administered into a RC injury animal model. Histological analysis was carried out on the isolated supra- and infraspinatus muscles to assess vorinostat anti-muscle degeneration potential. Results: Vorinostat, a HDACi compound, blocked the adipogenic transformation of muscle-associated FAPs in culture, promoting myogenic progression of the satellite cells. Furthermore, it protected muscle from degeneration after acute RC in mice in the earlier muscle degenerative stage after tenotomy. Conclusion: The HDACi vorinostat may be a candidate to prevent early muscular degeneration after RC injury.

The effects of a prehabilitation programme based on therapeutic exercise, back care education, and pain neuroscience education in patients scheduled for lumbar radiculopathy surgery: A study protocol for a randomised controlled trial.

The aim of this present clinical trial is to evaluate the effectiveness of a multicomponent prehabilitation programme administered through educational videos versus another programme based on written exercise recommendations, in patients scheduled for lumbar radiculopathy surgery. This study will be a multicentre, controlled, randomised, parallel clinical trial. One hundred participants undergoing lumbar radiculopathy surgery who meet the established inclusion criteria will be recruited at different Spanish hospitals. The experimental group will follow a 4-week prehabilitation programme combining therapeutic exercise, back care education, and pain neuroscience education delivered through videos designed for consumption at home. The control group will be provided with written instructions to perform therapeutic exercises during the same prehabilitation time period. The primary outcome of the study will be disability, assessed using the Spanish version of the Oswestry Disability Index. The secondary outcomes will be pain perception, health-related quality of life, fear avoidance, kinesiophobia, catastrophising, anxiety, depression, physical activity, and the treatment satisfaction of the patients. This study will provide evidence for the effectiveness of a home-based multicomponent prehabilitation programme that addresses some already identified barriers to patient attendance in face-to-face programmes. Understanding the medium and long-term effects of pre-surgery lumbar muscle training and pain neuroscience education administered via instructional videos watched by patients at home, will help improve the design of prehabilitation programmes in this population while also improving the cost-effectiveness of such interventions.

Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population.

Genome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0-2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04-2.07, P = 0.026 and OR = 2.04 95 % CI 1.32-3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06-1.65, P = 0.012; OR = 1.46, 95 % CI 1.11-1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.

[Intrahepatic cholestasis of pregnancy: a case report and review of the literature]. / Colestasis intrahepática del embarazo: reporte de un caso y revisión de la bibliografía.

Intrahepatic cholestasis of pregnancy has a prevalence of 1/1000 to 1/10000. Its etiology is multifactorial, involving genetic an hormonal factors, associated with adverse perinatal and obstetric outcomes. Report the case of patient 25 years old, with 32 weeks of gestation, which presents severe pruritus, jaundice, altered liver function tests and lipid profile, with presumptive diagnosis of intrahepatic cholestasis of pregnancy. Making weekly monitoring analytical biochemistry, test of fetal wellbeing, symptomatic management, with abdominal pregnancy termination at 35 weeks, for lack of clinical improvement, increase in metabolic disorders and intrauterine growth restriction, after induction of fetal lung maturity, with good obstetric and perinatal outcome. Definitive diagnosis by liver biopsy.