Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. ...Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD (PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.
Clinical management of polycystic liver disease van Aerts, René M.M.; van de Laarschot, Liyanne F.M.; Banales, Jesus M. ...
Journal of hepatology,
April 2018, 2018-04-00, 20180401, Volume:
68, Issue:
4
Journal Article
Peer reviewed
Open access
A 41-year old female underwent a computed tomography (CT) scan in 2010 because of symptoms suggestive of appendicitis. Incidentally, multiple liver lesions characterised as cysts were detected. The ...presence of small to medium sized liver cysts (diameter between <1 cm and 4 cm) in all liver segments (>100 cysts) and absence of kidney cysts in the context of normal renal function led to the clinical diagnosis of autosomal dominant polycystic liver disease (ADPLD). Five years later she was referred to the outpatient clinic with increased abdominal girth, pain in the right upper abdomen and right flank, and early satiety. She had difficulties bending over and could neither cut her toenails nor tie her shoe laces. In her early twenties she had used oral contraception for five years. She has been pregnant twice. Clinical examination showed an enlarged liver reaching into the right pelvic region and crossing the midline of the abdomen. Laboratory testing demonstrated increased gamma-glutamyl transferase (80 IU/L, normal <40 IU/L) and alkaline phosphatase (148 IU/L, normal <100 IU/L) levels. Bilirubin, albumin and coagulation times were within the normal range. A new CT scan in 2015 was compatible with an increased number and size of liver cysts. The diameter of cysts varied between <1 cm and 6 cm (anatomic distribution shown Fig. 2B). There were no signs of hepatic venous outflow obstruction, portal hypertension or compression on the biliary tract. Height-adjusted total liver volume (htTLV) increased from 2,667 ml/m in 2012 to 4,047 ml/m in 2015 (height 172 cm).
The case we present here is not uncommon, and prompts several relevant questions:I.What causes the development of liver cysts?II.Is genetic testing and genetic counselling recommended?III.What is the natural course of polycystic liver disease and what can patients do to stop growth of liver cysts?IV.Which complications may occur during the course of polycystic liver disease?V.What treatment options are currently available?VI.What other potential new and effective therapies will be available in the near future?
The voltage-gated sodium-channel type IX alpha subunit, known as Na(v)1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in ...these cells. Recent genetic studies have identified Na(v)1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Na(v)1.7 in pain sensation in humans.
Numerous pharmacological compounds that target the different molecular targets involved in the pathobiology of nonalcoholic steatohepatitis (NASH) are currently in clinical testing. So far, there are ...no regulatory approvals.
This paper sheds light on the molecular pathways involved in NASH and the drugs targeting these pathways. We have identified 10 compounds whose clinical development program has been halted. Moreover, we explore early phase clinical trials and dissect the reasons for termination of development.
The main goal of NASH pharmacotherapy is to halt or reverse hepatic fibrosis or to achieve the resolution of steatohepatitis. There is an intense competition to develop compounds with disease-modulating properties with a focus on anti-metabolic, anti-inflammatory or anti-fibrotic properties. Numerous study programs, even in late-phase trials, have been halted because of lack of efficacy, safety concerns or drug-drug interactions. This underscores the urgent need to provide robust preclinical data and an extensive clinical trial program that builds on reliable data generated in earlier stages of clinical development before moving into late stage development.
Polycystic liver disease (PLD) is arbitrarily defined as a liver that contains >20 cysts. The condition is associated with two genetically distinct diseases: as a primary phenotype in isolated ...polycystic liver disease (PCLD) and as an extrarenal manifestation in autosomal dominant polycystic kidney disease (ADPKD). Processes involved in hepatic cystogenesis include ductal plate malformation with concomitant abnormal fluid secretion, altered cell-matrix interaction and cholangiocyte hyperproliferation. PLD is usually a benign disease, but can cause debilitating abdominal symptoms in some patients. The main risk factors for growth of liver cysts are female sex, exogenous oestrogen use and multiple pregnancies. Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver and to differentiate between ADPKD and PCLD. Current radiological and surgical therapies for symptomatic patients include aspiration-sclerotherapy, fenestration, segmental hepatic resection and liver transplantation. Medical therapies that interact with regulatory mechanisms controlling expansion and growth of liver cysts are under investigation. Somatostatin analogues are promising; several clinical trials have shown that these drugs can reduce the volume of polycystic livers. The purpose of this Review is to provide an update on the diagnosis and management of PLD with a focus on literature published in the past 4 years.
To date, intergenotypic recombinant hepatitis C viruses (HCVs) and their treatment outcomes have not been well characterized. This study characterized 12 novel HCV recombinant strains and their ...response to sofosbuvir in combination with ribavirin (SOF/RBV) treatment. Across the phase II/III studies of SOF, HCV samples were genotyped using both the Siemens VERSANT HCV Genotype INNO‐LiPA 2.0 Assay (Innogenetics, Ghent, Belgium) and nonstructural (NS)5B sequencing. Among these patient samples, genotype assignment discordance between the two methods was found in 0.5% of all cases (12 of 2,363), of which all were identified as genotype 2 by INNO‐LiPA (12 of 487; 2.5%). HCV full‐genome sequences were obtained for these 12 samples by a sequence‐independent amplification method coupled with next‐generation sequencing. HCV full‐genome sequencing revealed that these viruses were recombinant HCV strains, with the 5' part corresponding to genotype 2 and the 3' part corresponding to genotype 1. The recombination breakpoint between genotypes 2 and 1 was consistently located within 80 amino acids of the NS2/NS3 junction. Interestingly, one of the recombinant viruses had a 34‐amino‐acid duplication at the location of the recombination breakpoint. Eleven of these twelve patients were treated with a regimen for genotype 2 HCV infection, but responded as if they had genotype 1 infection; 1 patient had received placebo. Conclusion: Twelve new HCV intergenotypic recombinant genotype 2/1 viruses have been characterized. The antiviral response to a 12‐ to 16‐week course of SOF/RBV treatment in these patients was more similar to responses among genotype 1 patients than genotype 2 patients, consistent with their genotype 1 NS5B gene (Hepatology 2015;61:471‐480)
Background & Aims Predniso(lo)ne with or without azathioprine is considered the mainstay in the treatment of autoimmune hepatitis (AIH), but many therapeutic options are available. The primary ...objective of this review was to explore the published literature on the optimal induction and subsequent maintenance therapy for AIH. Methods We performed a systematic search on electronic databases MEDLINE (1950-07.2009), Web of Science, Cochrane, and the website www.clinicaltrials.gov . Randomized controlled trials (RCTs) on apparent beneficial treatment regimens as induction or maintenance treatment in AIH were included. Pediatric studies were excluded. We calculated relative risks (RR) for comparison of treatment options on the primary outcome measure, which was defined as clinical, biochemical and histological remission. Results Eleven RCTs were included, of which 7 studies evaluated the induction therapy in AIH patients: 3 treatment naive ( n = 253), 2 relapse ( n = 53), 2 combination of naive and relapse ( n = 110). The remaining 4 studies ( n = 162) assessed maintenance therapy. All but one maintenance study (thymostimulin versus no therapy) studied predniso(lo)ne (PRED), azathioprine (AZA) or combination PRED + AZA. We found no differences in primary outcome between induction therapy with PRED and PRED + AZA in treatment naive patients (RR = 0.98; 95% CI 0.65–1.47). AZA monotherapy as induction was considered as not viable because of a high mortality rate (30%). This was similar in AIH patients who relapsed: RR for PRED versus PRED + AZA for inducing remission was not different: 0.71 (95% CI 0.37–1.39). PRED + AZA maintained remission more often than PRED (RR = 1.40; 95% CI 1.13–1.73). Also AZA maintained a higher remission rate than PRED (RR = 1.35; 95% CI 1.07–1.70). Maintenance of remission was not different between PRED + AZA and AZA (RR = 1.06; 95% CI 0.94–1.20). Conclusions Based on available RCTs, PRED monotherapy and PRED + AZA combination therapy are both viable induction therapies for AIH treatment naives and relapsers, while for maintenance therapy PRED + AZA and AZA therapy are superior to PRED monotherapy.
Summary Background & aims Gluten-free diet is the keystone of coeliac disease treatment. Despite adherence, some patients continue to suffer from symptoms that negatively influence health-related ...quality of life (HRQoL). Therefore we performed a systematic review and meta-analysis to assess the effect of gluten-free diet on HRQoL in coeliac disease. We specifically sought for determinants that negatively influenced HRQoL. Methods We systematically searched PubMed, EMBASE, CINAHL, PsycINFO and Cochrane Library for studies assessing HRQoL in untreated or treated adults using validated HRQoL-questionnaires from 1960 to September 2015, comparing HRQoL: (1) before and after gluten-free diet initiation or (2) in patients and non-coeliac controls. Results We included eighteen studies and sixteen were suitable for meta-analysis. Gluten-free diet significantly improves HRQoL, for psychological general well-being (PGWB)-Total (mean difference (MD) 7.34, 95% confidence interval (CI) 1.96; 12.72; p = 0.008), SF-36 Mental Component Score (MCS) (MD 7.37, 95% CI 1.84; 12.90; p = 0.009) and SF-36 Physical Component Score (PCS) (MD 5.72, 95% CI 1.50; 9.95; p = 0.008). Treated patients had similar HRQoL compared with controls for PGWB-Total (MD −0.72, 95% CI −2.71; 1.27; p = 0.48), but significantly lower levels for SF-36 MCS (MD −4.09, 95% CI −6.17; −2.01; p = 0.0001) and PCS (MD −4.57, 95% CI −6.97; −2.17; p = 0.0002). Symptom-detected gluten-free diet adhering patients have lower HRQoL compared with screening-detected patients (MD −3.73, 95% CI −6.77;−0.69; p = 0.02) Strict adhering patients have better HRQoL compared with non-strict adhering patients for SF-36 MCS (MD 7.70, 95% CI 4.61; 10.79; p < 0.00001) and for SF-36 PCS (MD 3.23, 95% CI 1.33; 5.14; p = 0.0009). Conclusions Gluten-free diet significantly improves but does not normalize HRQoL in adults with coeliac disease. Dietary adherence improves HRQoL. Better (self-reported) dietary adherence results in higher HRQoL.
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