scholarly journals Intra-articular hyaluronic acid in the treatment of knee osteoarthritis: a Canadian evidence-based perspective

2017 ◽  
Vol 9 (9) ◽  
pp. 231-246 ◽  
Author(s):  
Mohit Bhandari ◽  
Raveendhara R. Bannuru ◽  
Eric M. Babins ◽  
Johanne Martel-Pelletier ◽  
Moin Khan ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Symptom Relief ◽  
Cochrane Review ◽  
Pharmacological Therapy ◽  
Therapeutic Effects ◽  
Loss Of Function ◽  
Serious Adverse Events ◽  
Knee Oa ◽  
Therapeutic Benefits ◽  
Increased Risk

Osteoarthritis (OA) is a chronic condition characterized by a loss of joint cartilage and is a major cause of disability in Canada, with an estimated CN$195 billion annual cost. Knee OA leads to persistent pain and loss of function, and treatment goals primarily focus on symptom relief and retention of function. Intra-articular hyaluronic acid (IAHA) has therapeutic benefits, and numerous recently published meta-analyses (MAs) and commentaries have highlighted new evidence on the role of IAHA therapy for knee OA. A diverse, multidisciplinary group of specialists met independently in closed sessions to review findings from eight MAs with literature search end dates no earlier than 2012 to address controversies surrounding IAHA therapy for mild-to-moderate knee OA within the Canadian treatment context. Outcomes from a total of eight MAs were reviewed, and consistent and statistically significant improvements in pain, function and stiffness up to 26 weeks were found with IAHA therapy compared with IA placebo or controls, regardless of MA size or trial quality. These findings are in line with those of a Cochrane review, another recent systematic review and patient satisfaction survey. Overall, three MAs reported outcomes based on molecular weight (MW), with the two reporting effect sizes showing significantly improved pain outcomes for higher compared with lower MW HAs. Recent evidence suggests that HA therapy is well tolerated with no increased risk of serious adverse events compared with placebo and the full therapeutic effect of IAHA therapy appears to have considerable clinical importance, consisting of the combined IA placebo and HA therapeutic effects. IAHA therapy is a well-tolerated and effective option for patients with mild-to-moderate knee OA failing first-line pharmacological therapy.

scholarly journals A Prospective Study Evaluating Intra-Articular Hyaluronic Acid (1 ml) for Ankle Osteoarthritis

2017 ◽  
Vol 2 (3) ◽  
pp. 2473011417S0004
Author(s):  
Alastair Younger ◽  
Kevin Wing ◽  
Andrea Veljkovic ◽  
Murray Penner
Keyword(s):  
Hyaluronic Acid ◽  
Adverse Events ◽  
Pain Score ◽  
Symptom Relief ◽  
Loss Of Function ◽  
Ankle Arthritis ◽  
Variable Effect ◽  
Duration Of Effect ◽  
Patient Reported ◽  
Cortisone Injection

Category: Ankle Arthritis Introduction/Purpose: Early ankle arthritis can result in disabling symptoms and loss of function. However the degree of arthritis may not be severe enough or the symptoms severe enough to merit a fusion or replacement. For other patients they may wish to delay surgery to avoid financial issues with recovery time. Many of these patients have also been treated with NSAIDs, physiotherapy and bracing with variable effect. Stabilized long chain Hyaluronic acid (NASHA) has been used successfully in the knee, and has given a longer duration of effect compared to steroid injection. The purpose of this study was to determine the effect of hyaluronic acid in the ankle for sustainable symptom relief. Methods: A power analysis determined that a minimum of 29 patients would be required to appropriately power the study. A total of 37 adult patients with KL grade II and III ankle arthritis were enrolled in the study at a single institution. Patients recruited via a newspaper advertisement and from the surgical clinics and and screened for standard inclusion and exclusion criteria. The VAS pain preoperatively had to be greater than 30 / 100 mm. Outcomes were recorded at baseline, weeks 6, 12 and 26. The injection was performed after the baseline assessment using 1 ml of Hyaluronic acid NASHA (Q-Med AB, Uppsala, Sweden; DUROLANE 10 mg / mL) with or without local anesthetic to the skin. Outcomes included a VAS from the AOS scale for pain and disability, review of adverse events, physical exam, and use of rescue medication. Results: 35 of 37 patients completed the study. At baseline the VAS pain was 7.2 (SD +/-1.8). At 6 weeks the pain score was 5.4 (+/-2.5) improving by 1.8 points with a 26% improvement. At 12 weeks the pain score was 5.3 (+/-2.7) for a 29% improvement. At week 26 the pain score was 5 (+/- 2.7) for a 32% improvement. 4 adverse events were recorded – one patient reported increased pain after injection. One reported pain and swelling, one reported inflammation, and one pain after injection. Conclusion: This prospective cohort study shows promise for the use of Hyaluronic acid for the treatment of ankle arthritis with relief of symptoms up to 26 weeks after injection. The injection was safe for all 37 patients, although one patient reported pain and dropped out of the study. We would support the use of Hyaluronic acid for the treatment for moderate ankle arthritis. An RCT would be merited based on this study to compare results with placebo or cortisone injection.

scholarly journals Longterm Effectiveness of Intraarticular Injections on Patient-reported Symptoms in Knee Osteoarthritis

2018 ◽  
Vol 45 (9) ◽  
pp. 1316-1324 ◽  
Author(s):  
Shao-Hsien Liu ◽  
Catherine E. Dubé ◽  
Charles B. Eaton ◽  
Jeffrey B. Driban ◽  
Timothy E. McAlindon ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Knee Osteoarthritis ◽  
Corticosteroid Injection ◽  
Symptom Relief ◽  
Structural Models ◽  
Marginal Structural Models ◽  
Knee Oa ◽  
Patient Reported ◽  
User Design ◽  
Injection Use

Objective.We examined the longterm effectiveness of corticosteroid or hyaluronic acid injections in relieving symptoms among persons with knee osteoarthritis (OA).Methods.Using Osteoarthritis Initiative data, a new-user design was applied to identify participants initiating corticosteroid or hyaluronic acid injections (n = 412). Knee symptoms (pain, stiffness, function) were measured using The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). We used marginal structural models adjusting for time-varying confounders to estimate the effect on symptoms of newly initiated injection use compared to nonusers over 2 years of followup.Results.Among 412 participants initiating injections, 77.2% used corticosteroid injections and 22.8% used hyaluronic acid injections. About 18.9% had additional injection use after initiation, but switching between injection types was common. Compared to nonusers, on average, participants initiating a corticosteroid injection experienced a worsening of pain (yearly worsening: 1.24 points, 95% CI 0.82–1.66), stiffness (yearly worsening: 0.30 points, 95% CI 0.10–0.49), and physical functioning (yearly worsening: 2.62 points, 95% CI 0.94–4.29) after adjusting for potential confounders with marginal structural models. Participants initiating hyaluronic acid injections did not show improvements of WOMAC subscales (pain: 0.50, 95% CI −0.11 to 1.11; stiffness: −0.07, 95% CI −0.38 to 0.24; and functioning: 0.49, 95% CI −1.34 to 2.32).Conclusion.Although intraarticular injections may support the effectiveness of reducing symptoms in short-term clinical trials, the initiation of corticosteroid or hyaluronic acid injections did not appear to provide sustained symptom relief over 2 years of followup for persons with knee OA.

scholarly journals Therapeutic effects of turmeric or curcumin extract on pain and function for individuals with knee osteoarthritis: a systematic review

2021 ◽  
Vol 7 (1) ◽  
pp. e000935
Author(s):  
Kristopher Paultre ◽  
William Cade ◽  
Daniel Hernandez ◽  
John Reynolds ◽  
Dylan Greif ◽  
...  
Keyword(s):  
Knee Osteoarthritis ◽  
Physical Function ◽  
Therapy Group ◽  
Cochrane Review ◽  
Final Analysis ◽  
Cochrane Collaboration ◽  
Allocation Concealment ◽  
Therapeutic Effects ◽  
Knee Oa ◽  
And Function

PurposeTo determine whether supplementation with turmeric or curcumin extract effects pain and physical function in individuals with knee osteoarthritis (OA). Second, we investigated the therapeutic response (pain and function) of turmeric compared with non-steroidal anti-inflammatory drugs (NSAIDs).MethodsA search was conducted in MEDLINE, Embase, CINAHL and Cochrane Review. Inclusion criteria included randomised controlled trials reporting pain and physical function in humans with knee OA comparing turmeric therapy with NSAIDs or no therapy. Two reviewers screened 5273 abstracts. Risk of bias and quality were assessed via Cochrane Collaboration tool and CONSORT (Consolidated Standards of Reporting Trials) 2010, respectively.ResultsTen studies were included in the final analysis. Eight had high methodological quality and two were categorised as good with a mean CONSORT quality score of 21.1. Nine studies had adequate sequence generation and six had adequate allocation concealment. Participants and outcome assessors were blinded in eight studies. Three of the studies compared turmeric therapy to NSAIDs. All 10 studies showed improvement in pain and function from baseline with turmeric therapy (p≤0.05). In three studies comparing turmeric to NSAIDs, there were no differences in outcome scores (p>0.05). In all studies there were no significant adverse events in the turmeric therapy group.ConclusionCompared with placebo, there appears to be a benefit of turmeric on knee OA pain and function. Based on a small number of studies the effects are similar to that of NSAIDs. Variables such as optimal dosing, frequency and formulation remain unclear at this time.

scholarly journals A Systematic Review of Current Clinical Practice Guidelines on Intra-articular Hyaluronic Acid, Corticosteroid, and Platelet-Rich Plasma Injection for Knee Osteoarthritis: An International Perspective

2021 ◽  
Vol 9 (8) ◽  
pp. 232596712110302
Author(s):  
Mark Phillips ◽  
Mohit Bhandari ◽  
John Grant ◽  
Asheesh Bedi ◽  
Thomas Trojian ◽  
...  
Keyword(s):  
Systematic Review ◽  
Hyaluronic Acid ◽  
Clinical Practice ◽  
Knee Osteoarthritis ◽  
Clinical Practice Guidelines ◽  
Practice Guidelines ◽  
Platelet Rich Plasma ◽  
Symptom Relief ◽  
Current Evidence ◽  
Knee Oa

Background: There are many clinical practice guidelines (CPGs) for the prevention, diagnosis, and treatment of knee osteoarthritis (OA). They differ by region, considering local health care systems, along with cultural and economic factors. Currently, there are conflicting CPG recommendations across the various publications, which makes it difficult for clinicians to fully understand the optimal treatment decisions for knee OA management. Purpose: To summarize the current published CPG recommendations for the role of injections in the nonoperative management of knee OA, specifically with the use of intra-articular hyaluronic acid (IA-HA), intra-articular corticosteroids (IA-CS), and platelet-rich plasma (PRP). Study Design: Systematic review. Methods: A comprehensive search identified all nonoperative knee OA CPGs within the ECRI (formerly Emergency Care Research Institute) Guidelines Trust database, the Guidelines International Network database, Google Scholar, and the Trip (formerly Turning Research Into Practice) database. Guideline recommendations were categorized into strong, conditional, or uncertain recommendations for or against the use of IA-HA, IA-CS, or PRP. Guideline recommendations were summarized and depicted graphically to identify trends in recommendations over time. Results: The search strategy identified 27 CPGs that provided recommendations. There were 20 recommendations in favor of IA-HA use, 21 recommendations in favor of IA-CS use, and 9 recommendations that were uncertain or unable to make a formal recommendation for or against PRP use based on current evidence. Most recommendations considered IA-HA and IA-CS use for symptom relief when other nonoperative options are ineffective. IA-CS were noted to provide fast and short-acting symptom relief for acute episodes of disease exacerbation, while IA-HA may demonstrate a relatively delayed but prolonged effect in comparison. The CPGs concluded that PRP recommendations currently lack evidence to definitively recommend for or against use. Conclusion: Available CPGs provide recommendations on injectables for knee OA treatment. General guidance from a global perspective concluded that IA-CS and IA-HA are favored for different needed responses and can be utilized within the knee OA treatment paradigm, while PRP currently has insufficient evidence to make a conclusive recommendation for or against its use.

scholarly journals Increasing Intrinsic Hyaluronic Acid and Down-regulation of Inflammation Markers in Synovial Fluid from Patients with Knee Osteoarthritis may be Associated with Symptom Relief after Intra-articular Injection of Hyaluronic Acid

2021 ◽  
Author(s):  
Jih-Hsi Yeh ◽  
Po-Yen Ko ◽  
Chung-Jung Shao ◽  
Kuo-Chen Wu ◽  
Tai-Chang Chern ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Synovial Fluid ◽  
Knee Osteoarthritis ◽  
Symptom Relief ◽  
Functional Improvement ◽  
Ultrasound Guided ◽  
Analog Scale ◽  
Knee Oa ◽  
Significant Difference ◽  
Womac Questionnaire

Abstract Background: Hyaluronic acid (HA) is the most common intra-articular therapy used to treat mild to moderate osteoarthritis (OA). However, the mechanism involved in this treatment is still not fully understood. The aim of the present study was to examine the effect and the possible mechanism of intra-articular HA (IAHA) injection in patients with knee osteoarthritis (OA).Methods: Twenty-eight patients with Kellgren–Lawrence scale II to III were enrolled in this study. All patients underwent ultrasound-guided injection using three consecutive weekly IAHA. Functional ability and pain were determined by the Western Ontario and McMaster University Index (WOMAC) questionnaire and visual analog scale (VAS). Further, the levels of HA, metalloproteinase (MMP)-1, MMP-3, MMP-13, interleukin (IL)-1β and IL-6 in synovial fluid were determined weekly before HA injection. Results: Functional improvement and pain relief were observed 4 weeks after treatment. At week 4, a significant increase of HA concentration was found, and the concentration of inflammatory cytokines including IL-1β, and IL-6, as well as matrix MMP-3 and MMP-13 significantly decreased. However, no significant difference was observed in MMP-1 level. Conclusion: These results suggest that increasing HA accumulation in synovial fluid may be associated with disease relief after weekly IAHA injection in patients with knee OA.

scholarly journals FRI0398 COMPARISON OF THE EFFICACY AND SAFETY OF TWO HYALURONIC ACIDS IN THE TREATMENT OF KNEE OSTEOARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 797.2-797
Author(s):  
B. Cortet ◽  
S. Lombion ◽  
O. Bruyere
Keyword(s):  
Hyaluronic Acid ◽  
Oral Treatment ◽  
Demographic Data ◽  
Primary Objective ◽  
Womac Pain ◽  
Efficacy And Safety ◽  
Primary Analysis ◽  
Serious Adverse Events ◽  
Knee Oa ◽  
Significant Difference

Background:Several viscosupplement treatments are available to patients suffering from osteoarthritis (OA) but few comparative clinical trials have been conducted.Objectives:The primary objective of the study was to demonstrate at 24 weeks the non-inferiority of on hyaluronic acid over a second one in terms of efficacy (pain relief) in knee OA patients (Kellgren and Lawrence radiologic stage II or III) with whom oral treatment had failed.Methods:This was a prospective, multicenter, comparative, randomized, double-blinded study (one independent physician evaluator–one physician injector), comparing two viscosupplements: one containing a solution of hyaluronic acid (SYNOLIS VA® 80mg hyaluronic acid and 160 mg sorbitol – Group HA1) and the other containing one of Hylan (SYNVISC ONE ® 48 mg Hylane GF-20 – Group HA2) over a period of 24 weeks. At inclusion, the average VAS Pain (1-100) was 62.5. The patients were randomized in 2 parallel groups at D0 and followed until D168. They received an injection of either HA1 or HA2. Efficacy was primarily assessed using the WOMAC Pain index (daily assessed by the patient during seven days following the injection, and then at D14). During the follow up visits (D28-D84-D168) WOMAC pain, stiffness and function scores were assessed as secondary objectives. At D168, efficacy and satisfaction were also evaluated by the evaluator and by the patient using Likert scale (7 points). Moreover, the number of responders strict each group was evaluated according to the OMERACT-OARSI criteria. According to methodology guidelines, the per protocol (PP) population has been used as primary analysis. The PP population included all patients from the intention to treat (ITT) population who completed the study without any major protocol violation.Results:202 patients were randomized (ITT population, 96 in the HA1 group and 106 in the HA2 group). Baseline demographic data for the PP population at the time of randomization by treatment group. Patients were predominantly female (66%). The median age of the whole population was 65 years and the median body mass index of 27.4 kg/m2. No statistically significant differences between the two treatment groups were observed for any demographic criteria. At D168, 197 presented no protocol violations (94 in the HA1 group and 103 in the HA2 group). This population had a decrease on the overall score of the WOMAC Pain at -29.2+/- 24.1 (SD) in the HA1 group and -31.6 +/-25.5 (SD) in the HA2 group confirming the non-inferiority (P = 0.57 for the difference between groups). Regarding the secondary endpoints, no significant difference has been observed at D14, D28, D84, D168, in the PP population for all the outcome except stiffness at D28. There was also no difference between the responders rate in two groups (79 % for HA1 and 77% for HA2). In terms of safety, both products were well tolerated. No case of allergy or infection in the course of the injection was reported. Serious adverse events have been reported by 4 patients in HA1 group and 3 in HA2 group.Conclusion:In this study, we confirmed the non-inferiority of HA1 compared with HA2 in terms of both efficacy and safety.Disclosure of Interests:Bernard Cortet Consultant of: Aptissen, Sandrine Lombion Consultant of: Aptissen, Olivier Bruyere Consultant of: Aptissen

1,4-Dihydropyridine: A Dependable Heterocyclic Ring with the Promising and the Most Anticipable Therapeutic Effects

2019 ◽  
Vol 19 (15) ◽  
pp. 1219-1254 ◽  
Author(s):  
Abhinav Prasoon Mishra ◽  
Ankit Bajpai ◽  
Awani Kumar Rai
Keyword(s):  
Calcium Ion ◽  
Heterocyclic Compounds ◽  
Channel Blocker ◽  
Heterocyclic Ring ◽  
Therapeutic Effects ◽  
Voltage Gated ◽  
Therapeutic Benefits ◽  
Anti Cancer ◽  
Anti Oxidant ◽  
Synthetic Medicinal

: Nowadays, heterocyclic compounds act as a scaffold and are the backbone of medicinal chemistry. Among all of the heterocyclic scaffolds, 1,4-Dihydropyridine (1,4-DHP) is one of the most important heterocyclic rings that possess prominent therapeutic effects in a very versatile manner and plays an important role in synthetic, medicinal, and bioorganic chemistry. The main aim of the study is to review and encompass relevant studies related to 1,4-DHP and excellent therapeutic benefits of its derivatives. An extensive review of Pubmed-Medline, Embase and Lancet’s published articles was done to find all relevant studies on the activity of 1,4-DHP and its derivatives. 1,4-DHP is a potent Voltage-Gated Calcium Channel (VGCC) antagonist derivative which acts as an anti-hypertensive, anti- anginal, anti-tumor, anti-inflammatory, anti-tubercular, anti-cancer, anti-hyperplasia, anti-mutagenic, anti-dyslipidemic, and anti-ulcer agent. From the inferences of the study, it can be concluded that the basic nucleus, 1,4-DHP which is a voltage-gated calcium ion channel blocker, acts as a base for its derivatives that possess different important therapeutic effects. There is a need of further research of this basic nucleus as it is a multifunctional moiety, on which addition of different groups can yield a better drug for its other activities such as anti-convulsant, anti-oxidant, anti-mutagenic, and anti-microbial. This review would be significant for further researches in the development of several kinds of drugs by representing successful matrix for the medicinal agents.

Effects of Intensive Blood Pressure Control in Patients with Evident Cardiovascular Disease: An Investigation Using the SPRINT Study Data

2019 ◽  
Vol 17 (3) ◽  
pp. 298-306 ◽  
Author(s):  
Charalambos Vlachopoulos ◽  
Dimitrios Terentes-Printzios ◽  
Konstantinos Aznaouridis ◽  
Nikolaos Ioakeimidis ◽  
Panagiotis Xaplanteris ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Beneficial Effect ◽  
Harmful Effect ◽  
Adverse Outcomes ◽  
Intensive Treatment ◽  
Serious Adverse Events ◽  
Stroke Incidence ◽  
Increased Risk ◽  
All Cause Mortality

Background: Recent data advocate adoption of a more intensive treatment strategy for management of blood pressure (BP). </P><P> Objective: We investigated whether the overall effects of the Systolic Blood Pressure Intervention Trial (SPRINT) are applicable to cardiovascular disease (CVD) patients. </P><P> Methods: In a post hoc analysis we analyzed data from SPRINT that randomly assigned 9361 individuals to a systolic BP (SBP) target of <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). 1562 patients had clinically evident CVD (age=70.3±9.3 years, 24% females) at study entry and were followed for 3.1 years. Further, we assessed the effect of low (<150 mmHg) baseline SBP on outcome. </P><P> Results: In CVD patients, there was no benefit from the intensive treatment regarding all endpoints, except for a marginally significant benefit on all-cause mortality (hazard ratio [HR]: 0.67; 95% confidence interval [CI], 0.45 to 1.00; p=0.0509). Further, while there was no increase in serious adverse events (SAE) in the intensive group, there was increased risk for study-related SAE, acute renal failure and electrolyte abnormalities. In patients with low baseline SBP there was a beneficial effect on allcause mortality (HR: 0.56; 95% CI: 0.33 to 0.96; p=0.033), but with greater stroke incidence (HR: 2.94; 95% CI: 1.04 to 8.29; p=0.042). </P><P> Conclusion: We confirm the beneficial effect of the intensive strategy in SPRINT study on all-cause mortality and the harmful effect on specific adverse outcomes in patients with CVD. However, in patients with low baseline SBP stroke may increase.

Effects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases

2019 ◽  
Vol 14 (5) ◽  
pp. 442-452 ◽  
Author(s):  
Wenjie Zheng ◽  
Yumin Yang ◽  
Russel Clive Sequeira ◽  
Colin E. Bishop ◽  
Anthony Atala ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Liver Diseases ◽  
Therapeutic Potential ◽  
Mechanisms Of Action ◽  
Therapeutic Effects ◽  
Chronic Liver Injury ◽  
Mediated Effects ◽  
Therapeutic Benefits

Therapeutic effects of Mesenchymal Stem/Stromal Cells (MSCs) transplantation have been observed in various disease models. However, it is thought that MSCs-mediated effects largely depend on the paracrine manner of secreting cytokines, growth factors, and Extracellular Vesicles (EVs). Similarly, MSCs-derived EVs also showed therapeutic benefits in various liver diseases through alleviating fibrosis, improving regeneration of hepatocytes, and regulating immune activity. This review provides an overview of the MSCs, their EVs, and their therapeutic potential in treating various liver diseases including liver fibrosis, acute and chronic liver injury, and Hepatocellular Carcinoma (HCC). More specifically, the mechanisms by which MSC-EVs induce therapeutic benefits in liver diseases will be covered. In addition, comparisons between MSCs and their EVs were also evaluated as regenerative medicine against liver diseases. While the mechanisms of action and clinical efficacy must continue to be evaluated and verified, MSCs-derived EVs currently show tremendous potential and promise as a regenerative medicine treatment for liver disease in the future.

scholarly journals GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lucas D. Ward ◽  
Ho-Chou Tu ◽  
Chelsea B. Quenneville ◽  
Shira Tsour ◽  
Alexander O. Flynn-Carroll ◽  
...  
Keyword(s):  
Bile Duct ◽  
Extrahepatic Bile Duct ◽  
Association Studies ◽  
Missense Variant ◽  
Deficiency Anemia ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Extrahepatic Bile Duct Cancer ◽  
Hepatocellular Damage ◽  
Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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