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Management of commonly abnormal blood tests in primary careKevin Fernando FRCGP FRCP Edin. FAcadMEd MSc Diabetes University of Edinburgh Medical School 2000 GP Partner North Berwick Health Centre Specialist Interests in Diabetes/CVRM & Medical Education Content Advisor, Medscape Global & UK Honorary Clinical Reader @drkevinfernando @DrKevinFernando @drkevinfernando Disclosures 2023/4 Speaker fees: Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Daiichi Sankyo, GSK, Lilly, Menarini, Novartis, Novo Nordisk, Roche Diagnostics, Embecta Advisory Board fees: Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Menarini, Novartis, Novo Nordisk, Roche, Roche Diagnostics, Sanofi Conference attendance: Menarini, Daiichi SankyoMedscape UK. Guidelines Primary Care Hacks: Identification of CKD in Primary Care. Available at: https://www.medscape.co.uk/v iewarticle/identification-and- holistic-management-chronic- kidney-2024a10004ql# Accessed April 2024. PP-IN-UK-1620 / April 24Medscape UK. Guidelines Primary Care Hacks: Identification of CKD in Primary Care. Available at: https://www.medscape.co.uk/v iewarticle/identification-and- holistic-management-chronic- kidney-2024a10004ql# Accessed April 2024. PP-IN-UK-1620 / April 24 Talking Points • Management of abnormal liver blood tests in primary care • Management of abnormal iron studies in primary care • Use of CRP & ESR in primary care What is the likely cause of her abnormal LFTs? Cara Age 52 1.Chronic HCV infection ? Found to have fatty 2.MASLD History liver on USS for 3.MetALD (metabolic alcohol-related liver disease) suspected cholecystitis 4.Hepatocellular carcinoma BP 148/92 mmHg TC 6.3 TRG 4.9 HDL 0.8 5.Something else? Lipid profileUnable to calculate (mmol/l) LDL-C 2 BMI & Weight 33 kg/m Waist 88cm What is your next step with respect to her LFTs? ALT 62 (10-50), AST LFTs (U/L) 63 (8-50), ALP 85 (40- 1.Lifestyle advice – weight loss & alcohol consumption 125) GGT 65 (5-55) Bili 17 (3-21) 2.Check targeted liver screen HbA1c 45 mmol/mol 2 3.Refer hepatology eGFR >60 mL/min/1.73m 4.Check FIB-4 score Medications Nil 5.Refer liver elastography e.g., FibroScan Social Historyattoo artist, non- 6.Repeat4 weeks… smoker, social alcoholWhat is MASLD? • NAFLD is now termed Metabolic Dysfunction Associated Steatotic Liver Disease • MASLD encompasses individuals who have hepatic steatosis and at least 1 cardiometabolic risk factor: • BMI≥25 (23 if high-risk ethnic group) or waist circumference >94 cm (>90cm if high-risk ethnic group) or >80 cm (all ethnicities) • HbA1c 42-47mmol/mol or established T2D • Blood pressure ≥130/85 or antihypertensive drug treatment • Plasma triglycerides ≥1.70mmol/L or lipid-lowering treatment • Plasma HDL-C ≤1.0mmol/L or lipid-lowering treatment • MASH replaces NASH • MetALD describes individuals with MASLD who consume above recommended amounts of alcohol per week i.e. combined aetiology • MASLD is primarily a metabolic disease; it is the liver’s manifestation of the metabolic syndrome (MetS)Abnormal liver blood tests • Mildly abnormal LFTs are very common! • Degree of abnormality does not always correlate with disease severity • LFTs often checked for unexplained or non-specific symptoms • 1:5will have abnormal LFTs & most of these individuals will not have significant liver disease • BALLETS study BMJ Open 2013 • n=1290from primary care with abnormal LFTs and without known liver disease • Only 2.5% (n=32) of people with abnormal LFTs had a specific disease of the liver • 40% of whole cohort had ”fatty liver” on USS • 8 malignancies found • Repeating entire LFT panel in 1month is ineffective! • ALT & ALP most associated with significant liver disease • GGT had a very high false positive rate but was sensitive to alcohol intake • Liver disease is rare among those with abnormal LFTs in primary care • So, worth having a heuristic at hand to identify those with modifiable liver diseaseAbnormal liver blood tests: Key Points • LFTs may be normal even in advanced liver disease & are frequently abnormal in the absence of liver disease • Interpreting LFTs in isolation may be ineffective in diagnosing or excluding liver disease • Liver enzymes are a poor guide to the development of alcohol-related liver disease (ARLD) • But, if elevated, can be useful in promoting behaviour change • ARLD is not limited to those who are dependenton alcohol; the risk of liver disease doubles for any given alcohol intake if BMI>35 • Look for: • Predominant pattern of enzyme alteration (hepatocellular vs cholestatic) • Magnitude of abnormality <3x ULN, >3-10x ULN, >10x ULN • Rate of change over timeWhen to consider checking LFT s: • Non-specific symptoms suggestive of liver disease e.g. anorexia, fatigue or nausea • Evidence of chronic liver disease e.g. symptoms or signs of cirrhosis, portal hypertension or liver failure such as ascites, peripheral oedema, spider naevi and hepatosplenomegaly • Conditions associated with a risk of developing liver disease e.g. other autoimmune disease, IBD (10% risk of PSC) • Use of hepatotoxic drugs e.g. DMARDs, terbinafine NB statins • FH of liver diseases e.g. haemochromatosis, Wilson’s disease • Alcohol misuse though poor guide to development of ARLD but can motivate behaviour change. GGTbest predictor of mortality • Risk factors for viralhepatitisInterpreting liver blood tests • ALT is predominantly liver-specific enzyme & is a sensitive marker of hepatocyte injury or death e.g. viral hepatitis • Varies with age, sex, ethnicity, BMI, illness & exercise • AST is not as liver-specific (present in cardiac, smooth & skeletal muscle) but is a more sensitive marker of liver injury particularly alcohol • In children, checking CK can be helpful to determine whether isolated rise in AST is due to an underlying skeletal muscle disorder e.g. muscular dystrophy • Isolated GGT difficult to interpret as present in liver, intestines, kidneys, pancreas & prostate (but not bone) & raised by multiple factors: • Alcohol, obesity & several drugs • Best role is for establishing likely origin of an elevated ALP – bone or liver • disease low specificity, GGT is one of the best predictors of mortality in established liverInterpreting liver blood tests • ALP predominantly liver enzyme but also found in bone, intestine, kidneys, WBCs. ALP higher in childhood & pregnancy • ALP elevated in cholestatic liver disease, bone disease, hepatic congestion due to right- sided HF • If raised ALP worth checking GGT – if GGT normal think “bone”, if GGT high think “liver” • Also, ALPelectrophoresis can be used to differentiate • Consider checking AMA if persistently isolated ALP >200 of liver origin to exclude PBC • Isolated raised bilirubin (unconjugated, usually not >70) often due to Gilbert’s syndrome but exclude haemolysis (consider blood film, reticulocytes, LDH) • Raised conjugated bilirubin seen in HPB obstruction, hepatitis from any cause or advanced cirrhosisInterpreting liver blood tests • Albumin is a protein synthesised by the liver and is a sensitive marker of liver synthetic function • Albumin may also be reduced in other clinical scenarios e.g. sepsis, systemic inflammatory disorders, nephrotic syndrome, HF, malabsorption and GI protein loss • Clotting factors are synthesised in the liver and if significant liver damage (usually >70%) production is reduced and PT or INR can be prolonged • Prolonged PT or INR can also be caused by vitamin Kdeficiency in fat malabsorption & chronic cholestasis • Platelet reduction is an indicator of advanced liver disease usually due to splenic enlargement secondary to portal hypertension • LDH is not specific to liver (also heart & muscle) but is typically elevated in liver diseases associated with haemolysis, solid tumours, lymphomas & viral hepatitis Response to abnormal liver blood tests. PhilipN Newsome et al. Gut 2018;67:6-19 Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.Hugh Age 72 What do you do next? for around 3 weeksse History with mild headache 1. Look up “Raised ESR” on GPnotebook before realising you’ve used up your 3 open kneepain in his left access pages Generalised 2. Check a myeloma screen PMH moderate OA affecting back and 3. Trial of steroids for possible PMR both knees 4. Refer urgently to rheumatology for possible Systemic enquiry Nil of note GCA 5. Arrange abdominal USS to exclude renal Examination Unremarkable FBC/LFT/U&E normal carcinoma 6. Wait & see if he develops any symptoms Bloods ESR 35 CRP <1Use of CRP & ESR in Primary Care • BJGP 2019 & BMJ 2012 • Commonly requested in primary care for diagnosis & monitoring of inflammatory conditions, infections, autoimmune conditions and cancers • Linear increase in requests over last 15 years • Often both ESR & CRP checked •referralssitives common leading to increased appointments, tests & • Discordant results also common • Which is better ESR or CRP? • Little evidence comparing… • Guiding principle as always is treat the patient not the number• ESR • Rule of thumb for ULN • Women – (age+10) divided by 2 • Men – age divided by 2 • NB affected by gender, age, pregnancy, temperature, drugs, smoking, plasma protein concentrations & RBCs • Rises over 24-48 hours and decreases slowly taking weeks to normalise • ESR >100mm/hr >97% PPV for significant illness • Rule out malignancy esp. myeloma or renal & GCA • Evidence suggests ESR better for suspected myeloma (BMJ 2018) but actually protein electrophoresis or urinary BJP preferable if strong clinical suspicion • RA – refer if clinical suspicion of RA even with normal inflammatory markers (NICE NG100 2018) • CRP • Rises more rapidly in response to infection (within 12 hours);1/212-24 hours and 3- 7 days to normalise • Not affected by above factors • Can be useful to check CRP if elevated ferritin• BJGP 2019 • Large observational studies comparing diagnostic accuracies of CRP & ESR and also whether checking both improves accuracy • Little difference in accuracy of CRP & ESR • CRP had slightly superior diagnostic accuracy for infections • CRP equivalent for autoimmune conditions & cancers st • CRP should generally be 1 -line test • Testing multiple inflammatory markers simultaneously did not increase ability to rule out disease • Associated with more abnormal & discordant results and increased costs • NPV of a single test similar to that of multiple tests • Overall, inflammatory markers have low accuracy for disease outcomes with the exception of PMR • Inflammatory markers have poor sensitivity and should not be used as a rule-out test • “For every 1000 inflammatory marker tests performed, anticipate 236 false positive results generating an additional 710 GP appointments, 229 phlebotomy appointments and 24 referrals in the next 6 months”• Key take-home messages: • Normal inflammatory markers useful in ruling out only a few specific conditions – PMR, GCA, myeloma & infection of hip revisions • Raised inflammatory markers very common and do increase probability of a condition being present but further evidence required • Inflammatory markers are too non-specific to be a useful tool for diagnosing serious underlying disease • If raised inflammatory markers incidentally found and no clues from history or examination for cause, wait & see if symptoms develop • If levels markedly raised (ESR>100mm/h) likelihood of disease much higher and focused history, examination & investigations required to establish a diagnosisHugh Age 72 Non-specific malaise I phoned Hugh to discuss his results. for around 3 weeks History with mild headache and pain in his left His headache had settled but he was still feeling knee non-specifically unwell. Nothing new on history. Generalised PMH moderate OA affecting back and Hugh gradually improved over the subsequent 2 both knees weeks without treatment or further investigation. Systemic Nil of note enquiry Examination Unremarkable His bloods were not repeated FBC/LFT/U&E normal Bloods ESR 35 CRP <1“ ‘The art of medicine consists in amusing the patient while nature cures the disease’ Voltaire 1694-1778 Photo credit: Wellcome LibraryOscar What do you do next? Age 53 3-month history of fatigue, History joint pain & loss of libido 1. Check fasting iron studies 2. Check CRP PMH T2D 3 years 3. Check a full liver screen BMI 31 kg/m 2 4. Genetic mutation screening for hereditary BP & pulse 149/87mmHg, 72bpm haemochromatosis 5. Check gonadotrophins (LH & FSH) & testosterone Examination Nil of note FBC/U&E/LFT/TFT normal LDL 3.5mmol/L HbA1c What do you think is going on? Bloods 55mmol/mol 1. Liver disease – MASLD Ferritin 612µg/L (NR 20-300) Current Metformin 1g bd, 2. Liver disease – alcohol-related Medication atorvastatin 20mg od 3. T2D/metabolic syndrome Works in construction 4. Hereditary haemochromatosis Social History recruitment Non-smoker 40 units alcohol weekly 5. Hypogonadotrophic hypogonadismInterpreting Iron Studies • BMJ “Rational Testing” 2015, 2017 & 2023 • Commonly requested in primary care to investigate iron deficiency, possibility of iron overload and to screen for haemochromatosis • Comprises: • Ferritin is the intracellular storage form of iron & best investigation for IDA. NB Ferritin is an APP • Transferrin is the main iron transport protein that controls level of free iron • Serum iron is the amount of circulating iron bound to transferrin NB highly variable • Transferrin saturation is the proportion of iron-binding sites of transferrin being occupied by iron. Good test for iron overload • Some tips on requesting iron studies: • Iron studies should be measured on a fasting morning sample • Iron studies should not be tested during acute illness where iron levels may fallInterpreting Iron Studies • Do not assume all microcytic anaemias are IDAs – check ferritin levels • Low ferritin is diagnostic of IDA, however, a normal or high ferritin does not exclude IDA • If microcytic anaemia & normal/high ferritin – check iron studies • Low serum iron & higher transferrin >3g/l are then diagnostic of IDA • Can be useful to check CRP if serum ferritin is normal/high with low serum iron or transferrin saturation to exclude infection or inflammationOscar Serum iron 30µol/L (NR 14-32) Transferrin 3g/L (NR 2-4) Transferrin saturation 30% (NR 15-50) CRP <1Interpreting Iron Studies Condition MCV Ferritin Serum Iron Transferrin Transferrin (NR 80-96fL) (NR 20-300µg/L (NR 14- (NR 2-4g/L) Saturation males & 32µmol/L) (NR 12-45% postmenopausal females & 15- women, 15- 50% males) 200µg/L menstruating females) Iron deficiency anaemia Anaemia of or or or chronic disease Iron overload orInterpreting Iron Studies • A normal fasting TSAT usually excludes iron overload. If raised, consider: • Primary iron overload or hereditary haemochromatosis • Consider HFE mutation screen if elevated ferritin & TSAT >45% • Secondary iron overload e.g. blood transfusions, IV iron infusions, long-term iron supplements, chronic haemolytic anaemias, porphyria cutanea tarda • 90% of those with high ferritin levels will not have iron overload; most are “reactive” high ferritin levels: • Metabolic syndrome/T2D • Liver disease (NAFLD/NASH or viral hepatitis) • Alcohol excess • Thyrotoxicosis • Acute & chronic inflammatory conditions and infections • Malignancy • Renal failure • Acute MI • Consider referral for further investigation if unexplained serum ferritin >1000µg/LOscar Serum iron 30µol/L (NR 14-32) Transferrin 3g/L (NR 2-4) Transferrin saturation 30% (NR 15-50) CRP <1 • Likely reactive ferritin level secondary to alcohol or T2D – revisit • Recheck serum ferritin & any other relevant tests 3-4 months after any interventions • QIA: – Is serum ferritin used routinely in your practice as an investigation for IDA? – When prescribing iron therapy for IDA, 1 tablet daily is sufficientThank you for listening & please get in touch if you have any questions @drkevinfernandoctors.org.uk Kevin Fernando