9/28/2016. Elevated Liver Function Tests: A Case Based Approach. Objectives. Identify patterns of abnormal liver function tests

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1 Elevated Liver Function Tests: A Case Based Approach Terrance M. James, NP C The Oregon Clinic Hepatology tejames@orclinic.com Objectives Identify patterns of abnormal liver function tests Identify appropriate choices of liver related laboratory tests Identify appropriate choices for liver imaging studies Identify the elements that make the diagnosis of particular liver diseases 1

2 When are liver chemistries considered abnormal? Have they been confirmed more than once over a 1 2 month window? When are liver chemistries considered abnormal? Is the pattern consistent, changing, or evolving? When are liver chemistries considered abnormal? What has changed in their history? Medications? Substances? Supplements? 2

3 Incidental finding of Abnormal LFTs Total bili >5 and, abnl ALT +/ abnl ALP Urgent u/s HbsAg, HBcAb IGM HAV Ab IGM If acute hepatitis suspected ALT >30 IU/L males or, ALT >19 IU/L females or, ALP >120 IU/L Repeat & confirm in 1 2 mo If resolved, repeat in 3 12mo Isolated total bilirubin Fractionate bilirubin >15% direct <15% direct Consider GI referral if alcohol, illicit drug use, medications or supplements (inc. herbal) suspected: adjust and repeat in 3mo Dubin Johnson or Rotors syndrome Evaluate for hemolysis neg Hepatocellular1 Cholestatic2 Isolated ALP elevation3 Gilbert s syndrome HbsAg, antihcv, serum Fe, TIBC, ferritin; u/s U/S Ducts normal Ducts dilated Fractionate or GGT or 5 nucleotidase pos Further eval HBV: HBeAg, DNA level HCV: PCR, genotype neg ANA, SMA, ceruloplasmin, Α1 antitrypsin level, Consider celiac eval MRCP, ERCP AMA +/ EUS neg pos ERCP & Liver biopsy liver biopsy Liver origin or, GGT pos, 5 neg u/s, AMA Review recent meds Bone origin or, GGT neg, 5 pos Bone eval Consider liver biopsy Consider therapy Serologies neg; u/s pos fatty liver treat = refer to GI u/s: ducts normal, parenchymal dz &/or AMA pos Dilated ducts AMA neg +/ hx IBD Liver biopsy ERCP Patterns of abnormal liver function tests 1. Cholestatic 2. Hepatic 1. Cholestatic Alkaline phosphatase higher than AST/ALT levels Alkaline phosphatase higher with near normal AST/ALT levels sometimes referred to as infiltrative pattern Bone, first trimester placenta, kidneys and intestines can also lead to elevations in Alkaline phosphatase Adding on a GGT can help determine if this is a liver process in the setting of Alkaline phosphatase > AST/ALT 3

4 1. Cholestatic Alkaline phosphatase higher than AST/ALT levels 1. Cholestatic Alkaline phosphatase higher than AST/ALT levels Alkaline phosphatase higher with near normal AST/ALT levels sometimes referred to as infiltrative pattern 1. Cholestatic Alkaline phosphatase higher than AST/ALT levels Alkaline phosphatase higher with near normal AST/ALT levels sometimes referred to as infiltrative pattern Bone, first trimester placenta, kidneys and intestines can also lead to elevations in Alkaline phosphatase 4

5 1. Cholestatic Alkaline phosphatase higher than AST/ALT levels Alkaline phosphatase higher with near normal AST/ALT levels sometimes referred to as infiltrative pattern Bone, first trimester placenta, kidneys and intestines can also lead to elevations in Alkaline phosphatase Adding on a GGT can help determine if this is a liver process in the setting of Alkaline phosphatase > AST/ALT Hepatic/Hepatocellular AST and or ALT Alkaline phosphatase Higher Than Hepatic/Hepatocellular Skeletal muscle Cardiac muscles Red blood cells Kidneys Can All Lead To Elevations in AST/ALT 5

6 Hepatic/Hepatocellular When AST is 2x greater than ALT: Add a GGT to help determine if it s an alcoholic injury Other Labs Platelets helpful to determine the extent and length of disease, low platelets think low function Bilirubin high bilirubin reflects poor liver function and high amount of liver injury Albumin low albumin reflects changes in their nutritional status that could be related to their liver disease INR high INR think liver damage and poor function 6

7 Our Case.Meet Hal 60 year old white male, originally from the New York area, resettled in Portland 20+ years ago Persistently elevated LFTs for several years Felt to be due to fatty infiltration seen on Ultrasound by PCP as patient has diabetes, high cholesterol and high blood pressure; he also has RLS, colon polyps, HSV2, GERD, ED, and Achilles Tendonitis He is a gay male, happily married to same partner for 20 + years Reports distant IV and intranasal drug use It was the 70 s Family history of metabolic disease, alcoholic liver disease and I think someone had cirrhosis Has reports of frequent fatigue, since I got diagnosed with Diabetes, about 15 years ago Our Case.Meet Hal MeforminXL 500 mg, Atorvastatin 10 mg, Lisinopril 10 mg, Requip 0.25 mg, Cialis 20 mg, and ASA 81 mg BP 118/74, P 81, BMI 26 Alkaline Phosphatase 54 ALT 87 (79 one year ago) AST 52 (48 one year ago) Bilirubin total 1.1 Albumin 3.8 Total Protein 6.6 A1c 6.3 LDL 88, Triglycerides 125 What questions should we ask? Substance History we know he used IV and intranasal drugs so did you get hepatitis? Viral Hepatitis CDC recommendations currently anyone born between 1945 and 1965 ie. > 50 needs Hep C checked Autoimmune History patient and family if patient or family member has an AI disease, chances are higher for other autoimmune disease Bleeding signs of low platelets and high INRs 7

8 Now that you mention it. Had Hep B he thinks in 1973, and in 1978 had Hep A, no subsequent checks or testing He and his partner love Italy/Italian food and wine; drink at least one glass of wine a night Thinks he has had high liver function tests for a long time Smokes some pot and eats edibles to help with sleep and RLS No autoimmune disease but thinks a cousin had an issue with iron Never had any acute bleeding events Where to go from here? Viral Hepatitis Testing HepB surface antigen and core IgM HepC antibody with reflex to quantitative No need for Hep A testing in this setting Where to go from here? Alcohol related injury GGT, serum ethanol, ETG, serum fibrosis testing FibroSure NASH Iron Studies iron, total binding capacity, and ferritin Autoimmune markers ANA, Anti Smooth Muscle Antibody (if it had been a cholestatic picture Anti Mitochondrial Antibody) Genetic disease Hemachromatosis (Iron studies will lead you to this) and Alpha 1 antitrypsin Check an INR 8

9 Imaging Liver Ultrasound great screening test for liver injury and disease CT and MRI particularly helpful when looking for cancer Hepatitis B all patients with Hep B should be getting appropriate age and race related screening for Hepatoma #1 reason for healthcare related lawsuits in Asian patients aasld.org/publications/practice guidelines Results HepB surface antigen negative, core IgM negative (surface antibody and core IgG positive = proof of old infection) HepC antibody negative GGT, serum ethanol, FibroSure negative ANA, ASMA negative Alpha 1 antitrypsin negative INR 1.0 WBC 7.7, RBC 4.08, Hgb 13.2, Hct 39.3, Platelets 268 Iron Overload Ferritin 1584 Iron 255 TIBC 265 % Saturation 96 Transferrin 166 9

10 Hemachromatosis The patient was homozygous for C282Y hemochromatosis mutation If your patient has hemochromatosis this is the predominate pattern In patient s of Northern European decent this is one of the most common genetic diseases Heterozygotes are of less concern but if they have other forms of liver disease/injury can play a role in increasing dysfunction Hemachromatosis The patient was homozygous for C282Y hemochromatosis mutation If your patient has hemochromatosis this is the predominate pattern In patient s of Northern European decent this is one of the most common genetic diseases Heterozygotes are of less concern but if they have other forms of liver disease/injury can play a role in increasing dysfunction Negative for H63D and S65c We see very little of these in clinical practice 10

11 Hemachromatosis Nordic or Celtic Ancestry predominate Disease of inappropriate absorption of dietary iron due to defects in the HFE gene which can lead to development of cirrhosis, hepatocellular carcinoma, diabetes and heart disease. There are non HFE hemochromatosis syndromes, there is a juvenile version and in Sub Saharan Africa there is a non HFE related genetic abnormality that can be exacerbated by dietary iron loading (there is a fermented beverage that can lead to this in Africa) Hereditary Hemochromatosis (HH) Algorithm Elevated LFTs Diabetes Heart failure Arthropathy Hypogonadism symptomatic Skin hyperpigmentation TS <45% and normal ferritin Stop if first degree relative consider repeat in 2 yr Asymptomatic (incidental) serum iron / iron binding capacity (%TS) and ferritin nonc282y, C282Y/H63D or C282Y/wild type Very unlikely to be responsible for presentation individualize evaluation based upon clinical situation = GI referral first degree relative of HH patient TS >45% and Elevated ferritin HFE Genotype ferritin <1000ug/L And NL LFTs phlebotomy family screening C282Y/C282Y *Isolated ferritin (<350) or transferrin sat (TS) >45%: repeat in 2 3mo Consider: alcohol use fatty liver acute nonspecific inflammatory process ferritin >1000ug/L or elevated LFTs liver biopsy for histology and tissue iron content Keys to diagnosis and treatment of HH Patient must be homozygous to have HH Biopsy helpful in determining extent of disease and injury particularly when caught late in life Diabetes runs in parallel and often patients develop it early due to iron damage to the pancreas In males, there can be erectile dysfunction related to testicular atrophy leading to impotence and issues with libido Arthralgias (particularly 2 nd and 3 rd MCPs), chondrocalcinosis, and symptoms of heart failure. 11

12 Biopsy You need iron testing when looking at this for HH They will comment on the amount of steatosis and fibrosis The pathologist will also comment on which stains were read and how they fit into the diagnostic picture Don t be afraid to have the pathology be sent out for second opinion Randy Lee, MD at Legacy is an expert on Liver Pathology, he wrote the book, literally Treatment Phlebotomy 12

13 Treatment Phlebotomy Hepatoma Screening We utilize RUQ ultrasound and AFP tumor markers for hepatoma screening Know your local resources tumor boards at Portland Providence Medical Center and OHSU if you have concerns or questions about something you find on imaging Definitive testing for Hepatoma is a Triple Phase CT or MRI, also called a dynamic liver exam Not every hepatoma puts out AFP which is why it has fallen out of favor but many practitioners do still use it What if Hal was cirrhotic on the biopsy? Needs an upper endoscopy for variceal surveillance Cirrhotics form vascular changes in the portal flow around the liver due to back flow This back flow has a direct impact on the esophagus and stomach we see this through endoscopy and can also be seen on CT and MRI although these are not appropriate screening tests There are treatments for this and these include banding the varix or if they are bleeding interventional radiology procedures 13

14 Conclusion Hal did very well with phlebotomy After a year he started to notice improvement in his energy but never got his sex drive back often leads to permanent dysfunction He continues to have hepatoma screening but he was not cirrhotic so did not undergo EGD 14