Liver Disease in Women: Evaluation of Abnormal Liver Tests None - PDF document

Disclosures Liver Disease in Women: Evaluation of Abnormal Liver Tests  None UCSF Controversies in Women’s Health Symposium Monika Sarkar, MD, MAS UCSF Division of GI/Hepatology December 9th, 2016 Outline:  Outpatient evaluation Approach to Women with Abnormal LFTS (Liver  The key players Function Tests)  Why sex matters  Primary care management

Which are tests of liver FUNCTION? Approach to Women with Abnormal Liver Function  Total bilirubin Tests  Albumin  Prothrombin time/INR But not:  AST/ALT/Alkaline phosphatase What is “normal”? Two general patterns of liver injury   Hepatocellular: Predominately AST and ALT Normal = mean of Degree of Elevation Common Causes the distribution ± 2 SD Mild (<100 U/L) Chronic viral hepatitis, alcohol, NAFLD, drug of the “normal” population induced, hemochromatosis, autoimmune -5% of “normal” patients Moderate (100-300 U/L) As above will have values outside of Severe (>1000 U/L) Drug induced (ie acetominophen, antibiotics) Acute viral hepatitis the normal range Autoimmune hepatitis Ischemia/Hypoperfusion -2.5% above and 2.5% below  Cholestatic: Predominately Tbili and alk phos  Normal ALT varies by sex: Degree of Alk Phos Elevation Common Causes Low (less than normal) Wilson’s Disease - ULN of ALT = 19U/L in women & 30 in men 1 Mild elevation Biliary obstruction (ie stones) - Lower threshold than flagged by most labs! Moderate elevation Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) Severe (>1000 IU/L) Malignant infiltration by tumor 1. Prati et al, Annals of Internal Med, 2002

Case- history Case PMH: Hypertension, dyslipidemia, hypothyroidism,  60 yo woman presents for new primary chronic back pain, recurrent UTIs care evaluation Menopausal history: Menopause at age 46 yo  Routine labs: Tbili 0.8, AST 120, ALT Meds: HCTZ, pravastin, tylenol 2-3g 1-2x per 90, AP 111 (ULN 95) week, macrobid, levothyroxine  One year ago: Tbili 0.6, AST 97, ALT SHx: Has one glass of wine per night, no tobacco use, 83, AP 120 IVDU x 1 in 1973 FH M th ith t 2 di b t Initial Labs Physical Exam 0.8 VS: T 37.3 HR 72 BP 149/79 SaO2 99% RA, BMI 35 5.3 185 120 90 General: overweight, interactive 39.0 111 CV: Normal Albumin 3.8 Respiratory: Normal 137 8 Abdominal: soft, central adiposity, non tender, no 151 1.0 hepatosplenomegaly 3.8 0.8 Extremities: warm, no edema HgAIC 6.3 Skin - no palmar erythema, no spider angiomata, no acanthosis Lipids: TG 161, HDL 40, LDL 101

Case- Moderate Risk for Hepatitis C? Hepatocellular Injury PMH: Hypertension, hyperlipidemia, hypothyroidism, chronic back pain, recurrent UTIs (Tbili 0.8, AST 120, ALT 90, Alk phos 111) Menopausal history: Menopause at age 46 yo What additional testing would Meds: HCTZ, pravastin, tylenol 2-3g 1-2x per week, you perform? macrobid, levothyroxine SHx: Has one glass of wine per night, no tobacco use, IVDU x 1 in 1973 FHx: Mother with type 2 diabetes ID: 60 yo woman, born in 1956 Baby Boomers Does menopausal age matter in Hepatitis C?  Liver cells incubated in estrogen make less collagen- anti-fibrotic role of estrogens 1 Cross sectional data show:  More severe liver fibrosis in post compared to - Risk assessment misses pre-menopausal women 2,3 50% of infected patients  HRT protects against hepatic fibrosis 2,3 - Screen with HCV Ab  Fibrosis progression more rapid in nulliparous - Birth cohort testing women 3 is cost effective Majajan, Am J Public Health 2013; 1.Itagaki, Gut 2005, 2. Codes et al Gut 2007, 3.Di Martino, Hepatology 2004 MMWR Recomm Rep. 2012

Accelerated HCV Fibrosis Why Cure HCV? Begins in Peri-menopausal Years  High chance of cure (95-  For early stage disease, 15 year 100%), tolerable side survival higher in patients cured  n=405 HIV/HCV co-infected effects, short course of HCV (93% vs 82%, p=0.003) women, followed for 18 yrs  Cost of therapy declining as  Halt progression, cause  Anti-mullerian hormone more meds flood the market & regression of fibrosis (AMH) measured every 6 shorter durations  Reduced risk of months  Decreased transmission in IDU cirrhosis, liver cancer,  Assessed rate of fibrosis in  Extrahepatic manifestations each women and LT improve: cognitive function,  Captured peri-menopause  Decreased all cause quality of life, work productivity, (within 5 years of AMH loss) mortality and menopause insulin sensitivity  Fibrosis starts to accelerate in peri-menopausal years AASLD-IDSA, 2016; Morgan, Hepatology 2010; Bennett, Eur J Health Econ . 2016, Jezequel C, EASL 2016; Hellard M, Hepatology 2014; Gerber, Clin Gastroenterol Hepatol . 2016; Sarkar et al, AASLD November 11, 2015 Hsu, Hepatology . 2014 Who Should Be Referred for HCV Treatment? anyone Our patient is HCV Ab negative! AASLD-IDSA, February 2016

Sex Differences in Drug- Could This Be Medication Related? Induced Liver Injury  Women more likely to have drug induced 60 yo woman PMH: Hypertension, hyperlipidemia, hypothyroidism, liver injury from a spectrum of agents 1,2 chronic back pain, recurrent UTIs  Women account for ~ 70% of cases of Menopausal history: Menopause at age 46 yo drug induced acute liver failure (ALF) 2,3 Meds: HCTZ, pravastin 10 yrs, tylenol 3g per day 1-2 times per week, macrobid x 3 months SHx: Has one glass of wine per night, no tobacco use, IVDU x 1 in 1973 FHx: Mother with type 2 diabetes 1.Navarro, NEJM 2006, 2.Reuben et al, Hepatology 2010, 3.Sarkar et al, AASLD November 11 th , 2016 Acetaminophen (APAP/tylenol) toxicity  Most common cause of acute liver failure  So why do hepatologists love tylenol for pain control? ≤ 3g per day is safe for healthy livers ≤ 2g per day is safe for cirrhotic livers  Among 145 healthy adults taking 4 grams of APAP per day (RCT of different pain regimens):  76% had at least one ALT > 40  53% had peak ALT > 80  39% had peak ALT > 120  Similar risk by sex Watkins, JAMA 2006; livertox.nlm.nih.gov

Statin Hepatotoxicity  Mild elevations present- 3-15% of patients  Higher elevations (ALT > 3xULN) in < 1%  Dose dependent but typically self limited without dose reduction  Clinically significant injury extremely rare  Discontinue if ALT > 10xULN (ie ALT > 200 in women) Macrobid started 3 months ago, not the likely culprit … livertox.nlm.nih.gov Additional Viral Testing  HIV Ab - Recommended by CDC for all patients 13-64 yo Might be statin related, but let’s  Hepatitis B: HBsAg -, HBcAb IgG -, HBsAb - rule out other causes HBsAg: tests for chronic infection HBcAb IgG: tests for exposure to virus (past or current) HBcIgM: tests for acute hepatitis B HBsAb: tests for immunity to hepatitis B (cleared or vaccinated) HBeAg/eAb: characterizes chronic HBV  Hepatitis A: HAV Ab IgG+ HAV Ab IgG: to assess immunity HAV Ab IgM: tests for acute hep A (AST/ALT 1000s, N/V/jaundice)

Could This Be Hereditary Additional testing Hemochromatosis (HHC)?  Most common genetic disorder among Caucasians  Abdominal US with dopplers  Prevalence: 1:250 individuals of Northern European descent - smooth contour - normal spleen  Mutation in genes involved in iron regulation - patent hepatic vessels  AASLD guidelines: suspect HHC in patients with - hepatic steatosis transferrin saturation >45% AND elevated ferritin (>200 ug/L for women, >300 ug/L for men)  Diagnose by HFE genotype ( not needed in our patient)  Iron level 54, Tsat 21%, Ferritin 105  Elevated ferritin present in >20% of pts with nonalcoholic steatohepatitis (NASH) Bacon, Hepatology 2011; Knowdley, Hepatology 2012 Additional testing Risk for Autoimmune Disease?  Abdominal US with dopplers: smooth 60 yo woman contour, normal spleen, patent hepatic PMH: Hypertension, hyperlipidemia, hypothyroidism, vessels, hepatic steatosis chronic back pain, recurrent UTIs  Iron level 54, Tsat 21%, Ferritin 105 Meds: HCTZ, pravastin, tylenol PRN, macrobid,  Autoimmune markers: ANA + 1:40, ASMA levothyroxine + 1:80, IgG 1200 (normal) SHx: Has one glass of wine per night, no tobacco use, IVDU x 1 in 1973 FHx: Mother with type 2 diabetes

Autoimmune Liver Disease Question Primary Biliary Autoimmune Hepatitis Cholangitis (PBC) What is most likely cause of abnormal liver tests?  F:M = 4:1  F:M = 9:1  All ages  Mean age 50s 1) Autoimmune hepatitis  Prevalence: ~ 15/100,000  Prevalence: 40/100,000  Hepatocellular pattern  Cholestatic pattern 2) Autoimmune hepatitis plus NAFLD Diagnosis: Diagnosis: 3) Nonalcoholic Fatty Liver Disease (NAFLD)  Serologies: ANA, ASMA,  Elevated alk phos & AMA and IgG level  Liver biopsy not required  Liver biopsy  ~ 5% of PBC pts are AMA neg  No need for anti-LKM Manns, et al, Hepatology 2010, Kaplan/Gershwin, NEJM 2005 Question Autoantibodies in NAFLD What is most likely cause of abnormal liver tests?  Positive ANA > 1:160 or ASMA >1:40 present in ~ ¼ of patients with NAFLD 1) Autoimmune hepatitis  Positive AMA ~ 8% patients with NAFLD 2) Autoimmune hepatitis plus NAFLD  Autoimmune markers are not associated with 3) Nonalcoholic Fatty Liver Disease (NAFLD) severity of NASH on liver biopsy Vuppalanchi R et al., Hepatol Int 2011