Adults with Inherited Liver Diseases

Transcription

1 Kris V. Kowdley, MD, FAASLD Director, Liver Care Network and Organ Care Research Swedish Medical Center, Seattle, WA Postgraduate Course: Adults with Inherited Liver Diseases Challenges in Management of Common Liver Diseases 485 1

2 Case Information Juan is a 38 year old man with abnormal liver chemistries and a family history of liver disease Minimal alcohol consumption Two uncles died of liver disease, alcohol history unknown Ancestry Mexican American Laboratory tests: Iron 180, TIBC 220, (TS 81%), Ferritin 790 ng/ml ALT 90 U/L, AST 88 U/L Hepatitis C Ab, HBsAg negative 2016 AMERICAN ASSOCIATION FOR THE 486 STUDY OF LIVER DISEASES 2

3 Key Questions/Content Focus: What is the role of genetic testing in diagnosis of adults with chronic liver diseases: iron overload, Wilson disease, alpha 1 antitrypsin deficiency, and other liver diseases Which tests to order, how to interpret the results? Should family members be screened? 2016 AMERICAN ASSOCIATION FOR THE 487 STUDY OF LIVER DISEASES 3

4 Hereditary Hemochromatosis 488 4

5 o Primary Iron Overload Disorders o Secondary Iron Overload o Other Iron Overload Disorders o Iron Loading due to Liver Disease 2016 AMERICAN ASSOCIATION 489 FOR THE STUDY OF LIVER DISEASES 5

6 OMIM Classification of Hemochromatosis o Type 1: Classical HFE-associated HH o Type 2A:Juvenile HH (HJV mutation [1q21HJV]) o Type 2B:Juvenile HH (Hepcidin mutation [19q13.1]) o Type 3:TfR2 mutation-associated HH o Type 4:Ferroportin-associated HH 2016 AMERICAN ASSOCIATION 490 FOR THE STUDY OF LIVER DISEASES 6

7 Genetics of Type I HH o Putative gene between HLA A and B o HFE (HLA-H) identified in 1996 o HFE gene encodes a Class I protein o Two mutations identified o Cys Tyr at aa 282 o His Asp at aa AMERICAN ASSOCIATION 491 FOR THE STUDY OF LIVER DISEASES 7

8 C282Y +/+ mutation in HH USA (Feder) 83% USA (Beutler) 82% Norway (Oslo) 81% Germany(North) 95% France (Brittany) 91% Spain (Barcelona) 87% Portugal (Porto) 84% France (Toulouse)72% USA (Barton) 59% USA (Rochester) 60% Italy (North) 69% Greece (Athens) 50% 492

9 Gene Mutation Patterns in HFE-HH o C282Y homozygotes most important mutation Have the highest level of HIC Uniform hepatic iron deposition Majority of Caucasian patients (80-90%) o C282Y/H63D comprise 1.5-7% Have lower HIC compared to C282Y homozygotes o S65C, H63D mutations unimportant May be lead to iron overload with another risk factor 493

10 Percentage Histologic features: C282Y+/+ vs CPD heterozygotes Comparison of Histology p=0.04 P=0.03 P= Iron Staining Inflammation Steatosis C282Y/C282Y C282Y/H63D Simple Heterozygotes and Wild Type 494 Cheng J Clin Gastroenterol 2009

11 Juvenile Hemochromatosis o Distinct from classical HFE-linked hemochromatosis o Early onset of disease, no gender predominance P=0.01 o Greatly increased iron stores p=0.04 P=0.03 o Clinical symptoms similar to HFE hemochromatosis o Hypogonadism and cardiac disease common o Premature deaths due to cardiac disease 495

12 TfR2-associated HH o Southern Europe Portugal, Italy o Japan o Similar to Type 1 HH in: p=0.04 P=0.03 Degree of iron loading P=0.01 Pattern of hepatic iron deposition Response to phlebotomy o Possible earlier age at onset 496

13 Ferroportin Disease o Isolated hyperferritinemia, normal or slightly increased TS o Progressive hepatic iron overload Iron o Iron accumulation in Kupffer cells p=0.04 P=0.03 P=0.01 o Therapeutic phlebotomies may be poorly tolerated o Less severe than HFE-related hemochromatosis 497

14 Diagnosis

15 Diagnosis of HHC Screening tests TS% UIBC Ferritin HFE test Liver Biopsy Prognosis HFE+ Diagnosis And Prognosis HFE- 499

16 Hepatic Iron using MRI R2 Ferriscan; FDA Approved 500

17 Predictors of Cirrhosis in HHC o 182 patients with HHC based on: HIC>4,000 mcg/g HII>1.9 >4 g mobilizable iron o Liver biopsy reviewed o Bridging Fibrosis and cirrhosis recorded o Alcohol<20g/day o No risk factors for NASH % Cirrhosis Ferrtin<1000 Ferritin>1000 Morrison et al., Ann Intern Med. 2003;138: AMERICAN ASSOCIATION 501 FOR THE STUDY OF LIVER DISEASES 17

18 Treatment of iron overload o Phlebotomy therapy: o Reduce serum ferritin to <50 o Reduce serum TS to <50 o Weekly 500 cc phlebotomy o Reduce hematocrit to 75% of baseline o Avoid vitamin C supplementation 2016 AMERICAN ASSOCIATION 502 FOR THE STUDY OF LIVER DISEASES 18

19 Deferasirox for Hemochromatosis Hepatology Nov;52(5): AMERICAN ASSOCIATION 503 FOR THE STUDY OF LIVER DISEASES 19

20 Modifiers of expression in HHC o Alcohol consumption o Insulin resistance syndrome o Iron, vitamin C intake o Chronic blood loss o Celiac disease o Dietary factors 2016 AMERICAN ASSOCIATION 504 FOR THE STUDY OF LIVER DISEASES 20

21 Screening and Management of iron overload Transferrin sat >45% Further w/u <45% HHC excluded C282Y homoz CPD het not C282Y CPD het Ferritin>1,000 Ferritin<1,000 Liver biopsy Liver biopsy LFTs Normal LFTs Abnl Ferritin elevated Ferritin normal Liver biopsy Begin phlebotomy Follow 2016 AMERICAN ASSOCIATION 505 FOR THE STUDY OF LIVER DISEASES 21

22 Alpha 1 Antitrypsin Deficiency

23 Pathogenesis o Single amino acid substitution causes Z glutamic acid 342 lysine 342 o Abnormal folding: amino acid slowing of protein folding accumulation of a 1 AT in ER unstable and polymerizes unable to further traverse secretory path Lomas Nature 1992; 357: AMERICAN ASSOCIATION 507 FOR THE STUDY OF LIVER DISEASES 23

24 Diagnosis of A 1 AT deficiency o Alpha 1 AT phenotype PiZZ most common Up to 75 allelic variants described o Serum concentration of a 1 AT Generally 10-15% of normal values a 1 AT is an acute phase reactant may 3-4 fold during inflammation 2016 AMERICAN ASSOCIATION 508 FOR THE STUDY OF LIVER DISEASES 24

25 Heterozygotes o Chronic liver disease seen in: PiZZ PiSZ PiM malton /M malton PiMZ PiM1/M duarte o self-limited hepatic dysfunction is not rare 15-19% at 2 months ~1% by 12 months Reid Gastroenterology 1987; 93:181 Crowley Gastroenterology 1987; 93:242 Sveger Acta Paediatr Scand 1988; 77:847 Sveger Hepatology 1995; 22: AMERICAN ASSOCIATION 509 FOR THE STUDY OF LIVER DISEASES 25

26 Co-existent liver disease in A 1 AT % * HCV + HBV + Autoimmune Alcohol 0 cirrhosis CAH steatosis PiZZ or PiZ * Prior exposure Propst T et al: Ann Intern Med 1992;117: AMERICAN ASSOCIATION 510 FOR THE STUDY OF LIVER DISEASES 26

27 Wilson Disease

28 Wilson Disease o Pathophysiology related to copper overload o Gene localized to chromosome 13 o Encodes a p-type ATP-ase (ATP7B) o Decreased biliary copper excretion o Hepatic copper accumulation o Copper deposition in extrahepatic sites 2016 AMERICAN ASSOCIATION 512 FOR THE STUDY OF LIVER DISEASES 28

29 Clinical Features oneurologic ochronic active hepatitis ocirrhosis, portal hypertension oacute liver failure 2016 AMERICAN ASSOCIATION 513 FOR THE STUDY OF LIVER DISEASES 29

30 Clinical Pearls ocoombs - hemolytic anemia ohypouricemia olow alkaline phosphatase ohigh bilirubin:alk phos ratio 2016 AMERICAN ASSOCIATION 514 FOR THE STUDY OF LIVER DISEASES 30

31 Diagnosis of Wilson Disease Normal Wilson s o Serum Copper (micgm/dl) <80 o Urine Copper (mcg/24 hr) <40 >100 o Serum ceruloplasmin (mg/dl) <20 o Hepatic copper (micg/gm dw) o Serum Free-Copper Concentration = Total Cu - Ceruloplasmin X 3.15 Free Cu usually < 100 g/l Wilson s Disease: Free Cu >200 g/l 2016 AMERICAN ASSOCIATION 515 FOR THE STUDY OF LIVER DISEASES 31

32 Diagnosis of WD in patients with ALF 2016 AMERICAN ASSOCIATION 516 FOR THE STUDY OF LIVER DISEASES 32

33 Serum and Urine Copper in WD 2016 AMERICAN ASSOCIATION 517 FOR THE STUDY OF LIVER DISEASES 33

34 Hepatic Copper Levels Disease Wilson s Disease Primary biliary cirrhosis Primary sclerosing cholangitis Extrahepatic biliary obstruction Indian childhood cirrhosis Alcoholic/Cryptogenic cirrhosis Normal Mean Hepatic [Cu] 730 g/g dry weight 410 g/g dry weight 245 g/g dry weight 130 g/g dry weight 1830 g/g dry weight 40 g/g dry weight 30 g/g dry weight 2016 AMERICAN ASSOCIATION 518 FOR THE STUDY OF LIVER DISEASES 34

35 Treatment o Eliminate copper rich foods Organ meats Shellfish Nuts Chocolate Mushrooms Dried fruits or beans Peas 2016 AMERICAN ASSOCIATION 519 FOR THE STUDY OF LIVER DISEASES 35

36 Chelation Therapy o Penicillamine Reduces affinity of protein for copper Increases urinary copper excretion Increases hepatic ligand, metallothionein Fever & Rash most common side effects Nausea, vomiting and anorexia Aplastic anemia Proteinuria Nephrotic Syndrome Neurologic symptoms may initially worsen Pyridoxine 25mg qd 2016 AMERICAN ASSOCIATION 520 FOR THE STUDY OF LIVER DISEASES 36

37 Chelation Therapy o Trientine Increased urinary copper excretion Decreases intestinal copper absorption Gastritis Iron deficiency anemia Becoming more first line 2016 AMERICAN ASSOCIATION 521 FOR THE STUDY OF LIVER DISEASES 37

38 Chelation Therapy o Zinc Zinc acetate preferred over zinc sulfate Induces intestinal cell metallothionein and blocks absorption of copper into circulation Induces hepatic metallothionein and binds toxic copper in the liver Initial therapy use in conjuction with trientine Used in maintenance after urinary Cu excretion <500 g/day 2016 AMERICAN ASSOCIATION 522 FOR THE STUDY OF LIVER DISEASES 38

39 Wilson Disease Mutations 2016 AMERICAN ASSOCIATION 523 FOR THE STUDY OF LIVER DISEASES 39

40 Genetic Testing for Wilson Disease 2016 AMERICAN ASSOCIATION 524 FOR THE STUDY OF LIVER DISEASES 40

41 Summary o Hemochromatosis may be due to non-hfe Diagnosis should be based on phenotype o C282Y/H63D CPD heterozygotes often have co-factor o Deferasirox may be considered in anemic patients o Heterozygous A1AT deficiency possible co-factor Genotyping and Phenotyping available for diagnosis o Chronic cholestasis may mimic Wilson Disease o Genetic testing not commonly available for Wilson Disease o Family screening should not be overlooked 2016 AMERICAN ASSOCIATION 525 FOR THE STUDY OF LIVER DISEASES 41