0
Primary biliary cirrhosis and
autoimmune liver disease
台北榮民總醫院 內科部胃腸科
蘇建維 /黃惠君
Case presentation
A 66-year-old gentleman suffered from intermittent pruritus
for 8 years. But no yellowish discoloration ...
Case presentation
The serologic tests for HBsAg, anti-HBs, and anti-HCV
were all negative. But antibody against hepatitis ...
Liver Biopsy
H&E stain, x 800 Masson, x 1600
focal destruction of bile duct epithelium with lymphocytes infiltration,
foca...
Primary Biliary Cirrhosis
66
Epidemiology
Incidence: 0.7 to 49 per million per year
Point prevalence: 6.7 to 402 per million
Highest in Northern Eur...
Risk factors
Smoking, 1.67X Family history, 7.56X
UTI, 2.02XThyroid disease, 3.08X
Liang Y, et al. Hepatology Research 201...
Etiologies
• familial clustering
• prevalence: 100x in
first-degree relatives
MHC class II
Innate immunity
adaptative immu...
Pathophysiology
9 Kaplan MM, Gershwin ME. N Engl J Med 2005;353:1261-73
Cirrhosis with decrease of small bile ductsIncrease in connective tissue (bridging fibrosis)
Bile duct proliferation, infl...
Natural History
PBC progresses through three irreversible states: (a)
cirrhosis; (b) a terminal phase defined when serum
b...
Long-term survival rates are comparable between
PBC patients and general population
Floreani A, et al. Liver Int 2011;31:3...
Symptoms and Signs
50% patients: asymptomatic at diagnosis
Early phase: fatigue (78%), pruritus (20-70%), osteopenia (33%)...
Diagnosis Criteria
Diagnosis of PBC: two of the three criteria are met
Abnormal biochemical tests with elevation of ALK-P ...
Special Cases
AMA-negative PBC
Nearly all of the patients: ANA (+) and/or ASMA (+)
Require liver biopsy
No different progn...
Comparison of demographic and clinical characteristics at
diagnosis between AMA-positive and AMA-negative PBC patients
AMA...
Treatment
All PBC patients with abnormal liver biochemistry
should be considered for specific therapy
UDCA
13–15 mg/kg dai...
Treatment
Adjuvant therapies
Patients: features of AIH, severe interface hepatitis, abnormal
serum bilirubin level, poor r...
Factors associated with poor overall
survival in PBC patients in Taiwan
Su CW, Hung HH, Huo TI, Wu JC, et al. Liver Int 20...
Non-invasive serum markers for predicting
hepatic fibrosis in patients with PBC
AUROC 95% CI Standard error P
AAR 0.847 0....
The application of AAR for predicting
clinical adverse outcomes in patients
with primary biliary cirrhosis
Su CW, Chan CC,...
Greatly improved the survival
Decompensated cirrhosis or liver failure: the only
effective Tx
Premature ductopenic variant...
Liver transplantation for PBC in Taiwan
From 1984 to 2008, 539 primary liver transplantations
were performed in Chang Gung...
Autoimmune hepatitis
Clinical characteristics
Prevalence : 50-200 case/1 million in Western
Europe & North American
Presentation – heterogeneou...
Clinical characteristics
Chronic, unknown cause, in all age
Fluctuating course
Laboratory abnormalities
ALT or AST more st...
Extra-hepatic disorders associated with AIH
Thyroiditis (Hashimoto) Vitiligo
Ulcerative colitis Celiac disease
Type 1 diab...
Diagnosis scoring system
Czaja et al, Hepatology, 2002;36:479-497
Simplified diagnostic criteria (2008) of the international
autoimmune hepatitis group
Points
Autoantibodies ANA or SMA or ...
Histology of AIH
Interface hepatitis / zone 3 Plasma cell infiltration
Czaja et al, Hepatology, 2002;36:479-497
Management algorithm for patients with definite AIH
Lohse AW, Mieli-Vergani G. Autoimmune hepatitis J Hepatol 2011;55:171-...
Management for relapse of AIH
29.9% AIH patients suffered from relapses during tapering
of corticosteroid therapy
Yokokawa...
Management for relapse of AIH
Relapse
(n= 20)
With AZP
(n= 7)
Repeated
relapse
(n=0)
Sustained
remission
(n=7)
No AZP
(n= ...
Poor prognostic factors of AIH
Cirrhosis at diagnosis
Development of cirrhosis during treatment
Nonwhite ethnicity
Female ...
Long –term outcomes of patients with AIH
Hoeroldt B, et al. Gastroenterology 2011;140:1980-9
Hazard ratio 95% confidence
i...
AIH in Japan
Migita K, et al. Liver Int 2012;32:837-44
Mean age at presentation: 56.6 years
Cirrhosis at presentation: 10....
Clinical features of AIH patients in Taiwan
Number %
Clinical onset
Acute/insidious/asymptomatic
20/22/6 41.7/45.8/12.5
Ci...
Comparison of pretreatment data between cirrhotic
and non-cirrhotic patients with AIH in Taiwan
Parameters Cirrhotic (n=5)...
AIH in children
Robert EA. Liver Int 2011;31:1424-31
AIH in children in Taiwan
Yeh SH, Ni YH, Chang MH, et al. Pediatr Neonatol 2009;50:65-9
Incidence of AIH among children ho...
Take Home Message
PBC is a chronic inflammatory autoimmune disease that
mainly targets the cholangiocytes of the interlobu...
致謝
台北榮民總醫院
內科部胃腸科
黃惠君醫師 謝昀蓁醫師 李重賓副教授 霍德義教授
黃以信教授 林漢傑主任 李發耀主任
教學研究部
吳肇卿教授
家庭醫學部
黃信彰主任
胸腔部
丁文穎醫師
桃園分院
高偉育醫師
振興醫院
李壽東院長 洪宏緒醫師...
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Primary biliary cirrhosis and autoimmune hepatitis 20120902

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  • Australia: cumulative incidence that is almost 10-fold higherincreased exposure to an environmental factor, demographic changes with an increasedelderly at-risk population, increase survival of already diagnosedpersons, earlier diagnosis, improved care, and increase clinicianas well patient awareness, among other reasons.
  • Figure 4. Properties of Apoptosis in Somatic Cells and Biliary Epithelial Cells.In biliary epithelial cells, the pyruvate dehydrogenase E2 complex (PDC-E2), which is the dominant autoantigen, remainsimmunologically intact after apoptosis; this observation suggests a basis for the targeting of pathological and autoimmunechanges to biliary epithelial cells.
  • Transcript of "Primary biliary cirrhosis and autoimmune hepatitis 20120902 "

    1. 1. Primary biliary cirrhosis and autoimmune liver disease 台北榮民總醫院 內科部胃腸科 蘇建維 /黃惠君
    2. 2. Case presentation A 66-year-old gentleman suffered from intermittent pruritus for 8 years. But no yellowish discoloration of skin nor tea- colored urine was complained in that period. He denied any history of blood transfusion, acupuncture, tattoo, herbal medicine, smoking or alcohol drinking. He took a physical check up in September 2005. Serum biochemistry tests showed ALT level 86 U/L (normal, 0-40 U/L), AST level 92 U/L (normal, 5-45 U/L), Alk-P level 229 U/L (normal, 10-100 U/L), total bilirubin 0.9 mg/dL (normal, 0.2-1.6 mg/dL), GGT 630 U/L (normal, 8- 61 U/L), albumin 4.5 gm/dL (normal, 3.7-5.3 gm/dL), IgG 2270 mg/dL (normal, 1188-1800 mg/dL), IgA 309 mg/dL (normal, 158-358 mg/dL) and IgM 138 mg/dL (normal, 72- 216 mg/dL). 2
    3. 3. Case presentation The serologic tests for HBsAg, anti-HBs, and anti-HCV were all negative. But antibody against hepatitis B core antigen (anti-HBc) was positive, indicating a previous or occult HBV infection. Serum HBV DNA was negative by polymerase chain reaction (PCR) method. Serum autoantibodies including anti-nuclear antibody and anti-smooth muscle antibody were negative, but anti- mitochondrial antibody (Fluoro-kit; Incstar, Stillwater, MN) was positive. 3
    4. 4. Liver Biopsy H&E stain, x 800 Masson, x 1600 focal destruction of bile duct epithelium with lymphocytes infiltration, focal absence of bile duct combined with periportal fibrosis and necrosis
    5. 5. Primary Biliary Cirrhosis
    6. 6. 66 Epidemiology Incidence: 0.7 to 49 per million per year Point prevalence: 6.7 to 402 per million Highest in Northern European countries & Northern US Increase incidence and prevalence of PBC worldwide exposure to environmental factors↑, elderly population↑, survival↑, earlier diagnosis, improved care, earlier awareness… Selmi C, Bowlus CL, Gershwin MR, Coppel RL. Lancet 2011;377:1600-9
    7. 7. Risk factors Smoking, 1.67X Family history, 7.56X UTI, 2.02XThyroid disease, 3.08X Liang Y, et al. Hepatology Research 2011;41:572-8
    8. 8. Etiologies • familial clustering • prevalence: 100x in first-degree relatives MHC class II Innate immunity adaptative immunity adaptative immunity disturbances of host resistance to infection and the inflammatory process xenobiotics E.coli, Novosphingobium aromaticivorans Generate a transient or chronic immune response that is cross- reactive with self PDC: Molecular mimicry • M:F=1:10 • defects in the X chromosome↑ Selmi C, Bowlus CL, Gershwin MR, Coppel RL. Lancet 2011;377:1600-9
    9. 9. Pathophysiology 9 Kaplan MM, Gershwin ME. N Engl J Med 2005;353:1261-73
    10. 10. Cirrhosis with decrease of small bile ductsIncrease in connective tissue (bridging fibrosis) Bile duct proliferation, inflammatory infiltrate the periportal field (portal inflammation) Primary biliary cirrhosis (PBC) Histology (H.E., 100x) Stage I Stage II Stage IVStage III Bile duct destruction, inflammation (periportal fibrosis) Prof. Dr. U. Leuschner Interdisziplinäres Facharztzentrum, Frankfurt/Main (Germany)
    11. 11. Natural History PBC progresses through three irreversible states: (a) cirrhosis; (b) a terminal phase defined when serum bilirubin reaches 6 mg/dL with or without GI bleeding, ascites, or encephalopathy; and (c) death Pre-UDCA era Serum bilirubin increase preceding death UDCA era UDCA therapy  delay rate of histological progression to cirrhosis 13–15 mg/kg UDCA daily Start to treat in early stage good prognosis
    12. 12. Long-term survival rates are comparable between PBC patients and general population Floreani A, et al. Liver Int 2011;31:361-8
    13. 13. Symptoms and Signs 50% patients: asymptomatic at diagnosis Early phase: fatigue (78%), pruritus (20-70%), osteopenia (33%), and osteoporosis (11%) Hypercholesterolemia: typically caused by a rise in HDL, not increases cardiovascular risk. All forms of PBC: IgM↑ Typical: ALK-P & GGT↑↑, ALT/AST↑ PBC with AIH features: ALT/AST↑↑, IgG↑↑ Late phase: thrombocytopenia, polyclonal hyperglobulinemia, and hyperbilirubinemia, hypoalbuminemia Selmi C, Bowlus CL, Gershwin MR, Coppel RL. Lancet 2011;377:1600-9
    14. 14. Diagnosis Criteria Diagnosis of PBC: two of the three criteria are met Abnormal biochemical tests with elevation of ALK-P and GGT Presence of AMA with M2 specificity Evidence of non-suppurative destructive cholangitis (NSDC) at histology
    15. 15. Special Cases AMA-negative PBC Nearly all of the patients: ANA (+) and/or ASMA (+) Require liver biopsy No different prognosis to UDCA Tx compared with AMA(+) group
    16. 16. Comparison of demographic and clinical characteristics at diagnosis between AMA-positive and AMA-negative PBC patients AMA(+) (85, 84%) AMA(-) (16, 16%) p Sex (M/F) 19/66 4/12 NS Age of diagnosis (mean ± SD; year) 51.2 ± 12.3 52.5 ± 14.8 NS Symptoms at diagnosis (yes/no) 75/10 14/2 NS ANA (positive/negative) 52/28 13/3 NS Albumin (mean ± SD; gm/dL) 3.99 ± 0.53 3.99 ± 0.55 NS ALT (mean ± SD; U/L) 118.1 ± 88.3 165.8 ± 87.8 NS Bilirubin (mean ± SD; mg/dL) 2.14 ± 2.03 2.79 ± 2.39 NS ALK-P (mean ± SD; U/L) 404.0 ± 222.2 535.9 ± 286.4 0.042 Cholesterol (mean ± SD; mg/dL) 261.6 ± 128.6 371.1 ± 173.3 0.005 Child-Pugh (A/B/C) 62/19/4 9/6/1 NS Mayo score 5.58 ± 1.66 5.61 ± 1.86 NS Stage of liver histology (1/2/3/4) 7/22/4/5 3/5/1/2 NS Su CW, Hung HH, Huo TI, Wu JC, et al. Liver Int 2008;28:1305-13
    17. 17. Treatment All PBC patients with abnormal liver biochemistry should be considered for specific therapy UDCA 13–15 mg/kg daily Improves parameters of liver biochemistry Delays the progression of fibrosis and histological stage The survival rate of UDCA-treated patients in early stages of disease is similar to that in a control population Adverse effect: gastric discomfort, weight gain, increase pruritis
    18. 18. Treatment Adjuvant therapies Patients: features of AIH, severe interface hepatitis, abnormal serum bilirubin level, poor response to UDCA Glucocorticoids + UDCA Methotrexate + UDCA: benefit in a small subset of patients Cyclosporine monotherapy: prolonged the time to death or transplantation; high rate of side effects Colchicine, chlorambucil, penicillamine, azathioprine, malotilate, and thalidomide ineffective or toxic
    19. 19. Factors associated with poor overall survival in PBC patients in Taiwan Su CW, Hung HH, Huo TI, Wu JC, et al. Liver Int 2008;28:1305-13 Variable Risk ratio 95% Confidence interval Standard error p UDCA treatment 0.302 0.125-0.728 0.449 0.008 Albumin≧ 4.0 g/dL 0.321 0.123-0.839 0.491 0.021 Creatinine > 0.8 mg/dL 2.539 1.076-5.994 0.438 0.033
    20. 20. Non-invasive serum markers for predicting hepatic fibrosis in patients with PBC AUROC 95% CI Standard error P AAR 0.847 0.727-0.966 0.061 0.001 Mayo PBC risk score 0.722 0.535-0.909 0.095 0.028 MELD score 0.617 0.392-0.842 0.115 0.247 Child score 0.608 0.393-0.823 0.110 0.285 Su CW, Chan CC, Hung HH, Wu JC, et al. J Clin Gastroenterol 2009;43:876-83
    21. 21. The application of AAR for predicting clinical adverse outcomes in patients with primary biliary cirrhosis Su CW, Chan CC, Hung HH, Wu JC, et al. J Clin Gastroenterol 2009;43:876-83
    22. 22. Greatly improved the survival Decompensated cirrhosis or liver failure: the only effective Tx Premature ductopenic variant Recurrence 20% of patients at 5 years more frequent in patients w/o a glucocorticoid and cyclosporine regimen Liver transplantation for PBC
    23. 23. Liver transplantation for PBC in Taiwan From 1984 to 2008, 539 primary liver transplantations were performed in Chang Gung memorial Hospital- Kaohsiung Medical center, including 19 (3.5%) for PBC. Liver function returned to normal one month after transplantation. The overall 1-,3-, and 5-yr survival rates were 94.7%, 89.2%, and 89.2%, respectively Variable LDLD (n=14) DDLD (n=5) Mean age (yr) 51.0 ± 1.5 47.3 ± 3.9 M/F 1/13 1/4 MELD 20.7± 2.4 16.4± 2.4 CTP 11± 0.5 11± 1.1 Sun CK, Chen CL, et al. Clin Transplant 2011;25:47-53
    24. 24. Autoimmune hepatitis
    25. 25. Clinical characteristics Prevalence : 50-200 case/1 million in Western Europe & North American Presentation – heterogeneous Variable – no symptoms/signs to fulminant hepatic failure Malaise, anorexia, nausea, vomiting, abdominal pain, itching Arthralgia in small joint, hepatomegaly, splenomegaly Jaundice
    26. 26. Clinical characteristics Chronic, unknown cause, in all age Fluctuating course Laboratory abnormalities ALT or AST more striking than ALK-P, T bili γ-globulins, IgG, 1.2~3.0 X
    27. 27. Extra-hepatic disorders associated with AIH Thyroiditis (Hashimoto) Vitiligo Ulcerative colitis Celiac disease Type 1 diabetes mellitus Systemic lupus erythematosus Rheumatoid arthritis Mixed connective tissue disease Panniculitis Hyperthyroidism (Graves’ disease) Sjogren’s syndrome Mononeuritis Urticaria pigmentosa Sweet’s syndrome Idiopathic thromocytopenic purpura Polyglandular autoimmune syndrome, type 1 Glomerulonephritis Hemolytic anemia Polymyositis Uveitis 27 Caprai S, et al. Clin Gastroenterol Hepatol 2008;6:803-6 Teufel A, et al. J Clin Gastroenteorlo 2010;44:208-13 Lohse AW, Mieli-Vergani G. J Hepatol 2011;55:171-82
    28. 28. Diagnosis scoring system Czaja et al, Hepatology, 2002;36:479-497
    29. 29. Simplified diagnostic criteria (2008) of the international autoimmune hepatitis group Points Autoantibodies ANA or SMA or LKM > 1:40 1 ANA or SMA or LKM > 1: 80 SLA/LP positive (> 20 unit) 2 IgG (or gamma-globulin) Upper normal limit 1 > 1.10 times normal limit 2 Liver histology Compatible with AIH Chronic hepatitis with lymphocytic infiltration without features considered typical 1 Typical for AIH (1) Interface hepatitis: lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending in the lobule (2) Emperipolesis: active penetration by one cell into and through larger cell (3) Hepatic rosette formation 2 Absence of viral hepatitis Yes 2 No 0 29 Hennes EM, et al. Hepatology 2008;48:169-76 Definite AIH ≧7 Probable AIH ≧6
    30. 30. Histology of AIH Interface hepatitis / zone 3 Plasma cell infiltration Czaja et al, Hepatology, 2002;36:479-497
    31. 31. Management algorithm for patients with definite AIH Lohse AW, Mieli-Vergani G. Autoimmune hepatitis J Hepatol 2011;55:171-82
    32. 32. Management for relapse of AIH 29.9% AIH patients suffered from relapses during tapering of corticosteroid therapy Yokokawa J, et al. Hepatol Res 2011;41:641-6 OR 95% CI P Age at diagnosis (≧50 yr) 0.29 0.10-0.86 0.03 Bilirubin (≧1.5mg/dL) 4.50 1.23-16.45 0.02 AST (≧250 IU/L) 4.88 1.35-17.65 0.02 ALT (≧250 IU/L) 10.0 2.56-39.11 <0.01 Prothrombin activity (≧80%) 0.21 0.06-0.80 0.02 Gamma-globulin (≧3.4 mg/dL) 7.20 1.52-34.02 0.01 IgG (≧3400 mg/dL) 2.68 0.88-8.13 0.08 IAIHG score (≧17) 5.54 1.56-19.75 <0.01
    33. 33. Management for relapse of AIH Relapse (n= 20) With AZP (n= 7) Repeated relapse (n=0) Sustained remission (n=7) No AZP (n= 13) Repeated relapse (n=8) Sustained remission (n=5) Azathioprine (AZP) 50-100mg/day Yokokawa J, et al. Hepatol Res 2011;41:641-6
    34. 34. Poor prognostic factors of AIH Cirrhosis at diagnosis Development of cirrhosis during treatment Nonwhite ethnicity Female sex Presence of symptoms Severe liver dysfunction Less than 10-fold elevation of ALT levels at presentation Failure to normalize ALT levels with treatment Recurrent relapses Feld JJ, et al. Hepatology 2005;42:53-62 Verma S, et al. Hepatology 2007;46:1828-35 Montano-Loza AJ, et al. Am J Gastroenterol 2007;102:1005-12 Al-Chalabi T, et al. Clin Gastroenterol Hepatol 2008;6:1389-95
    35. 35. Long –term outcomes of patients with AIH Hoeroldt B, et al. Gastroenterology 2011;140:1980-9 Hazard ratio 95% confidence interval P Decompensation at presentation 3.92 2.40-6.38 <0.001 Failure to normalize serum ALT levels within 12 months of treatment 4.27 2.05-8.89 <0.001 No. of relapses per decade 1.12 1.01-1.25 <0.001 Nontreatment with azathioprine 2.71 1.59-4.60 0.001 Age at presentation (y) 1.05 1.03-1.07 <0.001
    36. 36. AIH in Japan Migita K, et al. Liver Int 2012;32:837-44 Mean age at presentation: 56.6 years Cirrhosis at presentation: 10.9% Mean prednisolone dose: 28.71 mg/day Mean follow-up: 8.0 years Cirrhosis: 7.8%; HCC: 3.6%
    37. 37. Clinical features of AIH patients in Taiwan Number % Clinical onset Acute/insidious/asymptomatic 20/22/6 41.7/45.8/12.5 Cirrhosis at presentation 17 35.4 Fatigue 29 60.4 Jaundice 27 56.3 Anorexia 24 50.0 Abdominal fullness 21 43.8 Splenomegaly 16 33.3 Abdominal pain 16 33.3 Ascites 12 25.0 Arthralgia 10 20.8 Edema 8 16.7 Hepatomegaly 6 12.5 Pruritis 5 10.4 Fever 3 6.3 Hepatic encephalopathy 1 2.1 Koay LK, et al. Dig Dis Sci 2006;51:1978-84 Treatment response to prednisolone: 70.3% 5-year overall survival rate: 85.4%
    38. 38. Comparison of pretreatment data between cirrhotic and non-cirrhotic patients with AIH in Taiwan Parameters Cirrhotic (n=5) Non-cirrhotic (n=17) P Age (years) 60 ± 22 53 ± 20 0.446 Female/Male 3/2 12/5 1.000 ALT (U/L) 100 ± 102 634 ± 394 0.002 AST (U/L) 154 ± 181 652 ± 479 0.015 ALK-P (U/L) 177 ± 127 230 ± 97 0.256 GGT (U/L) 71 ± 37 335 ± 277 0.002 Bilirubin (mg/dL) 1.7 ± 0.6 6.8 ± 7.4 0.247 Albumin (g/dL) 2.8 ± 0.4 3.7 ± 0.6 0.014 Globulin (g/dL) 4.2 ± 0.4 4.0 ± 1.0 0.636 IgG (mg/dL) 3650 ± 1143 2875 ± 1127 0.545 Platelet (/mm3) 79600 ± 24876 209571 ± 81149 0.002 Huang HC, Huang YS, Wu JC, et al. Chin Med J 2002;65:563-9 More than 30% of AIH patients in Taiwan have cirrhosis at diagnosis. Long-term prognosis are significantly poorer than those without cirrhosis. AIH should be diagnosed and treated before cirrhosis developed.
    39. 39. AIH in children Robert EA. Liver Int 2011;31:1424-31
    40. 40. AIH in children in Taiwan Yeh SH, Ni YH, Chang MH, et al. Pediatr Neonatol 2009;50:65-9 Incidence of AIH among children hospitalized with hepatitis: 2.3%
    41. 41. Take Home Message PBC is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. When administered at doses of 13-15 mg/kg/day of UDCA therapy, a majority of patients with PBC have a normal life expectancy. AIH is diagnosed based on elevation of IgG, demonstration of characteristics autoantibodies, and histological features of hepatitis in the absence of viral disease. Adequately dosed steroids are the mainstay of remission induction treatment, while remission maintenance may need azathioprine in some patients. AIH patients in Taiwan have comparable therapeutic effects to steroid in a lower doses.
    42. 42. 致謝 台北榮民總醫院 內科部胃腸科 黃惠君醫師 謝昀蓁醫師 李重賓副教授 霍德義教授 黃以信教授 林漢傑主任 李發耀主任 教學研究部 吳肇卿教授 家庭醫學部 黃信彰主任 胸腔部 丁文穎醫師 桃園分院 高偉育醫師 振興醫院 李壽東院長 洪宏緒醫師 中國醫藥大學附設醫院 陳祖裕主任
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