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335. Guanabens N, Pares A, Ros I, Alvarez L, Pons F, Caballeria L, Monegal A, etal. Alendronate
is more effective than etidronate for increasing bone mass in osteopenic patients with primary
biliary cirrhosis. Am J Gastroenterol. 2003;98:2268–74.
336. Zein CO, Jorgensen RA, Clarke B, Wenger DE, Keach JC, Angulo P, Lindor KD.Alendronate
improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled
trial. Hepatology. 2005;42:762–71.
337. Floreani A, Carderi I, Ferrara F, Rizzotto ER, Luisetto G, Camozzi V, Baldo V.A 4-year treat-
ment with clodronate plus calcium and vitamin D supplements does not improve bone mass
in primary biliary cirrhosis. Dig Liver Dis. 2007;39:544–8.
338. Nishiguchi S, Shimoi S, Kurooka H, Tamori A, Habu D, Takeda T, Kubo S.Randomized
pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis. J Hepatol.
2001;35:543–5.
339. Pereira SP, O’Donohue J, Moniz C, Phillips MG, Abraha H, Buxton-Thomas M, Williams
R.Transdermal hormone replacement therapy improves vertebral bone density in primary bil-
iary cirrhosis: results of a 1-year controlled trial. Aliment Pharmacol Ther. 2004;19:563–70.
340. Ormarsdottir S, Mallmin H, Naessen T, Petren-Mallmin M, Broome U, Hultcrantz R, Loof
L.An open, randomized, controlled study of transdermal hormone replacement therapy on
the rate of bone loss in primary biliary cirrhosis. J Intern Med. 2004;256:63–9.
341. Lindor KD, Janes CH, Crippin JS, Jorgensen RA, Dickson ER.Bone disease in primary bili-
ary cirrhosis: does ursodeoxycholic acid make a difference? Hepatology. 1995;21:389–92.
342. Floreani A, Zappala F, Fries W, Naccarato R, Plebani M, D’Angelo A, Chiaramonte M. A
3-year pilot study with 1,25-dihydroxyvitamin D, calcium, and calcitonin for severe osteo-
dystrophy in primary biliary cirrhosis. J Clin Gastroenterol. 1997;24:239–44.
343. Boone RH, Cheung AM, Girlan LM, Heathcote EJ.Osteoporosis in primary biliary cir-
rhosis: a randomized trial of the efcacy and feasibility of estrogen/progestin. Dig Dis Sci.
2006;51:1103–12.
344. Crippin JS, Jorgensen RA, Dickson ER, Lindor KD.Hepatic osteodystrophy in primary bili-
ary cirrhosis: effects of medical treatment. Am J Gastroenterol. 1994;89:47–50.
345. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of
estrogen plus progestin for secondary prevention of coronary heart disease in postmeno-
pausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
JAMA. 1998;280(7):605–13.
346. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML,
et al. Risks and benets of estrogen plus progestin in healthy postmenopausal women:
principal results From the Women's Health Initiative randomized controlled trial.
JAMA. 2002;288(3):321–33.
347. Seeman E.Raloxifene. J Bone Miner Metab. 2001;19(2):65–75.
348. Levy C, Harnois DM, Angulo P, Jorgensen R, Lindor KD.Raloxifene improves bone mass in
osteopenic women with primary biliary cirrhosis: results of a pilot study. Liver international:
ofcial journal of the International Association for the Study of the Liver. 2005;25(1):117–21.
349. Cremers S, Drake MT, Ebetino FH, Bilezikian JP, Russell RGG.Pharmacology of bisphos-
phonates. British journal of clinical pharmacology. 2019;85(6):1052–62.
350. Lindor KD, Jorgensen RA, Tiegs RD, Khosla S, Dickson ER.Etidronate for osteoporosis in
primary biliary cirrhosis: a randomized trial. J Hepatol. 2000;33(6):878–82.
351. Floreani A, Carderi I, Ferrara F, Rizzotto ER, Luisetto G, Camozzi V, etal. A 4-year treat-
ment with clodronate plus calcium and vitamin D supplements does not improve bone mass
in primary biliary cirrhosis. Digestive and liver disease: ofcial journal of the Italian Society
of Gastroenterology and the Italian Association for the Study of the Liver. 2007;39(6):544–8.
352. Danford CJ, Ezaz G, Trivedi HD, Tapper EB, Bonder A.The pharmacologic management
of osteoporosis in primary biliary cholangitis: a systematic review and meta-analysis. J Clin
Densitom. 2019;23(2):223–36.
353. Arase Y, Tsuruya K, Hirose S, Ogiwara N, Yokota M, Anzai K, Deguchi R, etal. Efcacy
and safety of 3-year Denosumab therapy for osteoporosis in patients with autoimmune liver
diseases. Hepatology. 2019;71(2):757–9.
N. V. Bergasa
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83
354. Lleo A, Ma X, Gershwin ME, Invernizzi P.Letter to the editor: might Denosumab t in PBC
treatment? Hepatology. 2019;72(1):359–60.
355. Acalovschi M.Gallstones in patients with liver cirrhosis: incidence, etiology, clinical and
therapeutical aspects. World J Gastroenterol. 2014;20(23):7277–85.
356. Summereld JA, Elias E, Hungerford GD, Nikapota VL, Dick R, Sherlock S. The biliary
system in primary biliary cirrhosis. A study by endoscopic retrograde cholangiopancreatog-
raphy. Gastroenterology. 1976;70(2):240–3.
357. Zak A, Zeman M, Slaby A, Vecka M. Xanthomas: clinical and pathophysiological rela-
tions. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc,
Czechoslovakia. 2014;158(2):181–8.
358. Ahrens EH, Jr., Kunkel HG.The relationship between serum lipids and skin xanthomata in
18 patients with primary biliary cirrhosis. The Journal of clinical investigation. 1949;28(6 Pt
2):1565–74.
359. Turnberg LA, Mahoney MP, Gleeson MH, Freeman CB, Gowenlock AH.Plasmaphoresis
and plasma exchange in the treatment of hyperlipaemia and xanthomatous neuropathy in
patients with primary biliary cirrhosis. Gut. 1972;13(12):976–81.
360. Peters MG, Hoffnagle JH, McGarvey C, Fox I, Gregg RE, Jones EA.Primary biliary cir-
rhosis: management of an unusual case with severe xanthomata by hepatic transplantation.
Journal of clinical gastroenterology. 1989;11(6):694–7.
361. Kew MC, Varma RR, Dos Santos HA, Scheuer PJ, Sherlock S.Portal hypertension in primary
biliary cirrhosis. Gut. 1971;12(10):830–4.
362. Lebrec D, Sicot C, Degott C, Benhamou JP.Portal hypertension and primary biliary cirrhosis.
Digestion. 1976;14(3):220–6.
363. Abraham SC, Kamath PS, Eghtesad B, Demetris AJ, Krasinskas AM. Liver transplanta-
tion in precirrhotic biliary tract disease: portal hypertension is frequently associated with
nodular regenerative hyperplasia and obliterative portal venopathy. Am J Surg Pathol.
2006;30:1454–61.
364. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J.Portal hypertensive bleeding in cirrho-
sis: risk stratication, diagnosis, and management: 2016 practice guidance by the American
Association for the Study of Liver Diseases. Hepatology. 2017;65:310–35.
365. Grace ND, Groszmann RJ, Garcia-Tsao G, Burroughs AK, Pagliaro L, Makuch RW, etal.
Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology.
1998;28(3):868–80.
366. Bressler B, Pinto R, El-Ashry D, Heathcote EJ.Which patients with primary biliary cirrhosis
or primary sclerosing cholangitis should undergo endoscopic screening for oesophageal vari-
ces detection? Gut. 2005;54:407–10.
367. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ, etal. Primary
biliary cirrhosis. Hepatology. 2009;50(1):291–308.
368. Boyer TD, Kokenes DD, Hertzler G, Kutner MH, Henderson JM.Effect of distal splenorenal
shunt on survival of patients with primary biliary cirrhosis. Hepatology. 1994;20:1482–6.
369. Vlachogiannakos J, Carpenter J, Goulis J, Triantos C, Patch D, Burroughs AK.Variceal
bleeding in primary biliary cirrhosis patients: a subgroup with improved prognosis and
a model to predict survival after rst bleeding. Eur J Gastroenterol Hepatol. 2009;21:
701–7.
370. Kuiper EM, Hansen BE, Adang RP, van Nieuwkerk CM, Timmer R, Drenth JP, etal.Relatively
high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not respond-
ing to ursodeoxycholic acid. Eur J Gastroenterol Hepatol. 2010;22(12):1495–502.
371. Cavazza A, Caballeria L, Floreani A, Farinati F, Bruguera M, Caroli D, Pares A.Incidence,
risk factors, and survival of hepatocellular carcinoma in primary biliary cirrhosis: compara-
tive analysis from two centers. Hepatology. 2009;50:1162–8.
372. Silveira MG, Suzuki A, Lindor KD. Surveillance for hepatocellular carcinoma in patients
with primary biliary cirrhosis. Hepatology. 2008;48(4):1149–56.
373. Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. Transplantation trends in
primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007;5(11):1313–5.
3
Primary Biliary Cholangitis
https://t.me/medicina_free
84
374. Shapiro JM, Smith H, Schaffner F. Serum bilirubin: a prognostic factor in primary biliary
cirrhosis. Gut. 1979;20(2):137–40.
375. Bonnand AM, Heathcote EJ, Lindor KD, Poupon RE. Clinical signicance of serum bili-
rubin levels under ursodeoxycholic acid therapy in patients with primary biliary cirrhosis.
Hepatology. 1999;29(1):39–43.
376. Neuberger J, Altman DG, Christensen E, Tygstrup N, Williams R. Use of a prognostic
index in evaluation of liver transplantation for primary biliary cirrhosis. Transplantation.
1986;41:713–6.
377. Christensen E, Altman DG, Neuberger J, De Stavola BL, Tygstrup N, Williams R.Updating
prognosis in primary biliary cirrhosis using a time-dependent cox regression model. PBC1
and PBC2 trial groups. Gastroenterology. 1993;105:1865–76.
378. Christensen E, Gunson B, Neuberger J.Optimal timing of liver transplantation for patients
with primary biliary cirrhosis: use of prognostic modelling. J Hepatol. 1999;30:285–92.
379. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A.Prognosis in primary
biliary cirrhosis: model for decision making. Hepatology. 1989;10:1–7.
380. Grambsch PM, Dickson ER, Kaplan M, LeSage G, Fleming TR, Langworthy AL.Extramural
cross-validation of the Mayo primary biliary cirrhosis survival model establishes its general-
izability. Hepatology. 1989;10:846–50.
381. Grambsch PM, Dickson ER, Wiesner RH, Langworthy A.Application of the Mayo pri-
mary biliary cirrhosis survival model to Mayo liver transplant patients. Mayo Clin Proc.
1989;64:699–704.
382. Cholongitas E, Burroughs AK.The evolution in the prioritization for liver transplantation.
Ann Gastroenterol. 2012;25(1):6–13.
383. Harms MH, Janssen QP, Adam R, Duvoux C, Mirza D, Hidalgo E, Watson C, etal. Trends
in liver transplantation for primary biliary cholangitis in Europe over the past three decades.
Aliment Pharmacol Ther. 2019;49:285–95.
384. Kim WR, Wiesner RH, Therneau TM, Poterucha JJ, Porayko MK, Evans RW, etal. Optimal
timing of liver transplantation for primary biliary cirrhosis. Hepatology. 1998;28(1):33–8.
385. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuberger J.Transplantation for
primary biliary cirrhosis: retrospective analysis of 400 patients in a single center. Hepatology.
2001;33(1):22–7.
386. Neuberger J.Incidence, timing, and risk factors for acute and chronic rejection. Liver Transpl
Surg. 1999;5(4 Suppl 1):S30–6.
387. Krawczyk M, Kozma M, Szymanska A, Leszko K, Przedniczek M, Mucha K, Foroncewicz
B, etal.Effects of liver transplantation on health-related quality of life in patients with pri-
mary biliary cholangitis. Clin Transpl. 2018;32:e13434.
388. Silveira MG, Talwalkar JA, Lindor KD, Wiesner RH.Recurrent primary biliary cirrhosis
after liver transplantation. Am J Transplant. 2010;10:720–6.
389. Neuberger J, Gunson B, Hubscher S, Nightingale P.Immunosuppression affects the rate of
recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl. 2004;10:488–91.
390. Manousou P, Arvaniti V, Tsochatzis E, Isgro G, Jones K, Shirling G, etal. Primary biliary
cirrhosis after liver transplantation: inuence of immunosuppression and human leukocyte
antigen locus disparity. Liver Transpl. 2010;16(1):64–73.
391. Montano-Loza AJ, Wasilenko S, Bintner J, Mason AL.Cyclosporine A protects against pri-
mary biliary cirrhosis recurrence after liver transplantation. Am J Transplant. 2010;10:852–8.
392. Jacob DA, Haase E, Klein F, Pratschke J, Neumann UP, Neuhaus P, Bahra M.Donor inu-
ence on outcome in patients undergoing liver transplant for primary biliary cirrhosis. Exp
Clin Transplant. 2010;8:104–10.
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of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_4
Chapter 4
Autoimmune Hepatitis
NoraV.Bergasa
A 39-year-old woman presented to the emergency room because of jaundice. She
did not have any symptoms. Her serum activity of AST and ALT was ten times the
upper limit of normal, and bilirubin was 6mg/dl. She was admitted to the hospital
where a liver disease workup was notable for positive antinuclear antibodies, and
high serum concentrations of immunoglobulin G (IgG). A liver biopsy revealed
moderate to severe interface hepatitis with marked lymphoplasmacytic inltrate,
focal lobular necrosis, ballooning degeneration, and giant cell transformation of
hepatocytes with Mallory bodies and focal regenerative rosette formation consistent
with autoimmune hepatitis (AIH); trichrome stain showed mild periportal brosis.
The patient was started on prednisone 60mg/day and referred to the hepatology
clinic. On follow up, she was feeling well. The liver prole was notable for a
decrease in the serum activity of AST and ALT and bilirubin concentration as com-
pared to the pre treatment values. Prednisone was tapered to 30 mg/day over
2weeks, at which time azathioprine at 50mg/day was added, after conrming nor-
mal TMPT phenotype. Prednisone was gradually tapered, and the patient was main-
tained on azathioprine 50mg/day in association with normalization of liver prole
and serum IgG.After 3years of treatment, including 2years of normal liver tests,
azathioprine was discontinued. She remained well and with a normal liver prole
for 2years, at which time her AST and ALT increased beyond the normal range.
Over a short period of observation, a liver biopsy was performed to rule out
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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recurrence of disease versus fatty liver for which she was at risk. Liver histology
revealed a relapse of AIH. The patient was restarted on treatment as initially. At
present, prednisone has been discontinued; her liver prole is normal. She is on
azathioprine 50mg/day, doing well.
Autoimmune Hepatitis
The patient described in this chapter presented with acute hepatitis. The liver dis-
ease workup at presentation excluded viral causes of acute hepatitis, and drug-
induced hepatitis, including that caused by over the counter medications and
supplements. The autoantibodies panel suggested an autoimmune etiology of liver
disease, as did the high serum concentration of immunoglobulin G.A liver biopsy
(Fig.4.1) supported the diagnosis. She responded to immunosuppressant medica-
tions also in support of a diagnosis of autoimmune hepatitis but subsequently
relapsed off treatment, as it happens in this disease.
Etiology
Autoimmune hepatitis (AIH) is dened as hepatitis associated with markers of auto-
immunity and typical histological ndings. The etiology of autoimmune hepatitis is
unknown.
Fig. 4.1 Liver histology of
autoimmune hepatitis. The
interface (arrows) between
inamed portal tract and
parenchyma is irregular
and blurred by
inammatory inltration
and hepatocyte loss.
Hematoxylin and Eosin,
original magnication, 20×
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Pathogenetics
Regulatory T cells, Tregs, mediate immune tolerance by suppressing lymphocytes
that react to self-antigens [1]. Studies of this type of cells in autoimmune hepatitis
have suggested alterations in their number and function, although not consistently.
Serum CD4+ CD 25+ Tregs cells were reported as decreased in patients with AIH
compared to those in the control group at the time of diagnosis and in remission. In
vitro, their ability to expand was decreased; however, their capacity to suppress
effector function, tested invitro by assessing interferon gamma production by the
CD4(+)CD25(−) T-cells, was preserved. The decrease in number and ability to
expand CD4(+)CD25(+) T cells was interpreted as possible causes for the develop-
ment of cellular responses that contribute to AIH [2]. Although the ability of Tregs
in AIH to suppress interferon gamma production by CD4+CD25- T-cells has been
reported to be intact, CD4+CD25+ (Tregs) were also reported not to be able to regu-
late the proliferation of CD8 T-cells and cytokine production in patients at the time
of diagnosis of AIH, however, they were able to suppress CD8 T-cell proliferation
and trigger an increase in the CD8 T cells that produce IL-4in remission after phar-
macological therapy, which was interpreted as indicating that treatment of AIH with
immunosuppressant medications restore proper function of CD4+CD25+ (Tregs)
[3]. In an exvivo study, regulatory CD4+CD25+ T cells (Tregs) from patients with
AIH and control subjects required direct contact with CD4+CD25− and CD8+ T
cells to suppress proliferation and production of interferon gamma, a proinamma-
tory cytokine. Direct contact with Tregs was also required for an increase in the
production of IL-10, TGF-β, and IL-4, all regulatory cytokines. It has been docu-
mented that serum levels of IL-33, sST2, IL-17A, IFN gamma and alpha, and IL-4
were signicantly elevated in patients with AIH and that IL-33 correlated positively
with hypergammaglobulinemia, and serum activity of alkaline phosphatase (AP)
and gamma glutamyl transpeptidase (GGTP), interpreted as markers of liver injury,
ndings that have suggested a role of the IL-33/sST2 axis in the progression of AIH
[4]. IL-17 has been reported to correlate with histology [5].
Serum levels of M2BPGi were increased in patients with untreated AIH and
were decreased following steroid treatment that resulted in clinical improvement.
This marker might reect liver brosis and autoimmune-mediated hepatic inam-
mation in parallel to the induction of hepatitis-related inammatory cytokines [6].
Co-culture of Tregs with CD4+CD25− T cells was associated with increased
interferon gamma and interleukin (IL)-10 production by cells from patients with
AIH and by those from control subjects; however, the production of TGF-beta,
involved in innate immunity, was signicantly lower from cells from the AIH group
than from the control group. The expression of FOXP3, a key transcription factor in
Tregs' regulation, was documented as decreased in the cells from the patients com-
pared to those from control subjects. In addition, it was reported that spontaneous
apoptosis of CD4(+)CD25(−) T cells was reduced in the patients. These results
have suggested that in AIH, Tregs do interact with their target cells to produce spe-
cic cytokines; however, they do not make interferon beta, a cytokine relevant in
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innate immunity, and that they have a decrease in their apoptotic process, which
may contribute to the development of autoimmunity [7]. In these experiments,
patients had been treated with immunosuppressant drugs; thus, the results of these
exvivo experiments might have been inuenced by pharmacotherapy [7].
From a study that used peripheral mononuclear cells from control and subjects
with AIH with active disease and in remission, it was reported that theregulatory T
cells (Tregs) compartmenthad fewer CD4(+)CD25(hi) T cells, particularly during
active disease, expressed lower levels of FOXP3 and inhibited cellular proliferation
in an invitro assay to a lesser degree than cells from control subjects. The number
of natural killer (NK) cells was reduced, and the production of IL-4 was less in
patients with autoimmune hepatitis than in control subjects. In regard to gamma
delta T cells, they were documented as being more numerous in patients than in the
control subjects; the Vdelta1/V delta2 ratio changed to a predominance of Vdelta 1
cells, which have an increased ability to produce proinammatory cytokines, and
their production of interferon gamma and granzyme B was raised, which was
reported to correlate with serum markers of liver inammation. The portal tracts of
patients with AIH had few FOXP3(+), which was interpreted to suggest that, in this
disease, the effector cells are gamma delta T cells [8].
The idea of the role of CD4+CD25+FOXP3+ regulatory T cells (Treg) in the
pathogenesis of AIH has been further explored by the use of more specic identi-
ers of this compartment of T cells, i.e. CD4+CD25(high)CD127(low)FOXP3+. The
frequency of CD4+CD25(high)CD127(low)FOXP3+ was not different in patients
with AIH as compared with those of control subjects, and the function, tested by an
invitro suppression assay, was normal. The frequency of Treg in patients with active
disease was, however, higher than in patients in remission; these results were inter-
preted to suggest that the number of Treg T cells may parallel the degree of inam-
mation. In this regard, it was documented that the population of FOXP3+ Treg in the
liver of patients with AIH correlated with the liver's inammatory activity. These
results have not conrmed an impaired compartment of Treg cells in AIH [9]. T cell
immunoglobulin mucin-3 (TIM-3) is a T helper type 1 specic cell surface mole-
cule that is reported to regulate T helper cell responses and the induction of periph-
eral tolerance whose ligand is galectin-9 [10]; in AIH, the levels of Tim-3 on
CD4posCD25neg effector cells and Gal 9+cells are decreased in Tregs, which is
associated with impaired Tregs control and with a reduced ability of Tregs to sup-
press proliferative activity. These results have suggested that the characteristics of
Tregs in AIH contribute to the pathogenesis of this disease [11].
Molecular mimicry may contribute to the pathogenesis of AIH, as suggested for
other autoimmune diseases [12]. In this regard, anti-LKM1 antibodies, prevalent in
the AHI type 2, which affects mostly children, bind to liver and kidney endoplasmic
reticulum and recognize cytochrome P450 2D6 (CYP2D6) [13]. Of interest, a study
documented similarity and cross-reactivity between CYP2D6, sequence 193–212,
and a sequence from the cytomegalovirus and the hepatitis C virus with similarities
to self, which may constitute a triggering factor to autoimmune disease, e.g. AIH
[14]; indeed, a case of autoimmune hepatitis type 2 induced by HCV has been
reported [15].
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The serum of patients with AIH was reported to recognize the IL-4 receptor
bronectin type III domain of the IL-4 receptor (CD124), which has an expression
on hepatocyte and lymphocyte surfaces, with documented inhibition of STAT6
phosphorylation induced by the binding of IL-4 to CD124; these results have sug-
gested that neutralization of IL-4 contributes to the pathogenesis of AIH [16].
Certain environmental factors are considered contributory to the development of
an autoimmune disease, including AIH.Exposure to antibiotics within 1year prior
to the diagnosis of AIH was an independent signicant risk factor in developing the
disease. In contrast, alcohol consumption and history of a childhood home with
wood heating were independently associated with reduced risks for its development
in a study from New Zealand [17]. Intestinal dysbiosis, which can result from anti-
biotic use[18], has been reported in patients with AIH; specically, it was docu-
mented in a group of 24 patients with AIH who had increased intestinal permeability,
a deranged microbiome, and bacterial translocation[19].
There is a developing interest in the role of chemokines in the pathogenesis of
AIH. Chemokines are small heparin-binding molecules secreted by hepatocytes and
other liver resident cells and cells that inltrate the liver, including neutrophils and
platelets[20].
An expert summary of the potential role of chemokines in AIH suggested that
T helper type 17 lymphocytes that express CXCR3 and CCR6 are attracted to the
liver by the chemokines CXCL9, CXCL10, and CXCL11, and they themselves
recruit proinammatory T helper type 1 lymphocytes that express CXCR3 and
CCR5 by secreting CXCL10. The local secretion of CXCL16 stimulates the move-
ment of NK cells, which contribute to the inammatory process. A decrease in the
inammatory process is mediated by chemokines CCL17 and CCL22, which attract
the T helper type 2 lymphocytes that express CCR4; in addition, Tregs that express
CXCR3 are attracted by the secretion of CXCL9, which also decreases the inam-
matory response. Fibrosis is promoted by CCL2, CCL3, CCL5, CXCL4, CXCL10,
and CXCL16 by the activation or attraction of hepatic stellate cells, whereas
CX3CL1 may prevent brosis by altering apoptosis of monocytes[20]. It is sug-
gested that the development of drugs that interfere with the proinammatory action
of some chemokines will improve the management of AIH[20].
Additional studies have reported that the C-C receptor 7 programmed cell death 1
(CCR7 PD-1) chemokine, a subset of follicular helper T cells (Tfh), was signicantly
increased in the blood of patients with AIH versus that from patients from viral hepa-
titis and normal controls, with correlation with serum IgG concentrations and markers
of liver function, and associated with a decrease after treatment with steroids; in addi-
tion, the number of activated Tfh cells was signicantly increased in the liver of
patients with AIH, correlated with their number in blood, and produced more IL-21
and Il-17 than those from control subjects, ndings interpreted to suggest an involve-
ment of this type of cells and their cytokines in the pathogenesis of AIH[21]. In this
regard, the frequency of CCR7 PD-1 Tfh was reported as signicantly higher in
patients with AIH versus those with viral hepatitis and from control subjects and was
found to correlate with the International Autoimmune Hepatitis Group scoring sys-
tem, suggesting an involvement in the inammatory activity associated with AIH[21].
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Genetics
Genetic susceptibility is presumed to contribute to the pathogenesis of AIH in asso-
ciation with genes on the human leukocyte antigen (HLA) class I.In children, HLA-
DRB1*1301 was reported as a susceptibility allele and HLA-DRB1*1302 as
protective; in contrast, in adult subjects from the same country, Argentina, HLA-
DRB1*0405 was identied in association with a risk for AIH, but not with markers
found in children. These ndings suggested that the triggering factors of AIH in
children and adults differ, at least in that part of the world [22]. In Brazil, in close
geographic proximity to Argentina, but with a different ethnic and racial population,
HLA DR13 and DRB1*1301 were found more frequently in the patients than in the
control group [23]. DRB1*0301 was identied as a risk for autoimmune hepatitis in
patients from North America, in which a secondary association with DRB1*0401
was also identied. This association was not detected in Italy, where the prevalent
phenotype was B8-DR3-DQ2, and HLA DR11 appeared to be protective against the
disease[24]; in a study from North America, the DRB5*0101-DRB1*1501 haplo-
type was identied as protective from the disease[25]. A relatively large genome-
wide association study (GWAS) from the Netherlands documented a signicant
association between AIH and a variant in the MHC region at rs2187668; in the
discovery cohort, HLA-DRB1*0301 was identied as a primary susceptibility gen-
otype and HLA-DRB1*0401 as a secondary, with HLA-DRB1*03:01 having been
reported as the strongest modier of disease severity [26]. Variants of SH2B3,
rs3184504, 12q24, and of CARD10, rs6000782, 22q13.1 were also associated with
the disease, in addition to some single nucleotide polymorphisms (SPN)s already
identied in other autoimmune liver diseases, which suggested a genetic over-
lap [26].
In association with AIH, genetic polymorphisms in genes outside the major his-
tocompatibility complex (MHC) that code for proteins that participate in the regula-
tion of the immune response have been identied including: (i) Fas [27, 28], coding
for a member of the tumor necrosis factor (TNF) receptor superfamily that contains
a death domain, which plays a fundamental role in the regulation of programmed
cell death [29], (ii) TNF-alpha [30], coding for TNF [31], a cytokine that is an acute
phase reactant, and that is produced by cells of the immune system mostly, activated
macrophages, but also natural killer cells (NK), and T lymphocytes [32], (iii) TGF-
beta1 [33], coding for TGF-beta1, a polypeptide that mediates immune suppression
in innate and adaptive immunity [34], (iv) TBX21 [35], coding TBX21, a Th1-
specic T box transcription factor that controls the expression of IFN gamma, a Th1
cytokine [36], (v) VDR [37], coding for the nuclear vitamin D receptor, which mod-
ulates adaptive immunity by direct activation of T cells, and which has effects on the
phenotype and function of antigen-presenting cells, including dendritic cells.
Vitamin D modulates the adaptive immune system by direct effects on T cell activa-
tion and the phenotype and function of antigen-presenting cells (APCs), particularly
of dendritic cells [38], and also, acts as a receptor for the secondary bile acid
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91
lithocholic acid; 1,25(OH)2D3-induced changes in their phenotype and function
ultimately affect T lymphocytes, and inconsistently, CTLA-4 [39–41], coding for
CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) [42], a receptor localized on the sur-
face of T cells that downregulates the immune response [42], (vi) the SH2B3 T and
the PTPN22 A allele, with protection being given by the presence of the CC and GG
genotypes; no signicant associations were documented in polymorphisms detected
in TGFβ1 and STAT4 [43], and (vii) IL-4 gene [44].
In addition, activated effector NK cells and exhausted memory Tregs were
reported to be increased in the blood of patients with AIH and decreased in associa-
tion with steroid therapy, suggesting a role of inadequate regulation of NK cells in
the pathogenesis of AIH [45]. In this regard, it has been suggested that the recruit-
ment of cytotoxic NK cells into the liver and not liver resident NK cells expansion
may contribute to the progression of AIH [46].
Dysfunction of Kupffer cells and a reduction in the capacity to phagocytize
E. coli were documented in patients with AIH; how this nding relates to the dis-
ease's pathogenesis is unknown [47].
Epigenetics
"An epigenetic trait is a stably heritable phenotype resulting from changes in a chro-
mosome without alterations in the DNA sequence" [48]. MicroRNAs (miRNAs) are
short RNA molecules that can be regulated by genetics and epigenetic mechanisms
[49] and that bind to specic mRNAs leading to translational repression and gene
silencing; deciencies or excess in certain microRNAs have been reported in asso-
ciation with disease [50].
Circulating serum levels of miR-21 were reported as signicantly higher in
patients with AIH than in disease and normal control subjects. Serum levels of
miR-21 and miR-122 correlated with serum activity of alanine aminotransferase
(ALT) and were signicantly reduced in patients with cirrhosis from AIH, in whom
they correlated inversely with the degree of brosis, with miR-21 correlating with
the degree of inammation. These results have suggested that the circulation of
these two microRNAs may reect an important role of these two microRNAs in the
pathogenesis of the disease [51].
Clinical Manifestations
The key to an expeditious diagnosis of AIH is to recognize that this disease can have
variable presentations. More women than men have AIH.Two peaks in the presen-
tation of this disease, in early adolescence and in the fourth to six decades, have
been recognized. However, it has been suggested that referral patterns may
4 Autoimmune Hepatitis
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