Alimentary Pharmacology and Therapeutics

Systematic review with meta-analysis: clinical manifestations and management of autoimmune hepatitis in the elderly J. Chen*, G. D. Eslick† & M. Weltman*

*Department of Gastroenterology and Hepatology, Nepean Hospital, Penrith, NSW, Australia. † The Whiteley-Martin Research Centre, Discipline of Surgery, The Sydney Medical School Nepean, Penrith, NSW, Australia.

Correspondence to: Prof. G. D. Eslick, The WhiteleyMartin Research Centre, Discipline of Surgery, The University of Sydney Nepean Hospital, Level 5, South Block, P.O. Box 63, Penrith, NSW 2751, Australia. E-mail: [email protected]

Publication data Submitted 3 July 2013 First decision 21 July 2013 Resubmitted 3 November 2013 Accepted 5 November 2013 EV Pub Online 22 November 2013 As part of AP&T’s peer-review process, a technical check of this meta-analysis was performed by Mr M. Siddiqui.

SUMMARY Background Autoimmune hepatitis is an uncommon chronic progressive inflammatory disease of the liver, characterised by hypergammaglobulianemia, circulating autoantibodies, and interface hepatitis histologically. It is traditionally thought to be a disease of young women. However, recent epidemiological and retrospective studies suggest that it might be a disease predominantly of older women. Studies of AIH in elderly patients have been fairly limited. Aim To investigate the differences in the clinical presentations and the management of AIH in the elderly and the younger patients. Methods We conducted a search on MEDLINE (from 1946), PubMed (1946) and EMBASE (1949) through to November 2013 using the terms ‘autoimmune hepatitis in the elderly’, and the combinations of ‘Autoimmune hepatitis’ AND the following terms: ‘elderly’, ‘aging’, ‘older patients’, and ‘older’. The reference lists of relevant articles were also searched for appropriate studies. Results A total of 1063 patients were identified with AIH in 10 retrospective studies. The definition of ‘elderly’ ranged from 60 to 65 years; 264 elderly and 592 younger patients were included for analysis. Elderly, 24.8%, were more likely to present asymptomatically, cirrhotic at presentation and HLA-DR4positive. They are less likely to be HLA-DR3-positive and to relapse after treatment withdrawal after complete remission. Conclusions AIH is an important differential in elderly patients with cirrhosis or abnormal LFTs. Elderly are more likely to be cirrhotic and asymptomatic at presentation. Glucocorticoids use should be readily considered in the elderly patients as the current evidence suggests that they respond well to the therapy, with less relapse after treatment withdrawal. Aliment Pharmacol Ther 2014; 39: 117–124

ª 2013 John Wiley & Sons Ltd doi:10.1111/apt.12563

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J. Chen et al. INTRODUCTION Autoimmune hepatitis is an uncommon chronic progressive inflammatory disease of the liver, characterised by hypergammaglobulianemia, circulating autoantibodies and the histological change of interface hepatitis, which is responsive to immunosuppressive therapy in the majority of cases.1–3 It was first described by Waldenstrom, Kunkel and others in the early 1950s as a progressive chronic hepatitis predominantly in young women.4–6 However, recent epidemiological and retrospective studies suggest that it might be a disease predominantly of older women.7–9 Studies of AIH in elderly patients have been fairly limited due to the traditional belief that it is a disease of young women. We conducted a literature search and meta-analysis on the topic of autoimmune hepatitis in the elderly population, to better understand the disease in this cohort of patients compared to the younger patients with autoimmune hepatitis. The aims of the literature review are to compare the differences in the presentations – clinically, biochemically, serologically and histologically, between the elderly and the younger patients; in the mode of presentation; the associated autoimmune diseases; as well as in response and tolerability to treatments. This should produce a better understanding of the disease process in the elderly and allow better management of the elderly patients who present with this condition. METHODS Study protocol We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.10 A systematic search of the databases MEDLINE (from 1946), PubMed (from 1946), EMBASE (from 1949) through to November 2013 was carried out to identify relevant articles. The search used the terms ‘autoimmune hepatitis in the elderly’, ‘autoimmune hepatitis’ AND ‘elderly’, ‘autoimmune hepatitis’ AND ‘aging’, ‘autoimmune hepatitis’ AND ‘older patients’, or ‘autoimmune hepatitis’ AND ‘older’, and these terms were searched as text word and as exploded medical subject headings where possible. The reference lists of relevant articles were also searched for appropriate studies. No language restrictions were used in either the search or study selection. No quality assessment was undertaken. A search for unpublished literature was not performed. Study selection We included studies that specifically looked at the differences in the presentation, and/or the treatment response, 118

and other aspects of autoimmune hepatitis between the elderly and younger patients.

Data extraction The data extraction was performed using a standardised data extraction form, collecting information on the publication year, study design, total sample size, the percentage of old patients, temporal direction, population type, country, continent, mean age at presentation, number of adjusted variables, the most common mode of presentation, the differences in presentation, the rate of cirrhosis, the time to diagnosis, the rate of other autoimmune diseases, the associated HLA haplotype, the treatment response, the rate of relapses and the tolerability of the treatment. Quality of the studies was not assessed and authors were not contacted for missing data. Statistical analysis Pooled odds ratios and 95% confidence intervals were calculated for the various aspects of autoimmune hepatitis in the elderly and young patients using a randomeffects model.11 We tested heterogeneity with Cochran’s Q statistics, with P < 0.10 indicating heterogeneity, and quantified the degree of heterogeneity using the I2 statistics, which represents the percentage of the total variability across studies, which is due to heterogeneity. Values of 25%, 50%, and 75% corresponded to low, moderate and high degrees of heterogeneity respectively.12 We quantified publication bias using the Egger’s regression model,13 with the effect of bias assessed during the failsafe number method. The fail-safe number was the number of studies that we would need to have missed for our observed result to be nullified to statistical nonsignificance at the P < 0.05 level. Publication bias is generally regarded as a concern if the fail-safe number is less than 5n + 10, with n being the number of studies included in the meta-analysis.14 All analyses were performed with Comprehensive Meta-analysis (version 2.0), Biostat, Englwood, NJ (1995). RESULTS Study characteristics A total of 10 studies15–24 were identified as appropriate for and included in the review (Figure 1) (Table 1). All were retrospective studies. The sample size of each study was fairly small, with the smallest study having 41 patients and the largest 205 patients. The small sample sizes of the studies are a reflection of the rarity of Aliment Pharmacol Ther 2014; 39: 117-124 ª 2013 John Wiley & Sons Ltd

Systematic review with meta-analysis: autoimmune hepatitis in the elderly 101 potentially relevant studies identified by searching MEDLINE, MedPub, and EMBASE 49 studies excluded: 25 duplicate articles; 24 review articles 52 studies retrieved for more detailed evaluation 39 studies excluded: not specific to the topic of autoimmune hepatitis in the elderly 13 potentially appropriate studies to be included in the meta-analysis

4 studies were excluded: epidemiological studies, inadequate comparative data One study obtained from reference lists

Figure 1 | Flow chart of the search strategy used in the review.

9 Studies included in metaanalysis

10 studies with usable information

Gender Seventy-six per cent of the patients in these studies were female; elderly female patients account for 21% of the total patients from the ten studies.

the disease. A total of 1063 patients were identified to have autoimmune hepatitis in the 10 studies. There were 264 elderly (defined as ≥65 in 7 studies and ≥60 in 3) patients and 592 younger (any patients below the defined age for elderly) included for analysis. However, in Czaja and Carpenter’s study, five age brackets were used and the comparison was made between the oldest age bracket (≥60 years) and the youngest bracket (18– 30 years) with 47 and 31 patients, respectively. In Schramm et al.’s study, although 120 patients were identified as having AIH, as there were 20 patients aged ≥65, data of the 20 of the youngest patients were used in the study.

Publication bias Egger’s regression revealed no evidence of publication bias for any of the groups assessed (acute onset, P = 0.10; chronic onset, P = 0.07; asymptomatic, P = 0.19; autoimmune diseases, P = 0.69; cirrhosis, P = 0.59; complete response, P = 0.34; partial response, P = 0.09; treatment failure, P = 0.22; HLA DR3, P = 0.86; HLA DR4, P = 0.26).

Percentage of elderly patients The elderly population was defined by the age of 65 or over in seven of the studies,15–19, 23, 24 and 60 or over in the other three.20–22 The percentages were fairly consistent, around 20–25% of the studied population, with one exception from the study by Parker and Kingham15 showing 56% of the patients with AIH aged over 60, making 1 in 4 patients diagnosed with AIH an elderly patient.

Presentations Clinical. Asymptomatic: Al-Chalabi et al.21 defined asymptomatic as the patient having no obvious signs or symptoms of liver disease and his/her AIH being detected incidentally in routine health screening or during investigation of another condition. The asymptomatic data from the study by Verslype et al.18 was extracted from numbers given under ‘incidental findings’ in Table 1 in their study. Granito et al.19 defined the

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J. Chen et al. Table 1 | Characteristics of the studies included in the meta-analysis No. of patients total (F:M)

Concurrent autoimmune

Clinical

Biochemical

Serological

Study

Elderly: young

Time span

Country

diseases

presentation

parameters

parameters

HLA haplotype

Treatment response

Parker and

41 (32:9)

1986–1996

UK

Yes, but no









Complete response,

Kingham

23:18

1997

distinction

partial response,

between the young and

treatment failure, relapse

the old Newton

54 (43:11)

et al. 1997 Schramm

12:42 120 (32:8)

et al. 2001 Verslype 2005 Granito et al. 2005

1979–1993 –

UK Germany

No

Major, minor,









Yes

asymptomatic Symptomatology:

ALT,

ANA, SMA,

HLA DR3, HLA DR4,

Complete response,

20:20 112 (77:35)

(acute icteric 1975–2002

Belgium

No

gamma- globulin

hepatitis) Symptomatology

28:84 76 (64:12) 20:56

ALT, bile, gammaglobulin



Italy

Yes

Mode of onset: acute, chronic,

ALT, AST, ALP, bilirubin, GGT,

asymptomatic

SLA/LP,

HLA A1, HLA B8,

LKM-1 ANA, SMA,

HLA A1-B8 –

relapse –

LKM, AMA ANA, SMA

HLA DR3, HLA DR4

Complete response, relapse

HLA DR3+/DR4 , HLA DR4+/DR3 ,

Complete response, partial response,

albumin, gammaglobulin

Czaja and Carpenter

205 (175:30) 47:31

1975–2005

USA

Yes

2006 Al-Chalabi et al. 2006

Mode of onset: symptom

AST, bilirubin, gamma-globulin,

duration 164 (128:36)

1971–2004

UK

Yes

43:121



HLA DR3

immunoglobulin

Mode of onset:

ALP, AST, GGT,

acute, insidious,

bilirubin, IgG,

and asymptomatic

IgM, IgA

ANA, SMA, LKM

+

-DR4+

HLA DR3,

treatment failure, relapse Complete response,

HLA DR4,

partial response,

HLA A1, HLA A8,

treatment failure, relapse

HLA A1-B8-DR3 or/and DR4 Xie et al. 2006

58 (47:11) 21:37





No

Symptomatology: acute icteric

AST, ALT, albumin

ANA, SMA





AST, ALT, GGT,







ANA or SMA





hepatitis and Floreani et al. 2006

Miyake et al. 2007

73 (63:10)

1981–2004

Italy

Yes

16:57

160 (140:20) 34:126

1988 – 2005

Japan

Yes, but no

asymptomatic Mode of onset – Acute and

ALP, IgG, IgA,

chronic onset

IgM, albumin, bilirubin

Mode of onset:

distinction

Acute and

between the young and

classical onset

Bilirubin, albumin, AST, ALT, IgG

the old

asymptomatic pattern as fortuitous detection of abnormal liver function tests with no clinical symptoms. Xie et al.’s abstract22 provided the number of asymptomatic patients with no definition. The elderly patients are more likely to present asymptomatically.

Acute onset: Granito et al.19 defined the acute pattern of presentation as recent onset (1:40;22 one as titre ≥1:4021; and one did not specify the titre of ANA17 which is considered positive. SMA: The same five studies also looked at the number of patients SMA-positive in both groups.17–19, 21, 22 Three studies defined SMA positivity as titre ≥1:40;18, 19, 21 one as titre >1:40;22 one study did not specify SMA positivity17 (Table 3).

Table 2 | Biochemical parameters in elderly and young groups with AIH Average

ALT AST Bilirubin Gammaglobulin Albumin Female Male

Elderly

Younger

P value

386 U/L 442 U/L 54 lmol/L 30 g/L

328 U/L 425 U/L 47 lmol/L 27 g/L

0.06 0.53 0.30 0.39

33 g/L 208* 208*

38 g/L 428* 112*

0.39

* Number not included from Floreani et al. as the study did not provide detailed numbers of elderly and younger patients.

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Table 3 | Summary of the odds ratio 95% CI, I2 and P value for all the parameters compared Parameter

OR (95% CI)

I2, P value

Cirrhosis HLA DR3 HLA DR4 Asymptomatic Relapse Autoimmune diseases Autoimmune thyroid disease ANA SMA Acute onset Chronic onset Complete response Partial response Treatment failure

1.58 0.45 2.94 2.59 0.38 1.25 2.71

(1.03–2.43) (0.27–0.75) (1.21–7.14) (1.11–6.05) (0.23–0.36) (0.76–2.08) (1.18–6.19)

10.99, 0.34 0.03, 0.39 55.70, 0.08 37.33, 0.19 0.00, 0.49 22.13, 0.27 30.42, 0.22

1.24 0.73 1.83 0.56 1.21 1.33 0.47

(0.42–3.66) (0.32–1.65) (0.90–3.74) (0.28–1.12) (0.66–2.22) (0.44–4.06) (0.09–2.41)

71.41, 66.32, 61.73, 56.66, 0.00, 33.23, 28.94,

0.007 0.02 0.03 0.08 0.88 0.22 0.24

Histological. Data for number of cirrhotic patients were available from 8 of the 10 studies.15, 17–23 Autoimmune diseases Five studies looked at the frequency of other autoimmune conditions in patients with autoimmune hepatitis17, 19–21, 23 (Table 3). HLA haplotype Four studies looked at the frequency of HLA haplotype, DR3+ and DR4+, between age groups17, 19–21 (Table 3). Treatment response The induction regimens in five of the ten studies that looked into the treatment responses all comprised either a corticosteroid alone or a combination of a corticosteroid and azathioprine.15, 17, 19–21 Glucocorticoids used include prednisone (one study did not specify the dose;20 20–60 mg/day was used in the other study15); prednisolone (doses used in two studies were 20–40 mg daily21 and 1 mg/kg body weight/day,17 respectively); or methylprednisolone (1 mg/kg body weight/day).19 One study did not specify the dose of azathioprine used.20 Doses of azathioprine used in other studies were 50 mg/day;19 75– 100 mg daily;15 1 mg/kg body weight/day;21 and 1– 1.5 mg/kg body weight/day.17 Complete response Five of the ten studies investigated the difference in rate of complete response between the elderly and the younger patients.15, 17, 19–21 Definition of complete response varies slightly in each study. Parker and 121

J. Chen et al. Kingham15 defined complete response as return of all liver test values to normal. Schramm et al.17 and Granito et al.19 defined complete response as proposed by International Autoimmune Hepatitis Group (IAIHG). Al-Chalabi et al’s definition21 was according to the revised criteria of the IAIHG. Remission was the term used in the study by Czaja and Carpenter20 and it was defined as absence of symptoms, improvement of serum aspartate aminotransferase (AST) levels to normal or near normal (less than twice the upper limits of normal), and histological improvement to minimal or no inflammatory activity (Table 3).

Partial response Three of the ten studies address this issue.15, 20, 21 Definition of partial response by Parker and Kingham15 was an improvement in liver tests that fell short of a return to normal. Al-Chalabi et al.21 defined partial response according to the original IAIHG criteria. Czaja and Carpenter20 used the term ‘continued treatment’, which was defined as clinical, laboratory or histological findings during therapy that indicated residual disease activity that had not worsened or improved sufficiently to satisfy end point criteria (in that study, it was either remission or treatment failure) (Table 3). Treatment failure Three of the studies compared the treatment failure rate.15, 20, 21 No response or treatment failure was defined according to the IAIHG criteria. Cjaza and Carpenter defined treatment failure as worsening of clinical, laboratory and/or histological features despite compliance with therapy (Table 3). Relapse Five of the ten studies compared the relapse rate between the elderly and the younger patients.15, 17, 19–21 The IAIHG criteria were used in four of the studies,12, 17, 19, 21 with Al-Chalabi et al.21 specifying that the revised IAIHG criteria were used. The definition in Cjaza and Carpenter’s study20 was ‘reappearance of symptoms and increase in the serum AST level to more than threefold normal after drug withdrawal.’ DISCUSSION Our meta-analysis has found that there is a statistically significant difference in the clinical and histological presentations of AIH in the elderly. Elderly patients are more likely to be asymptomatic and cirrhotic at

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diagnosis. They are less likely to have HLA DR3, but more likely to have HLA DR4. Response to treatment is similar between the elderly and the younger patients, but elderly patients are less likely to relapse after withdrawal of treatment. There is a variation in the definition of elderly population in the studies included. Seven of the studies defined elderly patients as aged ≥65,15–19, 23, 24 and the other three as aged ≥60.20–22 We included the studies that both defined elderly patients as aged ≥60 and ≥65 years because of the rarity of the disease, limited number of studies in the literature and because these three studies20–22 also addressed the issues investigated in our study. The meta-analysis revealed that a significant proportion of the patients diagnosed with AIH are elderly with one in four being the age of 60 or over. This challenges the traditional understanding that AIH is a disease of young females and with a second peak around the perimenopausal period. It sends a message that AIH is an important cause of liver disease in the elderly. One of the positive findings in this study is that elderly patients with AIH are more likely to be cirrhotic at presentation. This finding suggests that elderly patients have a subclinical aggressive disease that is commonly indolent and unsuspected.25 Newton et al found that the clinical diagnostic score before treatment was lower in the older group, whilst the histological grade, an indicator of the degree of hepatic inflammation, was higher.16 However, it is interesting to note that in the same study, the mean histological stage at presentation was similar in both groups. This clearly indicates that more detailed research is required into this finding as the implication is that elderly patients may need to be treated more aggressively. The presence of cirrhosis is also important, in that patients with established cirrhosis invariably relapse after discontinuation of medication.26 The results of the meta-analysis showed that the complete response, partial response and the treatment failure rates were similar in both groups. In fact, there is a trend for less treatment failure in the elderly group, but statistical significance was not reached. The elderly tend to have less relapse after treatment withdrawal, indicating that it is easier to maintain elderly patients in remission without continuing treatment. It is important to be aware that the medications used in the treatment of AIH can have significant side effects. Corticosteroids are associated with a considerable number of complications,

Aliment Pharmacol Ther 2014; 39: 117-124 ª 2013 John Wiley & Sons Ltd

Systematic review with meta-analysis: autoimmune hepatitis in the elderly including osteoporosis, immunosuppression, hypertension and myopathy, which could all be potentially more catastrophic in the elderly. One of our aims was to investigate the rate and severity of side effects of the therapy. However, no numerical data were available, although it was noted in some of the studies that the frequency of side effects was not increased in elderly patients.17, 19 Further studies are needed to investigate this issue. As high proportion of the patients, 80–85%, will respond to standard therapy,27 treatment should not be delayed or withheld due to concerns for treatment complications. In this meta-analysis, the elderly patients are also significantly more likely to be HLA DR4-positive and less likely to have HLA DR3. In the younger group of patients, DR3 occurred significantly more frequently than DR4 in those with an acute presentation.21 It has also been noted that relapses occurred significantly more frequently in patients with DR3 than in those without this allotype.21, 28 This may explain the lower rate of relapse in the elderly. Remissions and treatment failure also occur more frequently in patients with DR3 than in those with DR4.29 HLA haplotype may not only influence the age at presentation in AIH, but can also predict the course of the disease, the response to treatments and the prognosis.29, 30 It has also been suggested that HLA haplotype be taken into consideration prior to treatment withdrawal,26 and perhaps other clinical decisions. There are limitations to our meta-analysis. All studies included in the meta-analysis were retrospective ones, and this is subject to selection and recall bias. The parameters examined are variable. Only half of the studies looked into the treatment responses – complete response and relapse rates.15, 17, 19–21 Out of those five, only three examined the partial responses and treatment failure rates.15, 20, 21 Some studies looked at the mode of presentation, others at the symptomatology.17–22 For those studies19, 20, 24 that examined the parameter of mode of presentation, not all provided data for all three categories – acute, chronic and asymptomatic. There are other studies that compared the frequency of acute icteric hepatitis vs. asymptomatic presentation.17, 18, 21, 22 Other examples of disease characteristics addressed in some studies, but not in others, include the frequency of HLA haplotype, liver-related death and treatment side effects, etc. The variability not only makes the classification difficult, but also reduces the sample size available for analysis even further. It limits the other aspects of the disease we would like to assess, Aliment Pharmacol Ther 2014; 39: 117-124 ª 2013 John Wiley & Sons Ltd

such as liver-related mortality and the tolerability of the treatment. There is a high degree of heterogeneity in some of the analysed parameters. This may be due to the use of abstract only data, which obviously limits the amount of information available. The two major contributing factors are the small sample size and the differences in the definition of the parameters. As discussed previously, not all the studies examined the same aspects of the disease, data are only limited to those that did, hence the small sample size. The difference in the definition of the parameters is also a major contributing factor to the high degree of heterogeneity. Examples include the definition of acute onset of the disease presentation, and the positivity of ANA and SMA. There was no statistical significance found between the elderly and the younger patient groups in the parameters with high degree of heterogeneity. There is high degree of heterogeneity in HLA DR4. It is mainly due to the finding in the study by Al-Chalabi et al. We are unable to establish the reason as to why their results differ considerably from those of others. There was no evidence of publication bias. In conclusion, autoimmune hepatitis needs to be considered seriously as one of the differential diagnoses in an elderly patient with deranged liver function test and/ or cirrhosis, as significant proportion of patients with autoimmune hepatitis are elderly. Our study found that elderly patients are more likely to present asymptomatically with cirrhosis, more likely to have HLA DR4, and less likely to have relapse after withdrawal of treatment. There was a trend towards less treatment failure, although it did not reach statistical significance. In the management of AIH, glucocorticoids use should be readily considered in the elderly patients as the current evidence suggests that the older patients respond well to the therapy with less relapse after treatment withdrawal.

AUTHORSHIP Guarantor of the article: Guy D. Eslick. Author contributions: Jo Chen and Martin Weltman: study concept. Jo Chen: literature searching, data retrieval, data extraction. Guy D. Eslick: statistical analysis. Guy D. Eslick, Jo Chen and Martin Weltman: data interpretation, drafting manuscript and editing manuscript. All authors approved the final version of the manuscript. ACKNOWLEDGEMENT Declaration of personal and funding interests: None. 123

J. Chen et al.

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Aliment Pharmacol Ther 2014; 39: 117-124 ª 2013 John Wiley & Sons Ltd

Systematic review with meta-analysis: clinical manifestations and management of autoimmune hepatitis in the elderly.

Autoimmune hepatitis is an uncommon chronic progressive inflammatory disease of the liver, characterised by hypergammaglobulianemia, circulating autoa...
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