Impact of age on autoimmune hepatitis: A comparative study of patients diagnosed before and after sixty

Abstract

BACKGROUND

Autoimmune hepatitis (AIH) is characterized by inflammation, hepatocyte necrosis, autoantibodies, and elevated serum globulin levels. It can present at any age, with peaks reported at 30 years and after 60 years. No national studies have evaluated the impact of age at diagnosis on AIH presentation and outcomes.

AIM

To compare the presentation and progression of AIH in patients diagnosed before and after the age of 60 years.

METHODS

This cross-sectional analytical study included biopsy-confirmed AIH patients with at least one year of follow-up at Hospital Clínico Universidad de Chile, Santiago, Chile. Demographic, clinical, laboratory, and treatment response variables were analyzed. Group comparisons (diagnosis before or after 60 years) were performed using the χ² test for qualitative variables and the Mann-Whitney test for quantitative variables (significance P < 0.05).

RESULTS

Ninety-seven AIH patients were included; 85% were female, with a median age of 53 years (range 18-83 years). Forty-one percent were diagnosed after the age of 60. Younger patients exhibited more jaundice at diagnosis (75% vs 44%, P = 0.02) and higher aminotransferases levels (median alanine aminotransferase 998 IU/mL vs 334 IU/mL, P = 0.0002). In contrast, at diagnosis, ascites was more prevalent in patients over 60 (13% vs 2%, P = 0.028), and advanced fibrosis (F3-F4) was more frequent in this group (68% vs 41%, P = 0.020). Biochemical response at six months was similar between groups, despite lower corticosteroid doses being administered to patients over 60 years.

CONCLUSION

AIH in patients over 60 presented with less jaundice, lower aminotransferases levels, greater fibrosis, and more ascites. Biochemical response was similar independently of age and despite lower prednisone doses administered in patients over 60 years.

Key Words: Autoimmune hepatitis; Elderly; Diagnosis; Steroids; Fibrosis

Core Tip: This study highlights age-related differences in autoimmune hepatitis (AIH) presentation. Patients diagnosed after 60 years of age showed milder biochemical abnormalities but more advanced fibrosis and ascites at diagnosis. Despite receiving lower corticosteroid doses, their treatment response was comparable to younger patients. These findings suggest that AIH in older adults may represent a distinct clinical phenotype with important diagnostic and therapeutic implications.

INTRODUCTION

Autoimmune hepatitis (AIH) is an immune-mediated disease characterized by the presence of circulating autoantibodies, increased immunoglobulin G (IgG) concentration, and distinctive histological features. It is believed to result from the loss of immunological tolerance to hepatic cells triggered by environmental factors in genetically predisposed individuals[1].

The estimated prevalence in the United States is 31.2/100000 inhabitants, comparable to reports from Europe[2]. AIH affects individuals of all ages, genders, and ethnicities[3]. Most studies describe a bimodal age distribution, with peaks at 30 years and again after 60 years. Due to rising life expectancy, AIH diagnoses are becoming more common among older adults.

AIH presents with a wide clinical spectrum, ranging from asymptomatic cases to acute liver failure[4]. In older adults, the disease often follows an insidious course and is frequently diagnosed at more advanced stages[5,6]. While previous studies have described the clinical characteristics of elderly AIH patients, these cohorts have generally used higher age cutoffs (≥ 65 years or ≥ 70 years), involved predominantly European populations, and been conducted in referral centers with distinct diagnostic and therapeutic standards. A study from Latin America[7] has also described the clinical features of AIH in the region; however, it did not focus specifically on age-related differences nor compare younger and older subgroups within the same cohort. In contrast, our study examines a Latin American population stratified by age ≥ 60 years, providing one of the largest series of elderly AIH patients reported in the region. By employing a different age cutoff and a structured age-based comparison, our analysis identifies differences in clinical presentation, fibrosis severity, treatment regimens, and therapeutic outcomes, offering contextually relevant insights for clinical decision-making in similar healthcare settings.

The aim of this study was to compare the presentation and progression of AIH in patients diagnosed before and after the age of 60 years.

MATERIALS AND METHODS

Study design and population

This was a retrospective, observational, and analytical study involving a review of medical records of patients diagnosed with AIH based on the International Autoimmune Hepatitis Group criteria[8]. Inclusion criteria comprised biopsy-confirmed AIH diagnosis between February 2012 and March 2022, and a minimum follow-up of 12 months at Hospital Clínico Universidad de Chile, Santiago, Chile. Eligible patients were identified through the hospital’s electronic registry of outpatient and hospitalized AIH cases.

Variables included

Demographic (age and gender), clinical (comorbidities, AIH presentation type, and characteristics), laboratory (liver profile, platelets, albumin, IgG, autoantibodies, liver biopsy), treatment, and response variables, defined as normalization of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and IgG levels at 6 months of treatment[9], were collected from the medical records.

Statistical analysis

No imputation was performed for missing data. Patients with incomplete records for key variables were excluded from the corresponding analyses. Qualitative variables were expressed as frequency and percentage. Continuous variables were assessed for normality using the Shapiro-Wilk test and histograms. Parametric variables were described using mean and standard deviation, while non-parametric variables were presented as median and range. Group comparisons (age at diagnosis: Younger or older than 60 years) were performed using χ² tests for categorical variables and t-tests or Mann-Whitney tests for continuous variables, depending on the data distribution. P < 0.05 was considered statistically significant. Data were analyzed using STATA 16.0 software.

RESULTS

Medical records of 132 AIH patients diagnosed between February 2012 and March 2022 were reviewed. Of these, 97 patients had at least 12 months of follow-up at the hospital and were included in the analysis. Fifty-seven patients (59%) were diagnosed before the age of 60, and 40 patients (41%) were diagnosed at or after 60 years (Figure 1).

Figure 1 Patient selection flowchart. Out of 160 patients with a clinical diagnosis of autoimmune hepatitis, 132 had biopsy-confirmed disease. After excluding 35 patients due to incomplete data, 97 patients with at least 12 months of follow-up were included in the final analysis. These were stratified into two age groups: (1) 57 patients younger than 60 years; and (2) 40 patients aged 60 years or older. AIH: Autoimmune hepatitis.

Eighty-five percent of patients were female, with a median sample age of 53 years (range 19-83 years). Patients diagnosed after the age of 60 years had significantly more comorbidities, including hypertension, cardiovascular disease, and type 2 diabetes mellitus (T2DM), compared to those diagnosed before 60 years (Table 1).

Table 1 Sociodemographic characterization and comorbidities of patients with autoimmune hepatitis according to age of diagnosis, n (%).

	Younger than 60 years (n = 57)	Older than 60 years (n = 40)	P value
Age (years) [median (interquartile range)]	45 (18-59)	66 (60-83)	< 0.001
Gender			0.058
Female	52 (91)	31 (77)
Male	6 (9)	9 (23)
Comorbidities
Hypertension	8 (14)	14 (35)	0.015
Cardiovascular disease	0 (0)	5 (13)	0.006
Type 2 diabetes mellitus	4 (7)	9 (23)	0.028
Chronic obstructive pulmonary disease	1 (2)	0 (0)	-
Malignancy	1 (2)	0 (0)	-
Hypothyroidism	16 (28)	11 (27)	0.951
Dyslipidemia	7 (12)	6 (15)	0.699

A higher proportion of younger patients presented with jaundice (75% vs 44%, P = 0.002; Figure 2) and had higher bilirubin and aminotransferases levels [bilirubin 4.7 mg/dL (range 2.5-7.8 mg/dL) vs 1.8 mg/dL (range 1.1-6.7 mg/dL), P = 0.022; ALT 998 U/L (range 464-1438 U/L) vs 334 U/L (range 76-770 U/L), P = 0.0002 and AST 1016 U/L (range 581-1301 U/L) vs 299 U/L (range 100-746 U/L), P = 0.0008] (Table 2). Conversely, ascites was more prevalent in patients over 60 (13% vs 2%, P = 0.028). No significant differences were observed in the type of AIH presentation (asymptomatic, insidious, or acute) between groups.

Figure 2 Symptoms at diagnosis in patients with autoimmune hepatitis diagnosed before and after 60 years of age. Comparison of symptoms and signs at diagnosis between patients diagnosed with autoimmune hepatitis before age 60 (n = 57, light blue bars) and those diagnosed at or after age 60 (n = 40, dark blue bars). Percentages indicate the proportion of patients with each manifestation in each age group. Statistically significant differences were observed for jaundice (75% vs 44%, P = 0.002), fatigue (58% vs 31%, P = 0.09), and ascites (2% vs 13%, P = 0.028). AIH: Autoimmune hepatitis.

Table 2 Variables related to the presentation of autoimmune hepatitis according to the age of diagnosis, n (%).

	Younger than 60 years (n = 57)	Older than 60 years (n = 40)	P value
Type of presentation of autoimmune hepatitis			0.391
Asymptomatic	8 (14)	10 (25)
Insidious	25 (44)	15 (37.5)
Acute	24 (42)	15 (37.5)
Debut symptoms
Jaundice	43 (75)	17 (44)	0.002
Fatigue	33 (58)	12 (31)	0.009
Pruritus	10 (18)	2 (5)	0.071
Arthralgia	10 (18)	3 (8)	0.156
Ascites	1 (2)	5 (13)	0.028
Encephalopathy	0 (0)	1 (3)	-
Laboratory at diagnosis [median (interquartile range)]
Aspartate aminotransferase	1016 (581-1301)	299 (100-746)	0.0008
Alanine aminotransferase	998 (464-1438)	334 (76-770)	0.0002
Alkaline phosphatases	196 (146-254)	258 (143-394)	0.475
Total bilirubin	4.7 (2.5-7.8)	1.8 (1.1-6.7)	0.022
Albumin	3.7 (3.3-4.2)	3.4 (3.2-3.9)	0.128
Serology at diagnosis
Immunoglobulin G [median (interquartile range)]	2020 (1740-2380)	1810 (1410-2440)	0.198
Anti-nuclear antibodies (positive)	48 (87)	35 (92)	0.460
Anti-smooth muscle antibodies (positive)	33 (60)	23 (59)	0.920
Hepatic biopsy
Presence of fibrosis	37 (65)	37 (93)	0.002
Advanced fibrosis F3-F4	15 (41)	25 (68)	0.020
Prednisone doses			< 0.001
Without prednisone	0 (0)	2 (5)
10-20 mg	0 (0)	10 (25)
20-40 mg	16 (28)	12 (30)
40-60 mg	41 (72)	16 (40)
Pharmacological treatment at 6 months			-
Without prednisone	0	2
Prednisone only	0	0
Prednisone + azathioprine	55	32
Prednisone + mycophenolate	2	5
Prednisone + tacrolimus	0	1

Liver biopsy findings showed greater advanced fibrosis (F3-F4) in patients diagnosed after 60 years (68% vs 41%, P = 0.020). Treatment outcomes revealed no significant differences in achieving complete biochemical response at six months. However, older patients achieved this response with lower prednisone doses (Table 3).

Table 3 Response to treatment of patients with autoimmune hepatitis according to age of diagnosis, n (%).

	Younger than 60 years (n = 57)	Older than 60 years (n = 40)	P value
Aminotransferases
Normalization at 6 months	26 (46)	17 (43)	0.761
Normalization at 12 months	42 (74)	29 (70)	0.690
Time to normalization (months) [median (IQR)]	6 (4-10)	6 (4.5-8)	0.799
Immunoglobulin G
Normalization at 6 months	38 (67)	20 (56)	0.440
Time to normalization (months) [median (IQR)]	5 (3-7)	4.5 (2.5-7)	0.960

IQR: Interquartile range.

DISCUSSION

AIH is a highly heterogeneous disease, with an extremely broad age spectrum ranging from young adulthood to older ages. Indeed, AIH may even present for the first time in individuals in their eighties[10]. Our study found that 41% of patients were diagnosed after the age of 60 years, a proportion similar to other reports indicating that AIH often manifests in this age group[5]. Older patients in our cohort had more advanced fibrosis and ascites, similar to previous reports; longer duration of disease progression before diagnosis and age as a fibrosis driver, might explain this finding. Notably, despite aging and higher cirrhosis proportion in this group, biochemical response was similar and with lower steroids doses.

AIH can follow a very mild subclinical course, present insidiously, or manifest acutely, although acute liver failure is rare[10]. In our study, we did not find significant differences in the type of presentation between age groups. This contrasts with prior reports, particularly from European cohorts in which elderly patients more frequently exhibited an insidious onset[6]. One possible explanation is a higher detection rate of asymptomatic cases among older adults in our setting, who are more likely to undergo routine testing for comorbidities such as hypertension, hypothyroidism and diabetes. Additionally, our institution is a national referral center, with access to liver transplantation and a high complexity hepatic unit. This may introduce referral bias, as patients with more severe or atypical disease presentation are more likely to be evaluated. Such referral patterns could affect both the age distribution and disease severity of our sample, possibly obscuring differences in clinical presentation between groups. Nevertheless, we did observe older patients had significantly less jaundice and more ascites at diagnosis, findings that are consistent with a more insidious clinical course. Compared to earlier studies, our work also differs by using a lower age cutoff (≥ 60 years) and by including a larger subgroup of elderly patients from a Latin American population. These features, along with our structured age-based comparison, offer new insights into how AIH may present and progress in different healthcare settings and demographic contexts.

Regarding liver function tests, younger patients had significantly higher aminotransferases levels at diagnosis compared to older patients. One hypothesis for this difference is that younger patients may have a greater enzymatic expression in hepatocytes, which could explain the higher enzyme release in the absence of significant fibrosis[11]; indeed, older patients usually have lower ALT levels[12] which are associated to higher all-cause mortality. Low levels of aminotransferases have been associated with a higher degree of liver fibrosis, consistent with the results of our study, where older patients presented more fibrosis and ascites. This may be due to a longer duration of disease progression before diagnosis. Additionally, the aging process itself might contribute to increased fibrosis, as cellular senescence leads to impaired hepatic regeneration and a shift towards fibrogenesis, even in the absence of underlying liver disease[13]. In addition, this group had more chronic conditions than younger patients did, particularly hypertension and T2DM, diseases that are associated with advanced liver fibrosis/cirrhosis, in particular in AIH[14].

Complete biochemical response was similar in both groups. However, the steroid doses required for this outcome, were lower in the elderly. A possible biological explanation is the immune senescence, a process in which aging induces complex changes in both innate and adaptive immune responses, potentially reducing the inflammatory activity of AIH and modifying treatment responsiveness[15]. This phenomenon has been described in other autoimmune diseases; for example, the GLORIA study recently demonstrated that low doses of corticosteroids were effective in controlling disease activity in patients over 65 years of age with rheumatoid arthritis[16]. An alternative hypothesis is that lower corticosteroids doses may be equally effective in inducing biochemical remission regardless of age. This is supported by retrospective data showing no significant differences in aminotransferase normalization between patients receiving prednisone < 0.5 mg/kg/day and those receiving higher doses[17]. Taken together, these observations suggest that age-adjusted corticosteroid dosing could be considered in future treatment guidelines, particularly in older adults with comorbidities and increased risk of steroid-related adverse events. However, prospective studies are needed to confirm whether reduced doses offer comparable efficacy and better safety profiles across age groups.

The management of AIH in older patients is particularly challenging due to the higher risk of corticosteroid-associated complications in this group, including fractures and decompensation of chronic disease in this group, which are also more frequent[18,19]. Regardless of age, systematic reviews confirm the efficacy and safety of standard induction therapy with corticosteroids as the first-line treatment for AIH[20]. Nevertheless, in older patients, the use of lower corticosteroid doses may be a prudent strategy to mitigate adverse effects. Unfortunately, in our study, adverse effects were not consistently reported during the first year of follow-up, and thus, they were not included in the analysis.

Study limitations

The retrospective nature and single-center setting of this study may limit the generalizability of its findings. Furthermore, the exclusion of patients who underwent liver biopsy at our institution but continued follow-up elsewhere resulted in a reduced sample size. Another important limitation is the lack of systematic data collection regarding corticosteroid-related adverse effects, particularly in the elderly, where this issue is highly relevant clinically. Future prospective studies should incorporate standardized reporting of treatment-related complications to better assess the risk-benefit balance of lower steroid dosing strategies in older AIH patients.

CONCLUSION

In conclusion, we describe a cohort of AIH patients in which those diagnosed after the age of 60 presented with milder biochemical abnormalities but more advanced fibrosis and a higher prevalence of ascites. Despite these differences, their treatment response was comparable to that of younger patients, even with lower doses of prednisone.