An Atypical Presentation of Autoimmune Hepatitis with Delayed Menarche in a Nigerian Adolescent: Case Report

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Case Report

An Atypical Presentation of Autoimmune Hepatitis with Delayed Menarche in a Nigerian Adolescent: Case Report

https://doi.org/10.21203/rs.3.rs-5099054/v1

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Autoimmune hepatitis (AIH) is a chronic liver disease characterized by immune-mediated inflammation, necrosis, and potential progression to cirrhosis if not managed appropriately. This case report describes a rare presentation of AIH in a 16-year-old Nigerian adolescent with atypical features, including delayed menarche and bilateral leg swelling, but without jaundice which is a common symptom of liver dysfunction. The patient was initially misdiagnosed with other conditions before being correctly identified as having Type 1 Autoimmune Hepatitis following appropriate diagnostic evaluation, which included liver function tests, imaging, and autoantibody tests. She responded favourably to treatment with corticosteroids and azathioprine but her serum albumin remained low due to pre-existing cirrhosis. This case highlights the diagnostic challenges of AIH, particularly in resource-limited settings where diagnosis of infectious liver diseases often overshadows autoimmune conditions. The delay in diagnosis and treatment emphasizes the need for increased awareness and improved diagnostic resources in the sub-African region. Early intervention with immunosuppressive therapy is crucial for managing AIH and preventing progression to advanced liver disease. This report further emphasizes the importance of a high index of suspicion for AIH in adolescents with unexplained liver disease, even in the absence of classic symptoms.

Autoimmune hepatitis

Delayed menarche

Liver cirrhosis

Nigeria adolescent

Case report

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown cause. It is characterized by continuing hepatocellular inflammation, necrosis, and the potential to progress to cirrhosis if left untreated.(1) It has a universal distribution, affecting individuals of all ages and genders, with a global prevalence of 17.44 (95% CI: 12.01–22.87) per 100 000 persons.(2) The condition has been reported to be more prevalent in females, the elderly, and white individuals compared to males, younger age groups, and other ethnicities. Additionally, patients with AIH are more likely to have coexisting autoimmune conditions such as Sjögren's syndrome, systemic lupus erythematosus, and autoimmune thyroiditis, among others.(3) Unfortunately, there is limited reporting of AIH in Nigeria and the sub-African region.

The diagnosis of AIH requires the exclusion of other chronic liver diseases such as Wilson's disease, chronic viral hepatitis, and metabolic-associated steatotic liver disease (MASLD) along with the establishment of the presence of characteristic set of autoantibodies, elevated IgG concentrations, and histological demonstration of periportal necrosis and interface hepatitis.(4) The disease may present asymptomatically, with nonspecific symptoms such as fatigue and amenorrhea, or with an acute onset of jaundice, and can also have overlapping features with other liver diseases.(5) The preferred treatment for AIH involves corticosteroids such as prednisolone combined with azathioprine, while second-line treatments include alternative immunosuppressants like mycophenolate mofetil, calcineurin inhibitors, budesonide, and 6-mercaptopurine (6-MP). In cases of treatment failure, liver transplantation may be necessary.(6) Although the condition is relatively well-documented in Western populations, it is rarely reported in sub-Saharan Africa. This case report adds to the limited body of literature on AIH in African and emphasizes the importance of early diagnosis and treatment to prevent further liver damage in similar cases.

A 16-year-old Nigerian secondary school student presented at the Gynaecology Clinic of Enugu State University Teaching Hospital (ESUTH) Parlane with a 6-month history of bilateral leg swelling and delayed menarche. She was referred to the Gastroenterology Unit of the hospital following abnormal liver function tests result. The patient had no history of jaundice, abdominal pain, shortness of breath, or gastrointestinal symptoms. There was no significant past medical history, and she had no family history of liver disease.

On physical examination, the patient had grade 2 bilateral pitting oedema but was otherwise in no distress. Abdominal examination revealed a liver span of 10 cm with no palpable spleen or demonstrable ascites. Cardiovascular and respiratory examinations were unremarkable and neurologic examination showed no signs of encephalopathy.

Laboratory tests revealed elevated liver enzymes, hypokalaemia, and abnormal hormone profiles. Serum proteins revealed markedly reduced albumin and elevated globulin, and the electrophoresis pattern showed hypergammaglobulinemia with beta-gamma bridging and hypoalbuminemia, suggesting the presence of liver cirrhosis (Table 1). An abdominal ultrasound showed coarse echotexture of the liver with reduced periportal markings consistent with cirrhosis, and an echogenic mass in the gallbladder casting posterior acoustic shadow in keeping with cholelithiasis. Oesophagogastroduodenoscopy (OGD) revealed Grade 2 oesophageal varices while further investigations, including positive antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) tests, confirmed the diagnosis of Type 1 Autoimmune Hepatitis. The International Autoimmune Hepatitis pretreatment score (IAHPS) was 16, indicating probable AIH.

Table 1

Baseline investigation results.
Investigations	Result	Reference Interval
Liver Function Tests
Total Bilirubin	34.2 µmol/L	< 17 µmol/L
Conjugated Bilirubin	17.1 µmol/L	< 5.1 µmol/L
Aspartate Transaminase (AST)	287 IU/L	15–40 IU/L
Alanine Transaminase (ALT)	139 IU/L	13–34 IU/L
Alkaline Phosphatase (ALP)	697 IU/L	< 240 IU/L
Hormone Profile
Prolactin	10.99 mg/dL	1.2–19 mg/dL
Follicle Stimulating Hormone (FSH)	< 1 mIU/L	4.46–12.43 mIU/L
Luteinizing Hormone (LH)	< 1 mIU/L	2.95–13.65 mIU/L
Oestradiol	458.06 pg/mL	30–350 pg/mL
Serum Electrolytes
Sodium	141 mmol/L	135–145 mmol/L
Potassium	2.6 mmo/L	3.0–5.0 mmol/L
Bicarbonate	22 mmol/L	95–108 mmol/L
Chloride	99 mmol/L	59–108 mmol/L
Urea	3.5 mmol/L	2.5–6.5 mmol/L
Creatinine	76 umol/L	64–115 mmol/L
Serum Proteins
Total Protein	88.5 g/L	62–80 g/L
Albumin	10.2 g/L	30–50 g/L
Globulin	78.3 g/L	18–30 g/L
PT/INR	Normal
Serum Protein Electrophoresis	Reduced albumin fraction, elevated gamma fraction with beta-gamma bridging	Normal electrophoretogram
Viral Screen
HBsAg	Negative	Negative
Anti-HCV	Negative	Negative
Autoantibodies
Antinuclear Antibody (ANA)	Positive (1:320)	< 1:80
Smooth Muscle Antibody (ASMA)	Positive
Anti-mitochondrial Antibody (AMA)	Negative
Endoscopy
Oesophagogastroduodenoscopy (OGD)	Grade 2 oesophageal varices
Imaging
Abdominal ultrasound scan	Coarse echotexture of the liver with reduced periportal markings

Differential Diagnosis

The differential diagnosis of AIH involves ruling out several conditions that can present with similar clinical and biochemical features. One of the primary considerations was viral hepatitis, particularly hepatitis B (HBV) and hepatitis C (HCV), which are the leading causes of chronic liver disease and cirrhosis worldwide and particularly in Nigeria.(7, 8) In this case, serologic testing for HBsAg and anti-HCV was negative, effectively ruling out viral hepatitis as the cause of liver disease.

Wilson's disease, a genetic disorder of copper metabolism, was also considered due to the patient's young age and presentation with cirrhosis. However, the absence of Kayser-Fleischer rings and any neurological symptoms made Wilson's disease unlikely.(9) MASLD, which is commonly associated with metabolic syndrome and obesity, was considered but was less likely due to the absence of risk factors such as obesity or diabetes and the characteristic ultrasound features of steatosis.(10)

Primary biliary cholangitis (PBC) was another possibility given its autoimmune nature and potential to cause cirrhosis. However, negative testing for AMA and the absence of typical cholestatic liver function tests made PBC unlikely.(11) Drug-induced liver injury (DILI), which can mimic AIH,(12) was ruled out due to the lack of history of exposure to hepatotoxic drugs or herbal remedies.

Another consideration was Overlap syndromes where AIH coexists with conditions like PBC or primary sclerosing cholangitis (PSC). However, imaging showed no bile duct involvement, and antibody tests for these conditions were negative.(13) Thus, after ruling out these differential diagnoses, the presence of positive autoantibodies, elevated liver enzymes, serum protein findings and the absence of viral or metabolic causes supported the diagnosis of autoimmune hepatitis,(4) which was further confirmed by the patient's response to immunosuppressive therapy.

Finally, the diagnosis of Type 1 AIH in this patient was supported by several factors. The patient presented with elevated levels of ANA and ASMA, which are hallmark serological markers of Type 1 AIH. Although microsomal type 1 (anti-LKM1) antibodies were not tested to rule out type 2 AIH, the patient’s age at presentation is consistent with the typical presentation of Type 1 AIH which often occurs during adolescence or adulthood. This diagnosis was further reinforced by the patient’s remarkable response to treatment as opposed to type 2 AIH which is often more resistant to standard treatments like corticosteroids.(4)

Treatment and Outcome

The patient was initially treated with prednisolone 30mg daily and azathioprine 100mg daily, with other medications including Spironolactone 50 mg daily, Furosemide 40 mg daily, Astymin once daily and Livolin Forte 12 hourly. Two weeks into treatment, the patient reported weight gain and prednisolone was reduced to 10 mg daily. Her liver function tests and symptoms improved significantly with continued treatment over the next two weeks and prednisolone was further reduced to 5 mg daily while the patient was maintained on azathioprine and other supportive medications.

On follow-up in the sixth week of management, repeat liver function tests showed improved bilirubin levels, normalized alkaline phosphatase, and reduced transaminases (Table 2). Serum proteins also showed improvement, with albumin levels returning closer to normal. However, liver biopsy and serum electrophoresis assays were not performed.

Table 2

Follow-up investigation results.
Investigations	Result	Reference Interval
Liver Function Tests
Total Bilirubin	13.7 µmol/L	< 17 µmol/L
Conjugated Bilirubin	10.9 µmol/L	< 5.1 µmol/L
Aspartate Transaminase (AST)	77.5 IU/L	15–40 IU/L
Alanine Transaminase (ALT)	50.6 IU/L	13–34 IU/L
Alkaline Phosphatase (ALP)	75.4 IU/L	< 240 IU/L
Serum Proteins
Total Proteins	47.9 (g/L)	62–80 g/L
Albumin	29.4 (g/L)	30–50 g/L
Globulin	18.5 (g/L)	18–30 g/L

Type 1 AIH is characterized by a multifactorial pathogenesis, involving both genetic predisposition and environmental triggers that disrupt immune tolerance to liver antigens. A hallmark of the disease is the presence of autoantibodies, most notably ANA and ASMA, indicating immune dysregulation.(4) In this process, autoreactive CD4 + T cells are believed to target hepatocytes, triggering chronic inflammation, necrosis, and potential progression to fibrosis.(14) Genetic susceptibility is closely linked to HLA class II alleles, particularly HLA-DR3 and HLA-DR4, which are found in a significant proportion of AIH patients, suggesting impaired immune regulation and tolerance to liver-specific antigens. The association of these alleles points to defective antigen presentation and immune activation as central to the pathogenesis of AIH.(15, 16) Additionally, the disease exhibits a marked female predominance, with oestrogen being proposed as a modulating factor in the immune response, although various mechanisms have been proposed its exact role remains unclear.(3, 17, 18) Environmental factors, including viral infections and certain medications, can serve as potential triggers in genetically predisposed individuals, initiating or exacerbating the autoimmune process.(14–16) These factors converge to cause persistent liver inflammation, which, if untreated, may lead to cirrhosis and liver failure.

The paucity of reported AIH cases in sub-Saharan Africa may be due to underdiagnosis, limited awareness, and lack of diagnostic resources rather than a true lower incidence. Many healthcare providers in the region focus on infectious causes of liver disease, such as viral hepatitis, due to their higher prevalence.(7, 8) This can delay the recognition and treatment of autoimmune liver diseases like AIH, as was seen in this case where the patient was initially misdiagnosed with other conditions before being referred to the gastroenterology unit.

This patient presented with non-specific symptoms of liver disease, including bilateral leg swelling and delayed menarche, without classic signs such as jaundice or ascites. The absence of jaundice, a common early sign of liver dysfunction, made the initial diagnosis more challenging. This could be attributed to the predominance of non-cholestatic processes, where the liver's ability to excrete bilirubin remains relatively intact despite significant parenchymal damage, as seen in conditions like compensated cirrhosis.(19) The patient's delayed menarche, a rare feature of AIH, was likely due to chronic liver disease disrupting hormonal balance particularly oestrogen levels, as suggested by elevated oestradiol and undetectable FSH and LH levels,(20) prompting her initial referral to the gynaecologist. Her eventual diagnosis was based on clinical features, liver function tests, abnormal serum proteins, and positive autoantibodies, and it was supported by the IAHPS System which classified her as having probable AIH.

In resource-limited settings such as Nigeria, infectious liver diseases, particularly viral hepatitis, are more prevalent and are often the primary focus of diagnostic evaluation. This can delay the recognition of AIH, especially in patients who present with advanced liver disease and complications like cirrhosis. The diagnostic process was further complicated by the lack of access to specialized diagnostic approaches which are often necessary for confirming AIH. Consequently, underdiagnosis or misdiagnosis can lead to delayed treatment and increased risk of irreversible liver damage. This case emphasizes the need for a high index of clinical suspicion and improved diagnostic capacity to enable earlier identification and treatment of AIH, which is critical for preventing disease progression and improving patient outcomes.

Corticosteroids are the mainstay of treatment in AIH,(5) with their anti-inflammatory and immunosuppressive effects helping to reduce liver inflammation and prevent disease progression. Azathioprine, a purine analog, helps maintain remission and allows for a reduction in steroid dosage, thus minimizing long-term steroid side effects such as bone loss, diabetes, and hypertension.(21, 22) This patient responded well to treatment, with improvements in both her clinical symptoms and biochemical markers. However, despite the biochemical response and resolution of hepatic inflammation, her serum albumin remained low which is expected given the pre-existing cirrhosis. This further highlights the importance of early diagnosis and intervention in AIH to prevent progression to advanced liver disease.

The prognosis of Type 1 AIH largely depends on early diagnosis and the initiation of appropriate therapy. In untreated cases, the disease progresses to cirrhosis in over 40% of patients, with an increased risk of liver failure and death. However, with prompt treatment, the prognosis is generally favourable, with most patients achieving remission and long-term survival.(4, 23) In this case, the patient had already developed cirrhosis at the time of diagnosis, which complicates her long-term prognosis. Patients with AIH-related cirrhosis are at risk for decompensated liver disease, hepatocellular carcinoma, and the need for liver transplantation.(1, 4) Regular monitoring of liver function, imaging, and screening for complications such as varices and hepatocellular carcinoma will be critical in her long-term management.

Lessons Learned and Implications for Clinical Practice

Autoimmune hepatitis (AIH) should be ruled out in any young patient with unexplained liver disease, even in the absence of classic symptoms like jaundice. This necessitates high clinical suspicion and awareness.
Access to autoantibody testing and liver biopsies is crucial for accurate diagnosis, and improving access to these tools in resource-limited settings is essential for timely identification of AIH.
Early initiation of immunosuppressive therapy, such as corticosteroids and azathioprine, is critical for preventing disease progression and improving long-term outcomes.
The rarity of AIH in African adolescents underscores the need for greater clinician awareness, with training and education focused on recognizing and managing autoimmune liver diseases.
Further research is needed to understand AIH's epidemiology in Africa and to develop strategies for enhancing diagnostic capabilities and treatment access, with public health initiatives aimed at increasing provider awareness and training.

Autoimmune hepatitis (AIH) is a rare but significant cause of liver disease in adolescents, particularly in sub-Saharan Africa, where it is often underdiagnosed. This case report shows that AIH can present with advanced liver disease even in the absence of classic symptoms, emphasizing the importance of early recognition and intervention. Improving awareness and access to diagnostic and therapeutic resources is vital for enhancing the management and outcomes of patients with AIH in resource-limited settings.

Human Ethics and Consent to Participate Declarations:

Not applicable.

Consent for publication

Not Applicable in this study.

Availability of Data and Materials

The data from this study will be available upon reasonable request to the corresponding author.

Competing Interests

The authors declare that they have no conflict of interest.

FundingTop of Form

This research did not receive any dedicated funding from a public, commercial, or not-for-profit agency.

Authors’ contributions

All authors collaborated on this case report. P.U.A, N.U, GEA, E.O and C.O conceived the study and were involved in the direct clinical management of the patient. B.B. and W.N.A. were involved in conducting the investigations and reporting the results. All authors participated in drafting and critically revising the manuscript. They collectively approved the final version for publication and accepted responsibility for all aspects of the report.

Acknowledgements

The authors acknowledge the management of the Enugu State University Teaching Hospital, Parklane, the Department of Medicine and the patient for cooperating with the unit during the management period.

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No competing interests reported.

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An Atypical Presentation of Autoimmune Hepatitis with Delayed Menarche in a Nigerian Adolescent: Case Report

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Abstract

Introduction

Case Presentation

Differential Diagnosis

Treatment and Outcome

Discussion

Lessons Learned and Implications for Clinical Practice

Conclusion

Declarations

References

Additional Declarations

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