Diagnostic and Therapeutic Challenges in Seronegative Autoimmune Hepatitis With Concurrent Graves Disease and Immune Thrombocytopenia

Abstract

Autoimmune hepatitis (AIH) is commonly associated with extrahepatic autoimmune diseases. We discuss the challenges in managing a novel case of seronegative AIH occurring simultaneously with Graves disease and immune thrombocytopenia. Diagnosis was complicated by severe thrombocytopenia delaying liver biopsy and the challenge of managing thyrotoxicosis with antithyroid medications in the setting of acute hepatitis. We were able to safely perform transjugular liver biopsy to confirm AIH, after platelet transfusion. AIH and immune thrombocytopenia were treated with intravenous glucocorticoids, and hyperthyroidism was managed with graded escalation of carbimazole. This case highlights practical strategies for the diagnosis and management of concurrent autoimmune conditions with competing risks.

INTRODUCTION

Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory disease with a prevalence of 15.6 cases per 100,000 people.¹ The pathogenesis of AIH is not fully understood but involves exposure to an environmental trigger, loss of immune tolerance to liver autoantigens, and subsequent CD4 T-cell and B-cell–mediated hepatocyte injury in genetically susceptible individuals.^2,3 AIH is known to be associated with other extrahepatic autoimmune diseases, including Graves disease and immune thrombocytopenia (ITP).^4–6 In Graves disease, autoreactive T cells escape immune regulation, stimulating intrathyroidal B cells to produce autoantibodies, stimulating thyroid hormone overproduction.⁷ In ITP, there is autoantibody and T-cell–mediated platelet destruction with inadequate platelet production.⁸ Single associations between AIH and Graves disease or AIH and ITP have previously been described in case reports.^9,10 We report an index presentation of seronegative AIH with concurrent Graves disease and ITP, highlighting the diagnostic and management challenges created by their interaction.

CASE REPORT

A 21-year-old woman was referred to our tertiary hospital by their general practitioner after identification of deranged liver function tests and thrombocytopenia, in the context of 2 days of jaundice and vomiting. She was otherwise well with no abdominal pain, fevers, or changes to medications. Preceding this, she had 1 month of increased anxiety, diarrhea, and heat intolerance, without palpitations or diaphoresis. Medical history included non–transfusion-dependent thalassemia. Family history included the patient's mother having thyroid disease requiring thyroidectomy (unknown etiology). She was born in metropolitan Cambodia and moved to Australia 2 months before presentation. The patient did not drink alcohol, smoke, or use recreational drugs.

Physical examination showed sinus tachycardia of 113 beats per minute, jaundice with scleral icterus, and lower limb petechiae. The liver and spleen were not palpable. There was a diffuse palpable goiter and fine resting tremor in bilateral hands. She had mild exophthalmos but no ophthalmoplegia.

MRI cholangiogram demonstrated cholelithiasis with no evidence of biliary obstruction and possible mild irregularity of the central intrahepatic ducts.

Graves disease was confirmed by suppressed thyroid-stimulating hormone (TSH), elevated free thyroxine, and strongly positive anti-TSH receptor antibodies as per Table 1. A diagnosis of AIH was suspected, but because of seronegative antibodies, a liver biopsy was required to confirm the diagnosis. Liver biopsy was delayed due to elevated bleeding risk associated with severe thrombocytopenia. This was investigated with bone marrow biopsy, which showed abundant megakaryocytes in keeping with ITP. During this time, bilirubin continued to rise to 414 μmol/L as per Table 1. She received 4 units of platelets to facilitate a transjugular liver biopsy on day 8 of admission. Biopsy demonstrated active hepatitis and portal inflammation with dense inflammatory cell infiltrate of lymphocytes and plasma cells, interface hepatitis, lobular inflammation, and zone 3 necrosis. Histology features typical of AIH yielded a simplified scoring system score of 6, indicating probable AIH. Overlap with primary biliary cholangitis was excluded by negative antimitochondrial antibodies and absence of florid duct lesions on histology. Primary sclerosing cholangitis overlap was excluded due to the absence of characteristic MRI findings.

Table 1.

Laboratory data

Lab test	Reference range	Day 0	Day 8	Day 12	Day 22	Day 52
Alanine aminotransferase	5–35 (U/L)	1,122	1,168	469	258	32
Aspartate aminotransferase	5–30 (U/L)	1,364
Gamma-glutamyl transferase	5–35 (U/L)	64	46	99	70	26
Alkaline phosphatase	35–140 (U/L)	112	107	73	85	96
Total bilirubin	0–20 (µmol/L)	194	414	139	98	15
Unconjugated bilirubin	0–15 (µmol/L)	82
Conjugated bilirubin	0–5 (µmol/L)	125
International normalized ratio	0.8–1.2	1.6	1.3	1.1
Platelet count	150–450 (/L)	19 × 109	23 × 109	43 × 109	91 × 109	133 × 109
Thyroid-stimulating hormone	0.4–4.8 (mIU/L)	<0.01
Free thyroxine	9–16 (pmol/L)	63.9			45.9
Free T3	3.2–6.1 (pmol/L)	16
Antithyroid peroxidase antibodies	0–9 (IU/mL)	>1,090
TSH receptor antibody	<1.8 (IU/L)	103.5
Immunoglobulin G	7.5–15.6 (g/L)	25.7
Antinuclear antibody		Positive
Antineutrophil cytoplasmic antibody		Positive
Smooth muscle antibody		Negative
Mitochondrial antibody		Negative
Antiliver kidney microsome antibody		Negative
Hepatitis serology		Unremarkable

After liver biopsy, the patient received intravenous hydrocortisone 100 mg every 6 hours for 4 days, which reduced alanine aminotransferase (ALT) to 469 U/L and bilirubin to 192 μmol/L as per Table 1. Intravenous glucocorticoids were then transitioned to 40 mg oral prednisolone daily. Carbimazole was initially trialed at a low dose of 5 mg twice daily for 3 days and increased to 15 mg twice daily as liver function improved. Free thyroxine level reduced to 45.9 pmol/L and platelets increased to 110 × 10⁹/L after 14 days of treatment as per Table 1.

The patient was discharged home once transitioned to oral prednisolone. One month postdischarge, ALT reduced to 32 U/L and bilirubin to 15 μmol/L as per Table 1. Carbimazole will be gradually weaned to achieve euthyroidism on the lowest possible dose. If euthyroidism is not achieved within 18 months, definitive treatment such as radioactive iodine ablation or thyroidectomy may be considered.

DISCUSSION

From our literature review, we identified 1 reported case of simultaneous primary biliary cholangitis with AIH overlap with ITP and Graves disease at index presentation.¹¹ The immunopathogenic mechanisms linking these conditions remain unclear but are likely to be a combination of shared genetic factors, immune dysregulation and molecular mimicry.¹² Genetic factors including polymorphisms of immune regulatory genes increase the risk of developing multiple autoimmune diseases.^13,14 In these susceptible individuals, after an environmental exposure, there is dysregulation of T helper cells with increased Th1 and TH17 activity, resulting in a proinflammatory state in each of AIH, Graves disease, and ITP.^12,15 This may contribute to loss of tolerance to self-antigens.

Management of this case was made more challenging by the interactions between pathologies. Liver biopsy was required to guide diagnosis and staging but required careful procedural planning due to thrombocytopenia. Transjugular liver biopsy was selected to reduce bleeding risk and was facilitated with platelet transfusion. In parallel, management of hyperthyroidism required careful balancing the risks of untreated thyrotoxicosis against thioamide associated hepatotoxicity. In this case, carbimazole was chosen over propylthiouracil as it has lower incidence of liver injury, which is typically cholestatic as opposed to propylthiouracil.^16,17

Glucocorticoids are the first-line treatment for both AIH and ITP.^9,18 In our patient, commencement of glucocorticoids resulted in an immediate improvement in liver function tests and gradual increase in platelet count.

We present a unique case of a first episode AIH, with concurrent diagnoses of Graves disease and ITP. Investigation and management required careful multidisciplinary care coordination with close patient monitoring. Liver biopsy was safely facilitated via transjugular route and platelet transfusion. AIH and ITP were initially treated with glucocorticoids, and carbimazole was gently introduced, as the preferred agent in Graves disease in the setting of liver derangement due to AIH. The patient responded very well to therapy, without complication. Further maintenance therapy, such as use of azathioprine as a steroid-sparing agent in AIH, may additionally confer benefit to the risk of refractory or recurrent ITP. Synchronous acute autoimmunity is rare, and further research is required to understand the immunogenic mechanisms linking these conditions.

DISCLOSURES

Author contributions: B. McLeod: First author, manuscript writing, editing and revisions, treating resident and is the article guarantor. N. Walia: manuscript review and editing, treating registrar. V. Rao: manuscript review and editing, treating registrar. B. Krishnamoorthi: manuscript review, editing and treating endocrinology registrar. A. Lin: manuscript review, treating resident. P. Fuller: manuscript review, editing and treating consultant endocrinologist. M. Braude: manuscript review, editing and treating consultant gastroenterologist.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

ABBREVIATIONS:

AIH

Autoimmune hepatitis

ALT

Alanine aminotransferase

AST

Aspartte aminotransferase

GGT

Gamma-glutamyl transferase

IgG

Immunoglobulin G

INR

International normalised ratio

ITP

Immune thrombocytopenia

LFTs

Liver function tests

MRI

Magnetic resonance imaging

TSH

Thyroid stimulating hormone