A 76-year-old woman was admitted to our department because of 10-day history of right upper quadrant abdominal pain that extended to the back and progressive deep jaundice. The patient had sought medical help 7 days before admission because of the same pain which was considered as of musculoskeletal origin and, therefore, nonsteroid anti-inflammatory drugs (NSAIDs) were prescribed by her doctor. The patient received diclofenac 50 mg PO twice per day, which was stopped at admission. Blood biochemistry at that time point was normal. However, there was no relief of the symptoms, while she mentioned the onset of nausea and vomiting accompanied by jaundice after 3 days of diclofenac administration but she continued taking the drug. The patient had a past medical history of primary myelofibrosis diagnosed two years ago and arterial hypertension under treatment with quinapril for fifteen years, while she was heterozygous for beta thalassemia trait. She denied ever consuming herbal agents and/or dietary supplements, intravenous or nasal illicit drugs, or alcohol use. Her past medical history for liver disease was also negative. Apart from jaundice, physical examination revealed hepatosplenomegaly with no signs of hepatic encephalopathy.
The laboratory work-up (abnormal values) was as follows: haemoglobin 10.8 g/dL, platelets 73 x 103/muL, international normalized ratio (INR) 2.32, albumin 3.3 g/dL, total bilirubin 21.6 mg/dL, direct bilirubin 15.4 mg/dL, AST 717 IU/L, ALT 679 IU/L, gamma-GT 56 IU/L, and immunoglobulin G (IgG) 1760 mg/dL (upper limit of normal 1500 mg/dL). Chest X-ray showed pleural effusion on the left and the electrocardiogram right bundle branch block (RBBB). Arterial blood gases showed respiratory alkalosis (pH 7.52, pO2 68 mmHg, pCO2 28 mmHg, and HCO3 22.9 mEq/L).
The remaining haematological, microbiological, virological, and biochemical parameters including blood cultures and investigation for hepatitis viruses A, B, C, and E as well as Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), herpes simplex virus (HSV), tuberculosis, leishmaniasis, brucellosis, and leptospirosis were negative. Liver autoimmune serology according to our standard protocols for the diagnosis of AIH was positive for antinuclear (ANA; titre: 1/80) and smooth muscle antibodies (SMA; titre: 1/320) by indirect immunofluorescence; SMA specificity proved to be against F-actin antigen as confirmed by ELISA. Abdominal ultrasonography revealed massive splenomegaly, which was attributed to primary myelofibrosis and hepatomegaly with dilation of splenic and portal veins. No signs of thrombosis were observed in hepatic, portal, and splenic veins.
Due to the presence of pleural effusion, in combination with RBBB and respiratory alkalosis in a patient with underlying procoagulant condition (primary myelofibrosis), a computerized tomography of pulmonary vessels was performed, which excluded the presence of pulmonary embolism/thrombosis. Liver biopsy at this moment although valuable was not performed because of absolute contraindications.
The differential diagnosis included all potential causes of acute severe hepatitis and, first of all, acute viral hepatitis, which was excluded by the careful negative serological and virological tests. Due to patient's medical history of primary myelofibrosis, acute Budd-Chiari syndrome and ischemic hepatitis as a consequence of massive pulmonary embolism or thrombosis were also considered. However, both diagnoses were excluded by imaging studies. In addition, alcoholic hepatitis was excluded as there was no history of alcohol consumption. The case of an idiosyncratic drug induced liver injury (DILI) was seriously taken into account in the differential diagnosis, because the patient had a history of NSAID use and especially diclofenac administration for the last 7 days before admission. Last but not least, AS-AIH was considered to be the most likely diagnosis, either genuine or induced by diclofenac administration (idiosyncratic DILI-induced AS-AIH), due to the exclusion of other causes and especially viral hepatitis, the presence of hypergammaglobulinemia, which is infrequent in DILI cases, and the positive liver autoimmune serology. Indeed, the simplified score for the diagnosis of AIH without the histological data was 6 corresponding to the diagnosis of probable AIH. It should be stated, however, that this score has not been developed for the diagnosis of acute severe cases of AIH as the typical or compatible histological lesions of chronic cases of AIH are typically completely different from those reported in AS-AIH.
As the most probable diagnosis of the patient was AS-AIH (either pure AS-AIH or idiosyncratic DILI-induced AS-AIH), intravenous corticosteroids were initiated (1 g of methylprednisolone per day for 3 days followed by 1 mg/kg of prednisolone per day) as rescue therapy according to our experience and the guidelines of AIH management recently published by the European Association for the Study of the Liver (EASL). Of note, multiple sets of urine and blood cultures before and after corticosteroid administration were sterile for bacteria and fungi infections, making the diagnosis of sepsis in a haemodynamically stable patient very unlikely.
Despite the intravenous corticosteroid treatment, the patient deteriorated clinically, while her laboratory findings kept worsening (INR 4.74, albumin 2.66 mg/dL, total bilirubin 48.9 mg/dL, direct bilirubin 27 mg/dL, AST 1402 IU/L, and ALT 855 IU/L). On the 3rd day of hospitalization, she developed advanced hepatic encephalopathy and upper gastrointestinal hemorrhage, while her MELD score was 39. However, due to her medical history of primary myelofibrosis and her relatively advanced age, she was not considered as a good candidate for liver transplantation (LT). Finally, on the 4th day of hospitalization, she passed away. Her son did not consent to perform autopsy, but he consented to perform a postmortem liver biopsy, which revealed centrilobular confluent necrosis, focal interface hepatitis, portal inflammatory infiltration predominately with lymphocytes and portal fibrosis, cholestasis, and lobular inflammation with many giant hepatocytes (Figures 1 and 2). The whole histological picture was compatible with severe PIGCH probably as a result of AS-AIH.