Cirrhosis of the Liver: A Case Report and Literature Review of a Rare Case Presentation of Autoimmune Hepatitis With Systemic Sclerosis

Systemic sclerosis (SSc) is a chronic systemic disease that affects the skin, heart, lungs, kidneys, gastrointestinal tract, and musculoskeletal system. Although gastrointestinal involvement has been reported in approximately 90% of scleroderma patients, liver involvement is uncommon. A 51-year-old female was admitted to the hospital due to abdominal distension and pedal edema. She had a history of Raynaud's syndrome and multiple hypopigmented and hyperpigmented patches over her body for the last year. Her ascetic fluid analysis was transudative with a serum ascites albumin gradient >1.1, and the abdomen and pelvis ultrasonography reported liver cirrhosis with splenomegaly with perisplenic varices. Her antinuclear antibody and anti-centromere antibody were positive. Skin thickening was visible. Her alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum globulin were raised. Viral serology was negative. We managed her with diuretics, beta-blockers, prednisolone (30 mg/day administered orally), angiotensin-converting enzyme inhibitors, and calcium channel blockers. Edema and abdominal distension decreased with this management, and no Raynaud's phenomenon was observed during the hospital stay.

On general examination, she was conscious, afebrile, and pale, with a pulse rate of 100/min and blood pressure of 110/80 mmHg. She was anicteric, and bilateral pitting pedal edema up to the knee was present. Salt and pepper pigmentation around the neck, over the back, forearms, and legs was present ( Figure 1).

FIGURE 1: Photographs of the patient show the salt and pepper pigmentation on the skin over the neck, back, forearm, and both legs.
Skin distal to the metacarpophalangeal joint in the hands and at the elbow was tight, but there were no ulcers, swollen fingertips, calcinosis, sclerodactyly, or telangiectasia ( Figure 2). On systemic examination, the abdomen was distended with full flanks, the umbilicus was everted, fluid thrill and shifting dullness were present, and the liver was not palpable, but splenomegaly was present. The rest of the systemic (cardiovascular, respiratory, and central nervous system) examination did not reveal any abnormalities. On slit-lamp examination of the anterior chamber of the eyes, the Kayser-Fleischer (KF) ring was absent. Her hemogram revealed a hemoglobin of 9.6 g/dl, anisopoikilocytosis, microcytic hypochromic red blood corpuscles with a mean corpuscular volume of 71, a white blood corpuscle count of 3.88 with 77.1% granulocytes, and reduced platelets of 0.68 lac/ul. Her liver function tests showed hypoalbuminemia (2.44 gm/dl), hypergammaglobulinemia (4.08 gm/dl), and raised alanine aminotransferase (ALT) of 127 IU/L and aspartate aminotransferase (AST) of 276 IU/L with normal bilirubin and alkaline phosphatase (73 IU/L). Other parameters like blood sugar, serum electrolytes, lipid profile, kidney function tests, and electrocardiogram were normal. Her ascitic fluid was transudative in nature with a serum ascites albumin gradient of 1.35. Her blood, urine, and ascitic fluid cultures did not show the growth of any bacteria. The presence of bilateral pitting pedal edema, ascites, splenomegaly, hypoalbuminemia, and a serum ascites albumin gradient of 1.35 led to the diagnosis of liver cirrhosis with portal hypertension [5,6].
Ultrasonography of the abdomen showed a small-sized (9.7 cm) shrunken liver with coarsened echotexture of parenchyma with irregular margins, suggestive of liver cirrhosis with gross ascites, periportal fibrosis, and splenomegaly (14.1 cm), a dilated portal vein of 12 mm with the normal color flow on Doppler imaging, a dilated splenic vein of 15 mm, and a partially distended gall bladder. The common bile duct and intrahepatic biliary radicals were normal ( Figure 3). Her fibroscan of the liver could not be done due to the unavailability of this facility at our rural hospital. Her viral serology, hepatitis B surface antigen (HBsAg) for hepatitis B, antibody to hepatitis C virus (anti-HCV), and quantitative hepatitis C virus ribonucleic acid (HCV RNA) by polymerase chain reaction (PCR) and human immunodeficiency virus (HIV) infection test by enzyme-linked immunosorbent assay (ELISA) method were negative. Her serum ferritin of 69 ng/ml, serum ceruloplasmin of 30 mg/dL, and 24-hour urinary copper of 20 µg/day were normal. Her anti-mitochondrial antibodies were negative. Antinuclear antibody 17 profile blot (ANA17B) and anti-centromere antibody with a class index of four were positive ( Figure 4).

FIGURE 4: The report of the immunological profile of the patient.
On the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria for the classification of SSc (2013), her total score was 15. (nine for skin thickening and three each for Raynaud's phenomenon and positive anti-centromere antibody [7]. A liver biopsy could not be performed as the patient did not give consent. The provisional diagnosis of SSc with autoimmune hepatitis leading to cirrhosis of the liver was considered as per the international autoimmune hepatitis group diagnostic criteria [2] (Table 1). She had hypergammaglobulinemia and a positive ANA. We were unable to conduct ASMA and anti-LKM-1 antibody assays due to financial constraints.

Exclusion of other cirrhosis etiologies
We excluded chronic viral hepatitis (hepatitis B and C), alcoholic liver disease, hemochromatosis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, biliary cirrhosis, right-sided heart failure, medications (e.g., methotrexate and isoniazid), Wilson's disease, alpha-1 antitrypsin deficiency, celiac disease, polycystic liver disease, hereditary hemorrhagic telangiectasia, idiopathic adulthood ductopenia, granulomatous liver disease, infection (e.g., brucellosis, and echinococcosis) on the basis of history, examination and or biochemical, immunological, and radiological investigations. She was managed with diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, and steroids. She showed significant improvement in her symptoms; her edema and abdominal distension decreased, and no Raynaud's phenomenon was observed during the hospital stay.

Discussion
Systemic sclerosis is a multisystem disorder that primarily affects the skin, heart, lungs, gastrointestinal tract, musculoskeletal system, and kidneys. The disease is characterized by tissue fibrosis, vasculopathy, and an autoimmune response associated with specific autoantibodies. Gastrointestinal involvement is common, up to 95% [8]. However, the liver is rarely involved in this disease. As shown in the review, eight (1.1%) of 727 patients with scleroderma had involvement of the liver [9]. Primary biliary cirrhosis is the most commonly found hepatic disease in patients with SSc, while autoimmune hepatitis is rare [10,11,12].
Although the pathogenesis of the development of autoimmune hepatitis in patients with SSc is still unclear, it may be due to a dysregulated response of the cellular and humoral immune systems. According to the literature, anti-centromere antibodies are found in 3-13% of patients with autoimmune hepatitis [1,9]. Our patient was diagnosed with autoimmune hepatitis according to the criteria proposed by the international autoimmune hepatitis group, and she fulfilled all the diagnostic criteria as mentioned in Table 1 [2,13].
A few cases of autoimmune hepatitis without primary biliary cirrhosis in SSc patients have been reported. In three cases, SSc was diagnosed before the development of autoimmune hepatitis, while in one case, both conditions were diagnosed simultaneously [14][15][16][17]. The clinical characteristics of five patients and their laboratory profiles, along with the patients described in the current report, are summarized in Table 2    In our case, cirrhosis of the liver due to autoimmune hepatitis and SSc was diagnosed during the current admission. However, her fibroscan of the liver could not be done due to the unavailability of this facility at our rural hospital, and a liver biopsy could not be performed as the patient did not give consent. In the present case, liver involvement was advanced compared to the previous four cases. These previous case reports indicate that patients with SSc are at an increased risk of developing autoimmune hepatitis ( Table 2).
This case was diffuse SSc in which the patient had Raynaud's phenomenon, skin thickening in the hands, feet, and elbows, and salt and pepper pigmentation skin over the back and trunk also, but there were no calcinosis cutis, sclerodactyly, or telangiectasia. High-dose oral corticosteroids and azathioprine are the drugs of choice for treatment as they effectively alleviate symptoms and the outcome of autoimmune hepatitis [18].
Managing autoimmune hepatitis is difficult with diffuse cutaneous SSc patients, as these patients may develop a renal crisis with high-dose steroid therapy [19,20]. Future studies are required to determine the treatment outcome and complications of high-dose steroid therapy for combined autoimmune hepatitis and SSc.

Conclusions
Patients with SSc and autoimmune hepatitis should be observed for the development of other autoimmune diseases. A high degree of observation is necessary to diagnose autoimmune hepatitis in patients with SSc as symptoms are non-specific and may appear gradually over years. Patients with SSc should be monitored for liver function tests regularly as early diagnosis and treatment of autoimmune hepatitis will help achieve a reasonable remission rate.