(Original title: Healthy girl has mild symptoms of new crown infection, but acute liver failure 3 weeks later: liver biopsy has clues)
He Liping, chief reporter of The Paper
Recently, at least 348 cases of severe acute hepatitis of unknown cause in children have been reported in the UK, EU, US, Israel and Japan. Most children present with early gastrointestinal symptoms, which later develop jaundice and, in some cases, acute liver failure and even death. To the confusion of scientists, the hepatitis A, B, C, D and E viruses were not found in these children.
The UK Health Security Agency has placed adenoviruses at the top of the hypothesis for severe acute hepatitis of unknown cause in children, a claim that is increasingly being questioned. At present, academic and clinical analysis believe that the new coronavirus plays a role that cannot be ignored. Notably, the latest May issue of JPGN REPORTS, a journal of pediatric gastroenterology and hepatology, reported a rare case of a healthy girl infected with COVID-19 who had mild symptoms but then developed acute liver failure.
JPGN REPORTS is a joint publication of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). The case was reported by Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of Medicine.
Previous studies have found that liver damage such as elevated liver enzymes is common in children infected with the new crown, but acute liver failure is very rare. This clinical case study in the United States describes a healthy 3-year-old girl who had mild symptoms of COVID-19 but subsequently developed acute liver failure due to autoimmune hepatitis (type 2). The child tested negative for viral hepatitis and did not meet the diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C).
Notably, the investigators performed a biopsy of the girl’s liver tissue and found acute sub-massive hepatocyte necrosis in her liver tissue with active CD3+ T lymphocyte infiltration. Liver biopsies from the children showed no evidence of fibrosis or chronic liver disease.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), and blood ammonia levels after doctors treated the child with high-dose methylprednisolone Fast recovery to normal, thus avoiding liver transplantation. This clinical case study sheds light on a possible association between childhood SARS-CoV-2 infection and autoimmune liver disease that subsequently develops into acute liver failure.
The submission time for the study is October 2021, and considering the time span of this study is 1 year, the 3-year-old girl in the study was infected with the new crown and developed acute liver failure at least before October 2020.
The researchers said that the liver involvement after infection with the new crown has been reported before: about 15% to 65% of adult patients and 6% to 27% of children have abnormal liver biochemical indicators. However, severe liver damage, cholestasis, or liver dysfunction following infection with COVID-19 is rare, and even rarer in healthy people.
Before they reported this acute liver failure, there were only two clinical reports of acute liver failure after infection with the new coronavirus: one in a 35-year-old woman with systemic lupus erythematosus, and the other in an 11-year-old boy. The 3-year-old girl, reported by Cincinnati Children’s Hospital Medical Center and University of Cincinnati School of Medicine, developed acute liver failure after contracting the new crown. Laboratory and liver biopsy showed that the patient developed autoimmune hepatitis (AIH) type 2.
Available data show that autoimmune hepatitis (AIH) is a rare chronic autoimmune liver disease. Autoimmune hepatitis is characterized by elevated serum levels of alanine aminotransferase, aspartate aminotransferase, and immunoglobulin G, and the presence of interface hepatitis. The disease is divided into two broad categories based on autoantibody patterns: autoimmune hepatitis type 1, the most common form of AIH, is characterized by the presence of serum antinuclear or antismooth muscle antibodies; autoimmune hepatitis type 2, which is characterized by anti-liver-kidney antibodies Microsomal antibody (anti-LKM) and/or anti-hepatocyte cytosol antibody type 1 (anti-LC1). Immunosuppressive therapy with corticosteroids is considered the gold standard regimen for AIH.
The 3-year-old girl had no previous medical history or obesity problems. The researchers said that three weeks before being sent to their hospital’s emergency center, the child was diagnosed with the new coronavirus through nucleic acid testing and developed a mild fever and cough. As her symptoms were mild, she did not receive any medication and did not require hospitalization, and her symptoms resolved within 5 days. However, 2 weeks after being diagnosed with Covid-19, she developed fatigue, jaundice and decreased urination, so the 3-year-old girl was referred to the emergency department of their hospital.
Doctors searched the records and found that she had not received any previous medication or surgery, and had no underlying chronic liver disease or other chronic disease. In terms of family history, one of her first-degree relatives (editor’s note: parent or sibling) had Hashimoto’s thyroiditis and type 1 diabetes. The doctor performed a physical examination on her and found that she had yellow sclera, jaundice, no hepatosplenomegaly, and her mental state was normal.
After blood tests in the emergency department, the laboratory showed her ALT (alanine aminotransferase) was as high as 939 U/L (normal is 0-35 U/L). AST (aspartate aminotransferase) up to 1321U/L (normal 15-46U/L).
Clinically, there are two main types of transaminases used to detect liver function through blood tests, namely ALT and AST. ALT mainly exists in the cytoplasm, and AST mainly exists in the mitochondria of the cytoplasm. When liver cells are damaged, ALT first enters the blood, and when the cells are severely damaged and endanger the mitochondria, AST also enters the blood. Since ALT and AST mainly exist in hepatocytes, when they are significantly elevated, it often indicates liver damage. Generally speaking, if the ALT serum value exceeds the upper limit of normal by 2-3 times and persists for more than two weeks, it indicates the possibility of hepatobiliary disease.
The 3-year-old girl had elevated levels of total bilirubin 5.5 mg/dL, conjugated bilirubin 0.9 mg/dL, and INR (2.0). Total bilirubin is the sum of direct and indirect bilirubin. The determination of serum total bilirubin is an important test item in liver and gallbladder function tests, which can accurately reflect the degree of jaundice and is of great significance for the clinical diagnosis of recessive jaundice.
Further examination revealed that the patient’s blood ammonia level was 46 µmol/L. A complete blood count (CBC) was unremarkable, with a white blood cell count of 12,300/µL, hemoglobin of 11.8 g/dL, and a platelet count of 174,000/µL. The patient had evidence of mild hemolytic anemia with elevated lactate dehydrogenase to 1292 U/L and undetectable haptoglobin (<3 mg/dL).
The doctor tested the patient’s new crown nasopharyngeal swab nucleic acid test and new crown antibody test IgG and IgM again, all of which were positive.
Imaging, the patient’s abdominal Doppler ultrasound showed diffuse heterogeneous liver parenchymal lesions consistent with hepatocellular disease, borderline splenomegaly, and normal vasculature.
Since the patient was only 3 years old and there was a lack of proven Covid-19-specific treatment options for this age group, she was not given antiviral therapy. The doctor prescribed an adjunctive regimen of 5 mg of oral vitamin K to the patient. Vitamin K prevents bleeding disorders in newborn babies and prevents internal bleeding. However, the patient’s INR did not improve after this time, and the patient was transferred to the Department of Pediatrics at the University of Cincinnati School of Medicine because of acute liver failure.
After coming to the Department of Pediatrics at the University of Cincinnati School of Medicine, the patient continued to receive intravenous vitamin K and intravenous fluids. The doctor further examined the cause of her acute liver failure and found that the child’s anti-liver-kidney microsomal antibody (anti-LKM) titer increased to 1:1280, which suggested that the patient had type 2 autoimmune hepatitis. Anti-liver-kidney microparticle antibody is an autoantibody and a serological indicator for the diagnosis of type 2 autoimmune hepatitis.
The patient’s total serum IgG level was within the normal range at 1070 mg/dL. The rest of her tests included a thorough evaluation of infectivity, metabolic and genetic causes, and nothing unusual.
The patient’s immunological evaluation revealed that she had decreased natural killer cell function and increased frequency of CD3+ T cells, but normal ferritin and soluble IL-2 receptors. The patient had worsening coagulation (INR 2.7), cholestasis (conjugated bilirubin 3.8 mg/dL), and hyperammonemia to 317 µmol/L, along with altered mental status, consistent with grade I-II hepatic encephalopathy. Subsequently, the 3-year-old girl was evaluated for liver transplantation with concurrent intravenous methylprednisolone (2 mg/kg/day) along with rifaximin and lactulose. The patient’s AST and ALT levels, bilirubin, INR, and blood ammonia levels began to improve rapidly thereafter.
The child’s liver biopsy showed that she had acute sub-massive hepatic necrosis, lobular collapse, and a severe mixed inflammatory infiltrate, mainly due to CD3+ T lymphocytes.
Diagnostic liver biopsy highlighted massive CD3+ T cell infiltration and acute submassive necrosis. A) Acute submassive hepatocyte necrosis and collapse (black arrows) with alternative fibrosis, regenerative changes, and mononuclear-predominant inflammation (red arrows), in contrast to compensatory proliferative regenerative nodules (non- Inflamed areas, black arrows) alternate (H&E staining). B) Residual bile ducts (red arrows) with biphenotypic hepatocytes (blue arrows) in the lobular parenchyma, evident on CK7 immunostaining. C) Trichrome staining highlights massive post-necrotic fibrosis (blue), regenerating hepatocytes (light red), and bile ducts (red arrows). D) CD3 immunostaining highlights predominantly CD3+ T lymphocyte infiltration. E) CD79a immunostaining shows mixed B lymphocytes.
She was discharged on her 18th hospital day. As the cholestasis resolved, physicians initiated maintenance of immunosuppression with azathioprine (1 mg/kg/day) as a reserve steroid for type 2 autoimmune hepatitis. Her clinical symptoms have resolved and her ALT (19 U/L) and AST (29 U/L), bilirubin and INR have normalized.
One year later, liver biopsy of the patient demonstrated significant histological improvement with only focal residual portal/portal inflammation and focal structural changes.
Liver biopsy after one year.
The researchers said that new coronary infection usually affects the liver, which is manifested by elevated serum aminotransferase levels. Severe liver dysfunction just because of COVID-19 is rare, and has previously only been seen in patients with multiple organ dysfunction or underlying chronic liver disease. This case study describes a case of isolated acute liver failure in a previously healthy child due to autoimmune hepatitis type 2 following mild infection with COVID-19. Fortunately, the child responded well to high-dose steroids and was subsequently maintained on immunosuppressive therapy with azathioprine.
The researchers said that the etiology of liver injury related to new coronary infection has been studied a lot in clinical and academic circles, and more and more evidence shows that immune-mediated inflammatory response may play an important role in it. In the case of autoimmune hepatitis, this involves a complex interplay between genetic, immune and environmental factors, with infectious or viral triggers thought to play an important role in autoimmune hepatitis.
At present, it is known that new crown infection is related to the development of various autoimmune diseases, such as autoimmune hepatitis and type 1 diabetes in adults. It is worth noting that there have also been previous papers reporting that mRNA vaccination is associated with autoimmune hepatitis. Sexual clinical cases.
They believe that these all suggest that the molecular mimicry mechanism between the viral spike protein and liver antigens may trigger autoimmune liver disease associated with SARS-CoV-2. Although it is currently impossible to directly prove that the 2019-nCoV infection caused the 3-year-old to develop autoimmune hepatitis, the temporal association between infection and subsequent liver failure cannot be ignored. The researchers call on clinicians to focus on and evaluate the underlying causes of liver injury in patients with isolated severe liver dysfunction during and after COVID-19 infection.
It is worth noting that with regard to the formation mechanism between acute hepatitis of unknown cause and the new coronavirus in children, a study by the international authoritative academic journal “The Lancet Gastroenterology & Hepatology” shows that the Superantigens may be the crux of the matter.
A study published in The Lancet Gastroenterology and Hepatology shows that infection of children with the new coronavirus can lead to the formation of a virus reservoir in the body. Specifically, the persistent presence of SARS-CoV-2 in the gastrointestinal tract of children can lead to the repeated release of viral proteins in intestinal epithelial cells, resulting in immune activation. This repeated immune activation may be mediated by a superantigen motif in the spike protein of 2019-nCoV, which is similar to staphylococcal enterotoxin B and triggers broad and nonspecific T cell activation. This superantigen-mediated activation of immune cells has been suggested to be the mechanism behind Multisystem Inflammatory Syndrome in Children (MIS-C).
The so-called super antigen (SAg) is a kind of substance that can activate a large number of T cell clones and generate a strong immune response with only a very low concentration (≤10-9 times M). Compared with ordinary antigens, superantigens do not require conventional intracellular antigen presentation and have no MHC restriction.
According to different activated cells, superantigens can be divided into T cell superantigens and B cell superantigens, and according to their different sources, T and B cell superantigens can be divided into endogenous (viral) antigens and exogenous (viral) superantigens. bacterial type) superantigens.
Acute hepatitis has also been previously reported in children with multisystem inflammatory syndrome, but coinfection with other viruses has not been investigated. The researchers analyzed that the recent acute hepatitis of unknown cause in children may have been infected with the new coronavirus first, and the children were infected with adenovirus after the virus reservoir appeared in the intestine.
Specifically, as shown in the following figure: Schematic diagram of the pathology of adenovirus (AdV)-enhanced SARS-CoV-2 superantigen-mediated severe acute hepatitis.
Schematic illustration of the pathology of adenovirus (AdV)-enhanced SARS-CoV-2 superantigen-mediated severe acute hepatitis.
Following infection with 2019-nCoV, the viral reservoir may lead to repeated superantigen-mediated activation of immune cells over time, such as multisystem inflammatory syndrome (MIS-C). If such reservoirs exist and children are subsequently infected with adenovirus (AdV), this superantigen-mediated effect may be more pronounced and may lead to immunological abnormalities, as recently reported in acute severe hepatitis, which is why in these Cases should be investigated for evidence of this immunopathology.