COVID-19 as a Trigger of Acute-on-Chronic Hepatitis B Presenting With Undetectable INR Due to Hypercoagulability in a 16-Year-Old Girl : The Pediatric Infectious Disease Journal

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COVID-19 as a Trigger of Acute-on-Chronic Hepatitis B Presenting With Undetectable INR Due to Hypercoagulability in a 16-Year-Old Girl

Giugliano, Laura MD; Pinon, Michele PhD, MD; Calvo, Pier Luigi MD

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The Pediatric Infectious Disease Journal 42(2):p 143-145, February 2023. | DOI: 10.1097/INF.0000000000003771


In patients with SarS-CoV2 and chronic Hepatitis B (HBV) co-infection liver injury is associated with a worse prognosis. We report a case of acute chronic liver failure (ACLF) with encephalopathy due to HBV reactivation during COVID-19 with undetectable INR. Thromboelastography showed a profile consistent with a prothrombotic state so INR was not a reliable marker of liver function until plasma infusion. After plasma infusion, indeed, an imbalance of hepatic function was shown by an underlying INR prolongation that was consistent with an ACLF.


Hepatitis B is a chronic infection that can be quiescent with flare-ups. We report a case of reactivation of hepatitis B presenting with undetectable INR due to COVID-19 infection


A 16-year-old girl was admitted to the Emergency Department in September 2021 complaining of vomiting and abdominal pain. There was no history of fever, cough, or shortness of breath, nor travel, medication or herbal use, previous surgery, or contact with individuals with COVID-19. Her past medical history was significant for coeliac disease and HBV vertical infection. Her last hepatologic testing in June 2019 revealed stable HBeAg-positive chronic HBV infection (Table 1), then, during the COVID-19 pandemic, she was lost to follow-up.

TABLE 1. - Serologic HBV Assessment
June 2019 At the arrival At discharge 6 months later Normal values
HBV-DNA level 3.860.000 > 3.540 219 (0 IU/ml)
HBsAg positive positive positive positive (Negative S/CO)
Anti-HBs <10 <10 <10 <10 (<10 mIU/ml)
IgG AntiHBc positive positive positive positive (Negative S/CO)
IgM AntiHBc negative positive positive negative (Negative S/CO)
HBeAg positive positive positive positive (Negative S/CO)
AntiHBe negative negative positive negative (Negative S/CO)
anti-HBs, antibodies anti-hepatitis B surface antigen; antiHBe, antibodies anti-hepatitis B envelope antigen; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; IgG AntiHBc, immunoglobulin G anti-hepatitis B core antigen; IgM AntiHBc, immunoglobulin M anti-hepatitis B core antigen; HBeAg, hepatitis B envelope antigen.

At presentation, other than jaundice and fatigue, the general examination was unremarkable. Blood tests showed anemia, leukopenia and lymphocytopenia, severely elevated hepatic and pancreatic enzymes, hyperbilirubinemia in addition to an impaired coagulation profile with undetectable International normalized ratio (INR), activated partial thromboplastin time (aPTT) and fibrinogen level, which was persistent after vitamin K infusion.

An abdominal US study and a total body computed tomography showed an enlarged liver with inhomogeneous structure and hyperechoic parenchyma, a markedly enlarged pancreas, abundant ascites, with normal thoracic and brain scans.

SARS-CoV-2 nasopharyngeal PCR testing was positive. Empirical antibiotic therapy was started and, suspecting an ACLF, the patient was transferred to the Regina Margherita Pediatric Hospital in Turin. At the arrival, the patient showed irritability and mild cognitive impairment with confused thinking. Laboratory findings confirmed impaired coagulation and hepatic profile (Table 2). To better define the coagulation profile, a thromboelastography (TEG) performed to assess the global clotting function (see figure, Supplemental Digital Content 1,, showed a short reaction time (r), a wide maximum amplitude (MA) an increased alpha angle with a complete lack of clot lysis at 30 minutes (ly30). A pro-coagulant status, due to an increased rate of clot formation and clot strength associated with slower fibrinolysis, was then revealed. The patient was then transfused with fresh-frozen plasma (FFP). 12 hours after FFP administration, INR became detectable and was mildly prolonged (1,75).

TABLE 2. - Laboratory Findings
At the arrival After FFP infusion At discharge 6 months later Normal range
White blood count 2930 NA 4410 6680 (4500–13,000/mmc)
Absolute lymphocyte count 610 NA 1340 1700 (1000–6000/mmc)
Absolute neutrophil count 1830 NA 2260 4060 (1800–9000/mmc)
Absolute monocyte count 210 NA 680 510 (130–1170/mmc)
Hemoglobin 10.3 NA 10.0 10.9 (11.3-14.5 g/L)
Platelet count 193000 NA 294000 353000 (160,000–450,000/mmc)
Creatinine 0.51 NA 0.40 0.46 (0.55–1.02 mg/dl)
Glucose 79 NA 93 89 (70–100 mg/dL)
AST 1485 NA 51 28 (8–30 IU/L)
ALT 668 NA 52 31 (5–35 IU/L)
GGT 178 NA 51 20 (8–35 IU/L)
LDH 478 NA 150 160 (135–214 IU/L)
CK 33 NA 26 NA (25–140 IU/L)
Total bilirubin 4.4 NA 1.1 0.4 (0.2–1.01 mg/dL)
Direct bilirubin 4.1 NA 0.6 0.2 (0-0.2 mg/dL)
Lipase 851 NA 113 22 (8-57 IU/L)
Amylase 186 NA 131 45 (28-100 IU/L)
Albumin 2.9 NA 3.4 4.0 (3.6-5.2 g/dL)
Ammonia 80 NA NA NA (19-87 mcg/dL)
Lactate 1.5 NA NA NA (0.5-3 mEq/L)
INR undetectable 1.75 1.07 1 (0.8–1.2 INR)
aPTT 1.08 1.1 1.07 1.1 (0.8–1.2 ratio)
Fibrinogen 73 61 211 251 (200–400 mg/dL)
ATIII 25 47 72 NA (80–120 %)
D-dimer 17393 11458 385 NA (<500 ng/mL)
Ferritin 657 NA 24 NA (12–95 ng/mL)
CRP 31.8 NA 0.9 0.1 (< 5 mg/dL)
Procalcitonin 0.18 ng/ml NA NA NA (<0.5)
Immunoglobulin G 2637 NA NA NA (840–1660 mg/dL)
Immunoglobulin A 296 NA NA NA (90–395 mg/dL)
Immunoglobulin M 165 NA NA NA (48–220 mg/dL)
aPTT, activated partial thromboplastin clotting time; AST, alanine aminotransferase; ATIII, antithrombin III; CK, creatine kinase; CRP: C-reactive protein; GGT, gamma-glutamyl transferase; INR, international normalized ratio; LDH, lactate dehydrogenase; NA, not available.

Since the severe hepatic disease could not be explained by COVID-19 alone, HDV superinfection, HAV, HCV, HEV, CMV, and EBV infections, Wilson disease, acetaminophen intoxication, and autoimmune hepatitis were ruled out. The serologic tests revealed HBsAg and HBeAg positivity, anti-HBeAg and anti-HBsAg antibodies negativity, anti-HBcAg IgG and IgM positivity, HBsAg and HBV-DNA levels were 8250 IU/mL and > IU/L, respectively, suggestive for an acute on chronic HBV infection. Antiviral therapy with Entecavir was started.

The liver elastography performed at the admission showed a very high stiffness (23.1 kPA) that drastically reduced 2 weeks and 3 weeks later (16 and 9 kPA, respectively), according to the hyperacute liver injury on a chronic basis.

SARS-CoV-2 PCR testing resulted in negative 10 days after the admission. After 3 weeks, the patient was discharged with a marked reduction of liver and pancreatic enzymes, normalized INR values, and blood count, as reported in Table 2. In the follow-up, a normalization of pancreatic and liver enzymes and reduction of HBV-DNA level was documented, together with transient seroconversion to anti-HBe, as reported in Table 2. A liver biopsy one month after the acute decompensation revealed cirrhotic degeneration.


We presented a pediatric case of reactivation of chronic HBeAg HBV infection induced by COVID-19 infection. HBV is the leading cause of chronic viral hepatitis; it can result in cirrhosis, liver failure, and hepatocellular carcinoma.1 In our case, despite correct immunoprophylaxis at birth, vertical transmission occurred, as reported in 2–10% of baby born to HBeAg-positive or highly viremic mothers.1

COVID-19 in children and adolescents is often asymptomatic or associated with only mild symptoms2; several studies have reported that liver injury is quite common (4.8% to 78%).3 COVID-19-associated liver injury includes a broad spectrum of potential mechanisms, including direct cytotoxicity from active viral replication of SARS-CoV-2 in the liver 20 immune-mediated liver damage due to the severe inflammatory response, hypoxic changes induced by respiratory failure, vascular changes due to coagulopathy, 12 or cardiac congestion from right heart failure, drug-induced liver injury (DILI) and exacerbation of the underlying liver disease.4 Pathophysiology of the liver injury in SARS-CoV-2 infection in pediatric patients has been well described.5 Since both HBV and SARS-CoV-2 alter liver physiologic functions, it is not well characterized how coinfection might affect disease progression. Data on the exact prevalence of viral hepatitis in COVID-19 patients are limited.3; Zou et al. collected 105 patients with SARS-CoV-2 and chronic HBV co-infection and demonstrated that liver injury was associated with disease severity and worse prognosis.6 In particular, 4 patients developed ACLF with death from multiorgan failure, confirming the risk of fulminant hepatitis in HBsAg carriers. The mechanism of HBV reactivation following COVID-19 could be secondary to an imbalance between the host’s immune state and viral replication.7

In our patient, the most frequent causes of ACLF were ruled out. Reactivation of a chronic HBV infection presenting as ACLF with encephalopathy during COVID-19 infection was suspected. In particular, the undetectable INR was misleading, until the results of TEG with subsequent FFP infusion. TEG, indeed, provides a more comprehensive global coagulation assessment. It measures reaction time or latency until clot formation begins (r), the rate of clot formation (alpha angle), the maximal clot strength (MA), and the clot lysis in 30 minutes after maximum amplitude is reached (Ly30). In our case, a TEG profile consistent with a prothrombotic state characterized by increased clot formation rate and strength and decreased fibrinolysis was revealed. After FFP infusion, indeed, an imbalance of hepatic function was shown by an underlying INR prolongation that was consistent with an ACLF (INR >1.5 not influenced by vitamin K infusion with signs of hepatic encephalopathy).

In particular, pediatric acute liver failure (PALF) is defined as biochemical evidence of liver injury in a child without evidence of chronic liver disease-associated coagulopathy (INR >1.5 if the patient has encephalopathy or >2.0 if encephalopathy is absent) not corrected by vitamin K administration.8,9 Our case, with the presence of underlying chronic liver disease could be defined according to the Clinical Practice Guidelines of the EASL10 as “Chronic Liver disease presenting with a phenotype of ALF.” Unfortunately, in our case, the pro-coagulant status made INR a not reliable marker for hepatic function evaluation for 72 hours, until FFP infusion. Consequently, the need of getting our patient on the liver transplant waiting list was questioned, until INR became detectable and trustworthy.

In our patient antiviral therapy with Entecavir was promptly started. In fact, given the risk of reactivation, the American Association for the Study of Liver Diseases (AASLD) guidelines strongly recommends to start or continue anti-HBV treatment once COVID-19 is diagnosed, especially in case of suspicion of a hepatitis B flare or when initiating immunosuppressive therapy.11

In this case, since the severe hepatic and pancreatic disease, other causative conditions were ruled out. Immune reactions caused by COVID-19 may participate a role, but IgM anti-HBc positivity suggested that the acute hepatitis was, above all, due to HBV reactivation.

The cirrhotic evolution of our case is very alarming, underlying the need for adequate monitoring in HBV chronic pediatric infection to promptly start antiviral therapy when needed.1 In fact, our patient was lost at follow-up, as a result of the delay of a nonurgent visit during the COVID-19 pandemic.12

To the best of our knowledge, this is the first case of hyperacute liver disfunction caused by HBV reactivation in which the procoagulant imbalance linked to COVID-19 infection together with cirrhotic state made INR a marker not reliable for hepatic function evaluation until FFP infusion allowed us to detect an ACLF (INR>1.5 not corrected by vitamin K administration associated to hepatic encephalopathy).

Furthermore, we would like to reinforce the importance of the SARS-CoV-2 vaccine, recommended for children and adolescents with compensated and decompensated cirrhosis, or with chronic liver disease, view their risk for poorer outcomes from SARS-CoV-2 infection.5


Both L.G. and M.P. contributed to the final version of the manuscript. P.L.C. supervised the project. “All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”


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COVID-19; Hepatitis B virus (HBV); acute on chronic liver failure (ACLF); cirrhosis; coagulopathy

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