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Abnormal Liver Function Test Predicts Type 2 Diabetes

A community-based prospective study

Increased activities of liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltranspeptidase (GGT) are indicators of hepatocellular injury. Increased activity of these markers is associated with insulin resistance (1), metabolic syndrome, and type 2 diabetes (2–9). However, most of these studies were performed in Western countries (2–5,7,9), and the two studies from Japan and Korea were not community based (6,8). In this prospective community-based study, we evaluated the relationships between markers of liver function and the onset of type 2 diabetes after adjusting for potential risk factors including inflammatory markers.

RESEARCH DESIGN AND METHODS—

In 2001, the Korean government funded a large community-based epidemiological survey to investigate the trends in diabetes and the associated risk factors (10). For this study, two communities, one from a rural Ansung and the other from an urban Ansan community, were selected. The baseline examination was performed in 2001–2002, and biennial follow-up examinations will continue through 2010. The age range for eligibility was 40–69 years. Of the 7,192 eligible individuals in Ansung, 5,018 were surveyed (70% response rate) using a cluster sampling method. A total of 15,580 individuals were eligible in Ansan, and we successfully recruited 5,020 (32.4%) using a random sampling method of the local telephone directory. The study protocol was approved by the ethics committee of the Korean Health and Genome Study.

Anthropometric parameters and blood pressure were measured by standard methods. Fasting plasma glucose, lipid profiles, insulin, high-sensitivity C-reactive protein, and the activities of hepatic enzymes were measured in a central laboratory.

All participants except those on oral hypoglycemic medications or insulin therapy underwent a 2-h 75-g oral glucose tolerance test at baseline and at each follow-up visit. Pancreatic β-cell function and insulin resistance were calculated using the homeostasis model assessment (HOMA-β and HOMA-IR, respectively) and quantitative insulin sensitivity check index (QUICKI) (11,12).

All data are presented as means ± SD. Statistical analyses were conducted using t tests, Pearson’s correlation, and logistic regression models by using SPSS (version 12.0; SPSS, Chicago, IL). P < 0.05 was considered significant.

RESULTS—

At baseline, 594 (5.9%) of 10,038 participants were being treated for diabetes and 542 (5.4%) were newly diagnosed with type 2 diabetes by oral glucose tolerance testing. The clinical and biochemical features of men (n = 4,075) and women (n = 4,675) were investigated after excluding those with a known history of diabetes and those positive for hepatitis B or C by antibody testing. Mean ± SD age was 51.4 ± 8.7 and 52.1 ± 8.9 years in men and women, respectively. Regarding alcohol drinking, the proportion of current drinkers in men was much higher than that in women (71.0 vs. 26.5%, P < 0.01). Mean levels of liver enzyme activities were higher in men than those in women (30.8 ± 20.1 vs. 25.3 ± 13.1 IU/l in AST, 31.0 ± 24.8 vs. 21.4 ± 16.0 IU/l in ALT, and 50.4 ± 30.7 vs. 18.8 ± 20.4 IU/l in GGT, respectively; all P < 0.05).

Of the three liver enzymes, ALT activity correlated better with BMI than AST or GGT (r = 0.203 vs. r = 0.023 or r = 0.016 in men; r = 0.174 vs. r = 0.058 or r = 0.126 in women, respectively). In the correlation with HOMA-IR, ALT showed a stronger relationship than either AST or GGT (r = 0.104 vs. r = 0.044 or r = 0.025 in men; r = 0.082 vs. r = 0.061 or r = 0.074 in women). When divided into drinkers and nondrinkers, a similar pattern was found in both sexes. Accordingly, ALT was used as the marker for liver function in all subsequent analyses.

We stratified participants into quartiles according to ALT activity in each sex. In the percentage of participants who had obesity, bad lipid profiles, and high glucose, insulin and HOMA-IR increased progressively with ALT quartile in both sexes (Table 1). In contrast, increasing quartiles of ALT were associated with declining QUICKI, HOMA-β, and HDL cholesterol concentration after adjusting for age and alcohol status. The percentage of alcohol drinkers increased with ALT only in men.

At the 2-year follow-up, we found that the highest quartile of ALT level was a predictor of the incidence of type 2 diabetes in both sexes (Table 1). We also found similar results when GGT was used, although the relative risk was lower than that for ALT. However, we found no relationships when we used AST.

CONCLUSIONS—

In this study, we found that the highest quartile of ALT activity was associated with risk of type 2 diabetes both cross-sectionally at baseline and prospectively at the 2-year follow-up period, as well as before and after adjusting for alcohol intake. We also demonstrated the independent predictive value of ALT activity on the incidence of type 2 diabetes after controlling for potential risk factors including age, family history, BMI, alcohol intake, and insulin resistance in both sexes. This result supports the previous studies reporting an association between abnormal liver function and type 2 diabetes, conducted mainly in Caucasian populations (2–5,7,9).

The liver is an important site for insulin clearance (13) and production of inflammatory cytokines (4,9). A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue can lead to hepatic steatosis and insulin resistance (5). Other researchers have reported an association between elevated ALT activity and fatty liver (7,14) in obesity, insulin resistance, and type 2 diabetes (1). Another study has shown that ALT activity even within the normal range correlates with increasing hepatic fat infiltration (15). In contrast, elevated AST and GGT activities are not related to hepatic or whole-body insulin sensitivity (4). Although we did not confirm the presence of fatty liver by imaging, we showed a continuous relationship between ALT activity, lipid and glucose concentrations, HOMA-IR, HOMA-β, and QUICKI—all of which were independent predictors of type 2 diabetes.

Elevated liver enzyme activity may also reflect inflammation, which impairs insulin signaling (4). In agreement with other studies (16–18), our data show that individuals in the top ALT quartile have the highest levels of high-sensitivity C-reactive protein, which is also an independent predictor for type 2 diabetes (19).

In conclusion, in this population-based survey, increased activity of liver enzymes, notably ALT, was associated with a twofold increase in the risk of type 2 diabetes independently of conventional risk factors. Because the measurement of ALT activity is internationally standardized and often part of the routine clinical assessment, this marker may serve as a useful marker to identify individuals at high risk of type 2 diabetes in Asian populations.

Table 1—

Clinical and biochemical characteristics of male and female participants, stratified by ALT quartiles, and relative risk (RR) of ALT quartiles in logistic regression models for incidence of diabetes

Acknowledgments

This study was supported by the National Genome Research Institute, Seoul, Korea (2001-347-6111-221, 2002-347-6111-221, 2003-347-6111-221, 2004-347-6111-213, and 2005-347-24002-440-215).

Footnotes

  • Published ahead of print at http://care.diabetesjournals.org on 12 July 2007. DOI: 10.2337/dc07-0106.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted July 4, 2007.
    • Received January 17, 2007.
  • DIABETES CARE

References

  1. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N: Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850, 2001

  2. Wannamethee SG, Shaper AG, Lennon L, Whincup PH: Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care 28:2913–2918, 2005

  3. Sattar N, Scherbakova O, Ford I, O’Reilly DS, Stanley A, Forrest E, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J: Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study. Diabetes 53:2855–2860, 2004

  4. Vozarova B, Stefan N, Lindsay RS, Saremi A, Pratley RE, Bogardus C, Tataranni PA: High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 51:1889–1895, 2002

  5. Perry IJ, Wannamethee SG, Shaper AG: Prospective study of serum γ-glutamyltransferase and risk of NIDDM. Diabetes Care 21:732–737, 1998

  6. Nakanishi N, Suzuki K, Tatara K: Serum γ-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men. Diabetes Care 27:1427–1432, 2004

  7. Nannipieri M, Gonzales C, Baldi S, Posadas R, Williams K, Haffner SM, Stern MP, Ferrannini E: Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City Diabetes Study. Diabetes Care 28:1757–1762, 2005

  8. Lee DH, Ha MH, Kim JH, Christiani DC, Gross MD, Steffes M, Blomhoff R, Jacobs DR Jr: Gamma-glutamyltransferase and diabetes: a 4 year follow-up study. Diabetologia 46:359–364, 2003

  9. Hanley AJ, Williams K, Festa A, Wagenknecht LE, D’Agostino RB Jr, Haffner SM: Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes 54:3140–3147, 2005

  10. Lim S, Jang HC, Lee HK, Kimm KC, Park C, Cho NH: A rural-urban comparison of the characteristics of the metabolic syndrome by sex in Korea: the Korean Health and Genome Study (KHGS). J Endocrinol Invest 29:313–319, 2006

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  12. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ: Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410, 2000

  13. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR: Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6:87–97, 2000

  14. Marchesini G, Avagnina S, Barantani EG, Ciccarone AM, Corica F, Dall’Aglio E, Dalle GR, Morpurgo PS, Tomasi F, Vitacolonna E: Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome. J Endocrinol Invest 28:333–339, 2005

  15. Tiikkainen M, Bergholm R, Vehkavaara S, Rissanen A, Hakkinen AM, Tamminen M, Teramo K, Yki-Jarvinen H: Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 52:701–707, 2003

  16. Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, O’Reilly DS, Packard CJ, Sattar N: C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 51:1596–1600, 2002

  17. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327–334, 2001

  18. Kerner A, Avizohar O, Sella R, Bartha P, Zinder O, Markiewicz W, Levy Y, Brook GJ, Aronson D: Association between elevated liver enzymes and C-reactive protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome. Arterioscler Thromb Vasc Biol 25:193–197, 2005

  19. Herder C, Peltonen M, Koenig W, Kraft I, Muller-Scholze S, Martin S, Lakka T, Ilanne-Parikka P, Eriksson JG, Hamalainen H, Keinanen-Kiukaanniemi S, Valle TT, Uusitupa M, Lindstrom J, Kolb H, Tuomilehto J: Systemic immune mediators and lifestyle changes in the prevention of type 2 diabetes: results from the Finnish Diabetes Prevention Study. Diabetes 55:2340–2346, 2006

Blood Test: Liver Function Tests (for Teens)

What Is a Blood Test?

A blood test is when a sample of blood is taken from the body to be tested in a lab. Doctors order blood tests to check things such as the levels of glucose, hemoglobin, or white blood cells. This can help them detect problems like a disease or medical condition. Sometimes, blood tests can help them see how well an organ (such as the liver or kidneys) is working.

What Is a Hepatic (Liver) Function Panel?

A liver function panel is a blood test that helps doctors check for liver injury, infection, or disease. Liver function panels also can check for side effects in the liver from some medicines.

Why Are Liver Function Panels Done?

A liver function panel is done to learn information about the levels of:

  • Albumin and total protein, which help build and maintain muscles, bones, blood, and organ tissue. Low levels may be seen with liver disease or kidney disease, or nutritional problems.
  • Liver enzymes: Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). These enzymes help the liver turn food into energy. When their levels are high, it can be a sign of that the liver is injured or irritated.
  • Bilirubin. Bilirubin is made when red blood cells break down. The liver changes the bilirubin so that it can be excreted from the body. High bilirubin levels may mean there is a problem with the liver. This can make skin look yellow, a condition called jaundice.

How Should I Prepare for a Liver Function Panel?

You may be asked to stop eating and drinking for 8 to 12 hours before the test. Tell your doctor about any medicines you take because some drugs might affect the test results. 

It can help to wear a T shirt or other short-sleeve top on the day of the test to make things faster and easier for the technician who will be drawing the blood.

How Is a Liver Function Panel Done?

Most blood tests take a small amount of blood from a vein. To do that, a health professional will:

  • clean the skin
  • put an elastic band (tourniquet) above the area to get the veins to swell with blood
  • insert a needle into a vein (usually in the arm inside of the elbow or on the back of the hand)
  • pull the blood sample into a vial or syringe
  • take off the elastic band and remove the needle from the vein

It’s best to try to relax and stay still during the procedure because tensing muscles can make it harder and more painful to draw blood. And if you don’t want to watch the needle being inserted or see the blood collecting, you don’t have to. Look the other way and maybe relax by focusing on saying the alphabet backward, doing some breathing exercises, thinking of a place that makes you happy, or listening to your favorite music.

How Long Does a Liver Function Panel Take?

Most blood tests take just a few minutes. Occasionally, it can be hard to find a vein, so the health professional may need to try more than once.

What Happens After a Liver Function Panel?

The health professional will remove the elastic band and the needle and cover the area with cotton or a bandage to stop the bleeding. Afterward, there may be some mild bruising, which should go away in a few days.

When Are Liver Function Panel Results Ready?

Blood samples are processed by a machine, and it may take a few hours to a day for the results to be available. If the test results show signs of a problem, the doctor might order other tests to figure out what the problem is and how to treat it.

Are There Any Risks From Liver Function Panels?

A liver function panel is a safe procedure with minimal risks. Some people might feel faint or lightheaded from the test. A few teens have a strong fear of needles. If you’re anxious, talk with the doctor before the test about ways to make the procedure easier.

A small bruise or mild soreness around the blood test site is common and can last for a few days. Get medical care if the discomfort gets worse or lasts longer.

If you have questions about the liver function panel, speak with your doctor or the health professional doing the blood draw.

What Should I Do With This Abnormal ALT?

For more coverage on the clinical headlines and insights surrounding liver disease and more, visit our hepatitis C page.

You see a 48-year-old white man for his annual examination. He is in good health with no major medical problems and an unremarkable medical history. He states he regularly drinks one or two beers a day on the weekend but not usually on weekdays. He denies blood transfusions, tattoos or intravenous drugs. His father had diabetes. The patient is overweight with a body mass index (BMI) of 32. A screening chemistry panel is normal except for an aspartate aminotransferase (AST, formerly SGOT) level of 85 U/L (normal 15-50 U/L) and an alanine aminotransferase (ALT, formerly SGPT) level of 98 U/L (normal 5-50 U/L). He says you are the first doctor he has seen in more than 10 years and does not recall the last time he had a blood test.

What is your differential diagnosis, and what laboratory tests would you order?

Mild abnormal elevation of the aminotransferases is common in everyday practice. Most of the patients are asymptomatic and the liver test abnormalities are discovered incidentally during a routine check up or, sometimes when applying for a life insurance policy. It is important to see if these abnormalities are chronic or just of short duration and self limited. Liver test abnormalities of short duration and self limited are usually caused by medications, supplements or another underlying disease. The differential diagnosis in this patient includes nonalcoholic fatty liver disease (NAFLD)) since this is, by far, the most common cause of abnormal liver tests in the United States. Other possibilities include viral hepatitis (HBV, HCV and HEV), autoimmune hepatitis, iron storage disease, Wilson disease, alpha 1 antitrypsin deficiency and celiac sprue. Alcohol abuse is a consideration however, less likely because of the AST/ALT ratio. In alcoholic liver disease the AST is higher than the ALT.

>>> Medicine moves at breakneck speed. Get ahead with the MD Mag Newsletter.

The laboratory tests for the evaluation of this patient include: HBsAg, HB core Ab, HCV Ab, ANA, SMA, ferritin, transferring saturation, ceruloplasmin, alpha 1 antitrypsin phenotype and tissue transglutaminase.

Hepatitis serologies are negative. Results of antinuclear and smooth muscle antibody testing are negative. The serum iron value is 100 ïÂ

Correlation of Liver Function Tests and COVID-19 Outcomes

Introduction

Since November 2019, the outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has influenced over 200 countries, areas or territories worldwide.1 The evidence that human-to-human transmission has been reported among close contacts of patients with COVID-19.2 Although considerable efforts have been made to reduce transmission, the overall upward trend of COVID-19 is continuing around the world. As of 17 January 2021, the outbreak of COVID-19 brings the cumulative numbers to over 93 million reported cases and over 2 million deaths globally.3

Although patients with COVID-19 present most commonly with respiratory symptoms, multiple extrapulmonary organ dysfunctions have also been reported.4 Previous studies have reported the prevalence of abnormal liver function parameters in patients with COVID-19, primarily alanine aminotransferase (ALT) (12.9–41.6%) and aspartate aminotransferase (AST) (18.2–66.9%).5–7 Furthermore, some studies have reported abnormal liver function parameters were associated with clinical outcomes of patients with COVID-19, including longer hospital stays,7 higher risk for severe COVID-19,6,8 and death.9

Different from previous reports, the severity rate and mortality rate of COVID-19 is relatively low in Shanghai, China, owing to the “Four Early Principle” (early detection, early diagnosis, early isolation, and early treatment). Data remain limited about the incidence and clinical value of liver injury in patients with COVID-19 from areas with low severity rate and mortality rate. In this cohort of 1003 hospitalized patients with COVID-19 in Shanghai, China, we aim to report the incidence of liver injury, describe the longitudinal changes in liver function parameters during the hospitalization, and evaluate the association between liver injury and illness severity and mortality.

Methods

Participants

A total of 1003 confirmed patients with COVID-19 admitted to Shanghai Public Health Clinical Center, Shanghai, China, between January 20th 2020 and October 20th 2020, were retrospectively analyzed. Patients with COVID-19 were confirmed according to the positive results of SARS-CoV-2 RNA tests in nasopharyngeal or throat swab specimens using the polymerase chain reaction (PCR) method.10 Severe COVID-19 was diagnosed according to at least one of the following standards:10 (1) Respiratory frequency ≥30 breath/min; (2) Resting oxygen saturation ≤93%; (3) Oxygenation index ≤300 mmHg; (4) Mechanical ventilation; (5) shock; (6) Other organ failures and the intensive care unit (ICU) admission.

SARS-CoV-2 RNA Extraction Method and PCR Protocol

SARS-CoV-2 nucleic acids were detected using automatic magnetic extraction device and accompanying kit (Bio-Germ Medical Technology Co., Ltd, Shanghai, China) and screened with an RT-PCR kits (Bio-Germ Medical Technology Co., Ltd., Shanghai, China) with amplification targeting the ORF1a/b and N gene. The RT-PCR with 5 μL RNA was used to target the nucleocapsid gene and open reading frame lab gene using a SARS-CoV-2 nucleic acid detection reagent (Bio-Germ Medical Technology Co., Ltd., Shanghai, China). The final reaction mixture concentration was 500 nm for primer, and 200 nm for probe, respectively. Conditions for the amplifications were 50°C for 15 minutes, 95°C for 3 minutes, followed by 45 cycles of 95°C for 15 seconds and 60°C for 30 seconds.

Data Collection

In this retrospective study, all data were extracted from the electronic medical records of Shanghai Public Health Clinical Center. Demographic data including age, sex, body mass index (BMI), and comorbidity were obtained. Clinical data including epidemiological histories, clinical manifestations, laboratory parameters, chest CT scans, hospital stays, and clinical outcomes were collected. Liver function tests including serum ALT, AST, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin (TBIL), direct bilirubin (DBIL), and albumin, were performed using fully-auto-biochemistry-analysis-instruments (ARCHITECT C16000; ABBOTT LABORATORIES; SHANGHAI; CHINA).

Liver Function Tests Abnormalities and Liver Injury Classifications

Liver function test abnormalities were defined as the elevation of the following parameters in serum referring to Shanghai Public Health Clinical Center laboratory reference range standards: ALT > 44 U/L, AST > 38 U/L, ALP > 338 U/L, GGT > 73 U/L, LDH > 211 U/L, TBIL > 21 umol/L, DBIL > 7 umol/L, albumin <38 g/L. As of now, the guidance or consensus on liver injury classifications are lacking for COVID-19 patients. However, as the magnitude of the liver function test elevations in our patients ranged from mild elevations to severe elevations. To describe the severity of liver injury, in this study, patients who had raised liver function parameters more than 5× the upper limit unit of normal (ULN) were classified as significant liver injury; patients who had raised liver function parameters 2–5 ULN were classified as moderate liver injury; and patients who had raised liver function parameters 1–2 ULN were classified as mild liver injury.

Statistical Analysis

Normally distributed data, non-normal distribution data, and categorical data were presented as mean ± standard deviation, median (interquartile range, IQR), and frequency, respectively. The statistical differences were compared using the Student’s t-test for normally distributed data, non-parametric Mann–Whitney-test for non-normal distribution data, and Chi-square test for categorical data. Clinical outcomes were modeled using liver function test results at admission and at their peak during hospitalization. Multivariate logistic regression analysis was used to adjust for age, gender, obesity, comorbidity, and liver function parameters. The Kaplan–Meier curves and estimates of survival data have become a familiar way of dealing with differing survival times (times-to-event).11 In this study, we performed the survival estimates using the Kaplan–Meier method, comparing the death rates according to the liver function parameters between the groups. All statistical analyses were performed in SPSS (version 16.0) and GraphPad Prism (version 6.0), and p < 0.05 was considered statistically significant.

Results

Baseline Characteristics of Patients

Baseline characteristics of patients are summarized in Table 1. Of 1003 patients with COVID-19, the median age was 36 years (IQR, 25–51), 602 patients (60.0%) were male, 288 patients (28.7%) had obesity, and 183 patients (18.2%) had comorbidity, mainly including hypertension (11.5%) and diabetes mellitus (5.1%). In this study, twenty-three patients had chronic liver diseases, including chronic hepatitis B (n=15), alcoholic or nonalcoholic fatty liver disease (n=9), and autoimmune liver disease (n=1). Two patients had both chronic hepatitis B and fatty liver disease. Twenty-four patients had chronic heart diseases, including coronary artery disease (n=20), chronic cardiac dysfunction (n=4), and cardiomyopathy (n=3). Three patients had both coronary artery disease and chronic cardiac dysfunction. Sixteen patients had chronic pulmonary diseases, including asthma (n=10), chronic obstructive pulmonary disease (n=4), and interstitial pneumonia (n=2). Five patients had chronic kidney diseases, including chronic renal dysfunction (n=4) and nephrotic syndrome (n=1). The median levels of white blood count (WBC), lymphocyte, platelet, procalcitonin (PCT), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were 5.7×109/L (IQR, 4.4–7.0), 1.5×109/L (IQR, 1.1–2.0), 217×109/L (IQR, 172–262), 0.05 ng/mL (IQR, 0.02–0.10), 0.5 mg/L (IQR, 0.5–6.0), and 27 mm/h (IQR, 10–53), respectively.

Table 1 Baseline Characteristics of the Study Population

Severe patients with COVID-19 had higher age (median, 64 vs 35 years, p < 0.001) and BMI (mean, 27.9 vs 26.2 kg/m2, p < 0.001), more common male gender (80% vs 59.3%, p=0.014), obesity (51.4% vs 27.9%, p = 0.003), and comorbidity (68.6% vs 16.4%, p<0.001) than non-severe patients (Table 1). Compared with non-severe patients with COVID-19, severe patients had significantly higher PCT (0.10 vs 0.05 ng/mL, p < 0.001), CRP (37.6 vs 0.5 mg/L, p < 0.001), ESR (52 vs 26 mm/h, p < 0.001), but significantly lower lymphocyte count (0.7 vs 1.5×109/L, p < 0.001) and platelet count (172 vs 220 × 109/L, p < 0.001) (Table 1).

Antiviral Medications Use During Hospitalization

Antiviral medications were assessed, including Traditional Chinese medicines (TCM) (50.9%), hydroxychloroquine (27.7%), and lopinavir/ritonavir (12.4%). In this retrospective study, TCM included Ganlu Xiaodu Micropills, Yinqiao Powder, Xiangsu Powder, Shengjiang Powder, Agastache, Pinellia and Poria Decoction, Sanren Decoction, Maxing Shigan Decoction, Little Bupleurum Decoction, Qingfeipaidu decoction, Baihu Decoction, Dachengqi Decoction, LungCleansing and Detoxifying Decoction, Jinhua Qinggan Granule, Lianhua Qingwen Capsule, Huoxiang Zhengqi capsules, Shufengjiedu capsules, Huashibaidu Formula, Xuanfeibaidu Granule, and Xuebijing Injection.

Liver Function Parameters of 1003 Patients on Hospital Admission

Liver function parameters of 1003 patients on hospital admission are summarized in Table 2. The median levels of ALT, AST, ALP, GGT, LDH, TBIL, DBIL, and albumin were 20 U/L (IQR, 14–31), 20 U/L (IQR, 17–26), 75 U/L (IQR, 55–193), 21 U/L (IQR, 14–36), 198 U/L (IQR, 172–232), 8.4 umol/L (IQR, 6.5–11.3), 3.4 umol/L (IQR, 2.3–4.6), and 45 g/L (IQR, 41–47), respectively. Severe patients had significantly higher levels of ALT (26 vs 20 U/L, p=0.015), AST (31 vs 20 U/L, p < 0.001), GGT (30 vs 21 U/L, p < 0.001), LDH (334 vs 197 U/L, p < 0.001), TBIL (10.2 vs 8.3 umol/L, p=0.026), DBIL (4.9 vs 3.3 umol/L, p < 0.001), but significantly lower albumin (37 vs 45 g/L, p < 0.001) than non-severe patients. Abnormal AST (42.9% vs 7.2%, p < 0.001), LDH (88.6% vs 35.7%, p < 0.001), DBIL (22.9% vs 7.2%, p < 0.001), and albumin (51.4% vs 8.6%, p < 0.001) were commonly observed in severe patients, compared with non-severe patients.

Table 2 Liver Function Tests of 1003 Patients with COVID-19 on Hospital Admission

Hospital Admission vs Peak Hospitalization Liver Function Parameters in 1003 Patients

Hospital admission vs peak hospitalization liver function tests in 1003 patients with COVID-19 are shown in Table 3. Abnormal liver function parameters were observed at admission (ALT 13.2%, AST 8.5%, ALP 2.0%, GGT 7.4%, LDH 37.6%, TBIL 4.0%, DBIL 7.8%, albumin 10.1%) and peak hospitalization (ALT 29.4%, AST 17.5%, ALP 2.6%, GGT 13.4%, LDH 49.4%, TBIL 10.1%, DBIL 18.0%, albumin 30.6%) in hospitalized patients with COVID-19. Most patients with abnormal liver function parameters had minimal elevations 1–2 ULN at admission (ALT 84.8%, AST 84.7%, ALP 85%, GGT 78.4%, LDH 94.2%, TBIL 95.0%, DBIL 93.6%), as well as peak hospitalization (ALT 68.1%, AST 77.8%, ALP 88.5%, GGT 72.4%, LDH 89.1%, TBIL 90.1%, DBIL 86.7%). The significant elevations of liver function tests (>5 ULN) were rarely observed (ALT 4.7%, AST 2.3%, ALP 0, GGT 3.0%, LDH 0, TBIL 3.0%, DBIL 0.6%) during hospitalization. Most patients with abnormal liver function parameters had minimal reduction of albumin (32–38g/L) at admission (90.1%), as well as peak hospitalization (77.5%), and a small subset of patients had significant reduction of albumin (<32g/L) at admission (9.9%), as well as peak hospitalization (22.5%).

Table 3 Hospital Admission vs Peak Hospitalization Liver Tests in 1003 Patients with COVID-19

Predictors of Peak Hospitalization ALT > 5 ULN

Predictors of ALT > 5 ULN at time of peak liver test value during hospitalization are summarized in Table 4, including abnormal ALT and LDH on hospital admission, and medications use (Hydroxychloroquine, Lopinavir/Ritonavir, and TCM) during hospitalization. Compared to patients with ALT ≤ 5 ULN, those with ALT > 5 ULN had more common abnormal ALT (35.7% vs 12.8%, p=0.012) and LDH (78.6% vs 31.0%, p=0.001) on hospital admission, and more Hydroxychloroquine (57.1% vs 27.3%, p=0.013), Lopinavir/Ritonavir (42.9% vs 11.9%, p < 0.001), and TCM (78.6% vs 50.6%, p=0.037) use.

Table 4 Predictors of ALT > 5 ULN at Time of Peak Liver Test Value During Hospitalization

Association Between Liver Function Parameters and Clinical Outcomes

The association between liver function parameters and clinical outcomes is shown in Table 5. On multivariate analysis, age >60 years, male gender, BMI > 30 kg/m2, comorbidity, abnormal LDH and albumin on hospital admission, and abnormal peak hospitalization LDH and albumin were associated with progression to severe COVID-19 (OR > 1; p < 0.05). The dynamic profile of liver function parameters in patients by severity of COVID-19 is illustrated in Figure 1. Severe COVID-19 patients had markedly higher levels of ALT, AST, GGT, LDH, TBIL, DBIL, but significantly lower levels of albumin than non-severe patients from baseline to 30 days after admission (p < 0.05) (Figure 1). The peak of ALT, LDH, TBIL, DBIL value, and the trough of albumin was observed on 6–10 day of hospitalization. The peak of ALP and GGT value was observed on 11–15 day of hospitalization (Figure 1).

Table 5 Association Between Admission and Peak Hospitalization Liver Tests and Clinical Outcomes

Figure 1 Dynamic profile of liver function tests in patients by severity of COVID-19. The liver function tests in non-severe group (blue line) and severe group (red line) were analyzed at different time points after hospital admission. The liver function tests are shown using median and IQR. “*” means p < 0.05; “**” means p < 0.01; “***” means p < 0.001. Severe group had markedly higher levels of ALT, AST, GGT, LDH, TBIL, DBIL, but significantly lower levels of albumin compared with non-severe group from baseline to 30 days after admission (p < 0.05).

On multivariate analysis, age >60 years (OR=6.44; 95% CI 2.24–14.77; p < 0.005), BMI > 30 kg/m2 (OR=1.78; 95% CI 1.23–4.35; p=0.024), comorbidity (OR=6.74; 95% CI 2.93–21.85; p < 0.001), and abnormal peak hospitalization ALT (OR=3.37; 95% CI 1.25–8.16; p=0.008), AST (OR=4.82; 95% CI 1.28–16.16; p < 0.001), and TBIL (OR=5.65; 95% CI 1.87–18.20; p < 0.001) were associated with death. Kaplan‐Meier curves for cumulative rate of death in patients with different level of ALT (a), AST (b), and TBIL (c) are illustrated in Figure 2. ALT > 2 ULN (HR=7.0; CI%= 1.6–31.4; p = 0.011), AST > 2 ULN (HR=34.7; CI%= 7.8–155.3; p < 0.001), and TBIL > 2 ULN (HR=54.6; CI%= 6.6–453.8; p < 0.001) were associated with a higher mortality.

Figure 2 Kaplan‐Meier curves for cumulative rate of death during hospitalization in patients with different level of ALT (A), AST (B), and TBIL (C). ALT > 2 ULN (HR=7.0; CI%= 1.6–31.4; p = 0.011), AST > 2 ULN (HR=34.7; CI%= 7.8–155.3; p < 0.001), and TBIL > 2 ULN (HR=54.6; CI%= 6.6–453.8; p < 0.001) were associated with a higher mortality.

Discussion

Although COVID-19 is well known for causing respiratory symptoms, it can also cause extrapulmonary manifestations, including hepatocellular injury.12 In this study of 1003 patients with COVID-19, ALT and AST abnormalities were observed in 13.2% and 8.5% of patients at admission, respectively, and in 29.4% and 17.5% of patients at peak hospitalization, respectively. Based on a meta-analysis, the pooled prevalence estimates of elevated liver function abnormalities in China were as follows: ALT 15.0% and AST 15.0%.13 However, some studies from America showed higher prevalence ranging between 40–50.6% in cohorts ranging from 116 to 2780 patients.14–16 Obviously, abnormal liver function parameters are less common in Chinese patients than that reported in the U.S.5,13,15,16 The differences in baseline factors (chronic liver diseases, obesity, alcohol consumption) and hospital management (antiviral medication use) may potentially account for some of this disparity. Moreover, the different laboratory references of liver function parameters in different health-care systems might lead to the different definitions of liver injury, which may be one of the reasons for the disparity in the prevalence of liver injury between Chinese patients and the US patients. For example, the ULN of ALT ranges from 40 U/L to 50 U/L in the studies from China,6,8,9 but ranges from 33 U/L to 50 U/L in the studies from the US.5,16,17

This study showed that the pattern of abnormal liver function tests is predominantly hepatocellular (at admission: ALT 13.2%, AST 8.5%; at peak hospitalization: ALT 29.4%, AST 17.5%) rather than cholestatic, although less common elevations in ALP (2.0% at admission, and 2.6% at peak hospitalization), GGT (7.4% at admission, and 13.4% at peak hospitalization), and TBIL (4.0% at admission, and 10.1% at peak hospitalization) can be observed. Given that angiotensin converting enzyme-2 (ACE2), the entry receptor for SARS-CoV-2, is much more heavily expressed in cholangiocytes than in hepatocytes,18 therefore our findings suggest that the direct cytopathic effect of the SARS-CoV-2 may not be the main mechanism of COVID-19-related liver damage. Hepatic dysfunction in COVID-19 could be related to an uncontrolled immune reaction, sepsis or drug-induced liver injury, besides the direct cytopathic effect of the virus.19

Abnormal liver parameters are usually minimally elevated, although some significant abnormal liver function parameters (>5 ULN) (ALT 4.7%, AST 2.3%, GGT 3.0%, TBIL 3.0%, DBIL 0.6%) may be observed at peak hospitalization. The current results are consistent with prior observations.5,6 An American study reported that only 5.9% and 6.0% of ALT and AST elevations, respectively, were beyond 5 ULN at hospital admission, and 20.6% and 16.6% of ALT and AST elevations, respectively, were beyond 5 ULN at peak hospitalization.5 A Hong Kong study of 1040 COVID-19 patients reported that only 4.9% and 1.3% of ALT and AST elevations, respectively, were beyond 5 ULN during hospitalization.20

This study shows an association between antiviral medications use (Hydroxychloroquine, Lopinavir/Ritonavir, and TCM) and peak hospitalization ALT > 5 ULN in patients with COVID-19. Previous studies also showed that the use of certain drugs showed an association with the progression of liver damage in patients with COVID-19.5,7,20 An American study reported that Hydroxychloroquine and Lopinavir/Ritonavir use was the predictor of peak hospitalization liver parameters >5 ULN.5 A Chinese study reported that a significantly higher proportion of patients with abnormal liver function (57.8%) had received Lopinavir/Ritonavir after admission compared to patients with normal liver function (31.3%).7 Another Chinese study reported that the use of Lopinavir/Ritonavir ± Ribavirin + interferon beta (OR 1.94, p=0.006) was independently associated with ALT/AST elevation.20 Based on previous studies and our results, we suggested Hydroxychloroquine, Lopinavir/Ritonavir, and TCM should be used with caution in patients with abnormal ALT and LDH at hospital admission.

In a Chinese cohort of 675 patients with COVID-19, compared to patients with normal AST levels, mortality and risk of mechanical ventilation significantly increased 19.27-fold and 116.72-fold, respectively, in patients with AST above 3-fold ULN.21 In another Chinese cohort, Cai et al found that the presence of abnormal liver tests and liver injury were associated with the progression to severe COVID-19.6 In a large Hong Kong cohort of 1040 COVID-19 patients, Yip et al found ALT/AST elevation and acute liver injury are independently associated with adverse clinical outcomes including admission to intensive care unit, use of invasive mechanical ventilation and/or death in COVID-19 patients.20 Saini et al retrospectively analysed liver function tests of 170 patients with confirmed COVID-19, and also found number of patients with raised levels of any of the liver enzymes were 89 (58.5%), out of which 43 (48.31%) had liver injury, which manifested as increased severity in terms of ICU requirement (p=0.0005).22 In this study, abnormal liver parameters during hospitalization are associated with illness severity and mortality of COVID-19, with the strongest associations observed between peak liver tests and severe COVID-19, as well as peak liver tests and death. Based on previous studies and our results, we suggested monitoring levels of liver function parameters, which could assist in the optimum management of patients with COVID-19.

Many TCM were used in patients with COVID-19 in our cohort; therefore, the effect of TCM on liver functions should not be neglected in COVID-19 patients.23 In fact, the TCM-related liver injury is not uncommon in patients with COVID-19.24 A meta-analysis showed that the TCM as a complementary therapy for treating COVID-19 may not be beneficial for improving liver function based on the current evidence.23 In this study, we found that the TCM use is one of the predictors of peak hospitalization ALT > 5 ULN. Based on previous studies and our results, we suggested that prevention and management of TCM-induced liver injury should be concerned in COVID-19 patients who received TCM therapy.

Besides liver injury, other gastrointestinal manifestations were also concerned in COVID-19 patients. At the age of COVID-19 crisis, gastrointestinal physicians may face rare gastrointestinal symptoms such as dysentery, pure hyperbilirubinemia, and so on. For example, Hormati et al have reported the clinical data in details as well as the result of chest CT of a COVID-19 patient with dysentery.25 In a case series, Hormati et al also have reported pure hyperbilirubinemia may be considered as rare gastrointestinal symptom of COVID-19.26 Therefore, it is necessary that all gastrointestinal physicians should be aware of the possible occurrence of these gastrointestinal symptoms (hepatic involvement, pure hyperbilirubinemia, dysentery) as an important prognosis of COVID-19 pneumonia and it should be exactly addressed in new referred patients to gastrointestinal clinic. In addition, Hormati et al address preventive strategies that may significantly reduce close contact between patients and gastrointestinal physicians for successful control of COVID-19 infection.27 Preventive strategies should be performed to prevent transmission of COVID-19 infection from infected patients to uninfected gastrointestinal physicians and staff members during the performance of high-risk procedures.27

This study has several limitations. First, retrospective observational cohort study design with inclusion restricted to patients who were hospitalized within a single hospital, and limited access to laboratory, and medication variables, which may influence clinical outcomes. Second, this study did not elucidate the etiology of liver function test elevations in hospitalized patients with COVID-19. However, based on previous studies, we have reasons to believe that the drug’s effects, possible viral inclusion in liver cells, systemic inflammation, and hypoxia are potential causes of liver injury in patients with COVID-19.28 Third, in our hospital, the qualitative analysis (positive or negative) of SARS-CoV-2 RNA is used to guide the diagnosis and treatment of COVID-19 patients. Although CT (cycle-threshold)-value for viral load can support in the better interpretation of clinical decisions, in this retrospective study, the quantification of SARS-CoV-2 viral load is not available.

In conclusion, in this large sample retrospective cohort study, we described the longitudinal changes of liver function parameters in patients with COVID-19. In addition, we confirmed patients with abnormal liver function parameters were at increased risk of severe COVID-19 and death. The COVID-19-related liver injury is related to antiviral medication use.

Ethics Approval and Consent to Participate

Although this is a retrospective study, at hospital admission, all patients provided verbal consent for their clinical data might be used for further medical study. Shanghai Public Health Clinical Center Ethics Committee approved this study, including the verbal informed consent process. When we performed the study, all personal information of patients was de-identified to protect privacy. The procedures followed were in accordance with the ethical standards of the Helsinki Declaration (1964, amended most recently in 2008) of the World Medical Association.

Consent for Publication

All authors read and approved the manuscript.

Acknowledgments

We thank all doctors who work in Shanghai Public Health Clinical Center for their efforts in the diagnosis and treatment of patients with COVID-19.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Role of the Sponsor

The funding organization is a public institution and had no role in the design and conduct of the study; collection, management, and analysis of the data; or preparation, review, and approval of the manuscript.

Funding

This study was supported by grant No. 19YF1441200 from Shanghai Sailing Plan Program.

Disclosure

The authors reported no conflicts of interest for this work.

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Frontiers | Abnormal Liver Function Tests Were Associated With Adverse Clinical Outcomes: An Observational Cohort Study of 2,912 Patients With COVID-19

Introduction

The current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), has become a serious threat to global public health (1–4). Although initially reported in Wuhan, China, it has rapidly spread around the world (5). Outcomes of COVID-19 range from asymptomatic infection to death (6, 7). Older age; male gender; and comorbid conditions, such as hypertension and diabetes, have been identified as risk factors for severe outcomes (7, 8). While COVID-19 is typically characterized by symptoms of viral pneumonia, SARS-CoV-2 causes a systemic disease, with possible involvement of the heart, liver, pancreas, and kidneys, as well as alterations in circulating lymphocytes and the immune system, because of the ubiquitous distribution of the main viral entry receptor, namely angiotensin converting enzyme 2 (ACE2) (2, 9, 10).

Liver impairment has been reported as a common manifestation, with a derangement of liver function tests (LFTs) ranging from 14 to 75% (11–27). Nevertheless, the clinical relevance of LFTs abnormalities remains controversial, with some studies suggesting its association with the severity of COVID-19 pneumonia and adverse outcomes, while others not. Most of those reports were small-sized and the parameters of LFTs, the diagnostic time point (i.e., on admission or during disease progression) and cut-off values of abnormal LFTs varies among studies (28, 29). Furthermore, composite outcomes combining admission to intensive care unit (ICU), mechanical ventilation, and/or death, are used in a majority of studies, thus it is difficult to determine whether LFTs abnormalities are equally predictive of all the outcomes evaluated. In addition, due to LFTs were categorized in almost all previous studies, the actual relationship between the LFTs and outcomes (liner, dose-response, threshold/saturation effect pattern, or others) remains unknown. It is also yet unclear whether the effect of LFTs on the outcomes equal or differ among patients with different severity of COVID-19 infection.

Thus, the aim of this study was to assess the clinical features and the impact of abnormal LFTs on the outcomes (mortality, ICU admission, and mechanical ventilation) in a large cohort of hospitalized patients with COVID-19.

Methods

Study Design and Participants

We retrospectively extracted the data from the electronic charts of consecutive patients with confirmed COVID-19 at Huoshenshan hospital (Wuhan, China) from 5 February to 23 March 2020. The Huoshenshan hospital, a makeshift hospital with 1,000 beds, was opened by the government on 5 February 2020, and assigned to treat exclusively COVID-19 patients. This study was approved by the National Health Commission of China and the institutional review board at Huoshenshan hospital. Written informed consent was waived by the ethics committee of the Huoshenshan hospital for patients with emerging infectious diseases.

Inclusion criteria for the study were (i) hospitalized patients with confirmed COVID-19 infection; (ii) age >18 years old. Patients with no data on LFTs were excluded from the study. COVID-19 was diagnosed by clinical manifestations, chest computed tomography (CT), and confirmed by real-time polymerase chain reaction (RT-PCR) according to World Health Organization (WHO) interim guidance (30), and the New Coronavirus Pneumonia Prevention and Control Program (7th edition) published by the National Health Commission of China (31). The severity of COVID-19 was categorized as mild, severe, or critical (31, 32). Mild type was defined as having slight clinical symptoms without signs of pneumonia or with mild pneumonia (multiple small patchy shadows and interstitial changes, mainly in the outer zone of the lung and under the pleura) by radiography (31, 32). Severe cases were characterized by dyspnoea, respiratory frequency ≥30/min, blood oxygen saturation ≤ 93%, PaO2/FiO2 ratio <300 mmHg, and/or lung infiltrates >50% within 24–48 h (31, 32). Such patients were considered as critical case if they developed respiratory failure requiring mechanic ventilation, septic shock, and/or multiple organ dysfunction/failure (31, 32).

Data Collection

Baseline data collected within 24 h after admission include patient demographics, clinical features at inclusion, clinical history, comorbidities, initial blood pressure, and heart rate, laboratory values (peripheral white blood cell, neutrophil, lymphocyte, hemoglobin, platelet count, creatinine, blood urea nitrogen, potassium, sodium, D-dimer, prothrombin time, activated partial thromboplastin time, international normalized ratio, creatine kinase, lactate dehydrogenase, procalcitonin, and c-reactive protein), and radiological reports. Data regarding the specific drug therapy provided during the hospitalization also were collected. Liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bilirubin, (TBIL), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT)] from the time of hospital admission until discharge or death were obtained. The performing of LFT was determined by the attending physicians based on the demand of clinical decision. LFTs were considered as abnormal when at least one among AST, ALT, albumin, TBIL, ALP, and GGT were above the upper limit of normal (ULN) of laboratory reference range standards (i.e., AST >40 U/L, ALT >45 U/L, albumin <35 g/L, TBIL >26 μmol/L, ALP >125 U/L, GGT >60 U/L). All data were reviewed and confirmed by two certified investigators (Yong Lv and Huahong Xie) to ensure accuracy.

Outcome and Definitions

The primary endpoint was all-cause mortality during hospitalization. Secondary endpoints included ICU admission and use of mechanical ventilation. All clinical outcomes were obtained from clinical charts and assessed on April 15, 2020, when all survived patients were discharged and the Huoshenshan Hospital was shut down. The criteria for discharge are: (i) throat swab specimens collected 24 h apart were negative for tests of SARS-CoV-2; (ii) body temperature was normal for three consecutive days; (iii) symptoms of COVID-19 were resolved; (iv) the radiographic findings of COVID-19 significantly improved (31).

Statistical Analysis

For all analyses, missing data of the covariates were imputed with multiple imputations methods (detailed in Supplementary Materials and Methods). Data are presented as frequencies (percentage), mean ± standard deviation (SD), or medians with interquartile range (IQR) as appropriate. Comparisons of variables between groups were performed using Student t-test, non-parametric Mann-Whitney U-test, chi-squared test, or Fisher’s exact test as appropriate. Dynamic changes in liver function were presented using locally weighted scatterplot smoothing (LOESS). The cumulative probability model [an ordinal regression model for continuous outcomes (33)] was used to evaluate the association of baseline characteristics and treatment before peaking of FLTs with the peak levels of LFTs in hospital, where the liver function markers were treated as continuous response variables. The non-linear relationships between liver function markers and the risk of the evaluated outcomes were visualized using restricted cubic splines by entering the liver function markers as a continuous variable into the logistic regression analysis. Cumulative risks of death was assessed with Kaplan-Meier curves and compared using the log-rank test. Cumulative incidences of ICU admission or mechanical ventilation were estimated in a competing risks setting, where the death competed with the event of interest. The contribution of each variable to the risk of developing the endpoint was reported as a hazard ratio (HR) with 95% confidence interval (CI). We assessed the unadjusted and confounder-adjusted effects of LFTs on the evaluated outcomes using Cox regression models. Age, gender, severity of COVID-19 (severe/critical vs. mild), comorbidities (include hypertension, cardiovascular disease, diabetes, chronic pulmonary diseases, cerebrovascular disease, malignancy, and autoimmune disease) and chronic liver diseases (include hepatitis B virus infection, hepatitis C virus infection, and autoimmune liver disease) were considered as potential confounders. We assessed the heterogeneity in the effect of LFTs across the severity of COVID-19 by including a LFTs-by-COVID-19-severity interaction term in the Cox regression models. A significant interaction would indicate that the effect of LFTs was different across the severity of COVID-19. Significance was established at p < 0.05. All statistical calculations were performed using R 3.6.1(http://www.R-project.org/) with the add-on packages Hmisc, rms, riskRegression, pec, prodlim, and cmprsk.

Results

Baseline Clinical Features of Patients With COVID-19

During the study period, 2,922 patients with confirmed COVID-19 were admitted to the Huoshenshan hospital, and 10 patients were excluded because of incomplete relevant data. Ultimately, 2,912 patients with COVID-19 were included in the study. In the entire cohort, the mean age was 58.4 ± 14.4 years, and 1,512 (51.9%) were female. On admission, the severity of COVID-19 was mild in 2,160 (74.2%) patients, severe in 714 (24.5%) and critical in 38 (1.3%). Among the 752 serious and critically ill patients, 54 (7.2%) patients had multiple organ dysfunction syndromes. A total of 1236 (42.4%) patients had comorbidities, with hypertension (910 patients [31.2%]) being the most common one, followed by diabetes (392 patients [13.5%]). Sixty-eight patients (2.3%) had chronic liver disease, among which 58 had hepatitis B virus infection, 8 had hepatitis C virus infection, and 2 autoimmune liver disease. No patients had cirrhosis. The most common symptoms of COVID-19 were fever (2,057 patients [70.6%]), followed by cough (2,001 patients [68.7%]), fatigue (1,461 patients [50.2%]), dyspnea (1,394 patients [47.9%]), myalgia (774 patients [26.6%]), anorexia (523 patients [18.0%]), and expectoration (420 patients [14.4%]). Nausea, vomiting, abdominal pain, diarrhea, headache, dizziness disorders of consciousness were rare.

On admission 1,414 patients (48.6%) had abnormal LFTs, with ALT, AST, TBIL, ALP, and GGT above ULN in 662 (22.7%), 221 (7.6%), 52 (1.8%), 135 (4.6%), and 536 (18.5%) patients, respectively, and hypoalbuminemia (<35g/L) in 737 (25.3%) patients. The baseline characteristics of the study population according to normal and abnormal LFTs on admission are summarized in Table 1. Compared with patients with normal LFTs, patients with abnormal LFTs were older, with more severe COVID-19 disease and more likely to have symptoms of fever, cough, expectoration, dyspnea, fatigue, myalgia, anorexia, and nausea. The mean values of white blood cell count, neutrophil count, lymphocyte count, hemoglobin, platelet count, creatinine, D-dime, activated partial thromboplastin time, creatine kinase, lactate dehydrogenase, procalcitonin, and C-reactive protein were also higher in patients with abnormal LFTs. Mover, patients with abnormal LFTs had a higher likelihood of receiving antiviral therapy, antibiotics, immunoglobin, glucocorticoid therapy, high flow nasal cannula, and continuous renal replacement therapy during hospitalization (Table 2).

Table 1. Baseline characteristics of patients according to normal vs. abnormal liver function test on admission.

Table 2. In-hospital treatment and outcomes according to normal vs. abnormal liver function on admission.

When stratified according to the severity of COVID-19 infection, patients with severe or critical COVID-19 had higher median values of AST, TBIL, ALP, and GGT and lower median value of albumin. The proportion of patients with abnormal AST, albumin, TBIL, ALP, and GGT were higher in severe or critical cases (Figure 1 and Supplementary Tables 1, 2). Nevertheless, the median value of ALT and the proportion of patients with abnormal ALT were not significantly across the severity of COVID-19.

Figure 1. Liver function tests on admission. (A) Violin and box plots showing the median values of ALT, AST, albumin, TBIL, ALP, and GGT by severity of the COVID-19 disease. (B) Bar plots showing the proportion of abnormal ALT, AST, albumin, TBIL, ALP, and GGT tests on admission by severity of the COVID-19 disease. ALT, alanine aminotransferase; AST, aspartate transaminase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; TBIL, total bilirubin abnormal.

Dynamic Changes of Liver Functions

Figure 2 depicts the dynamic trajectories of ALT, AST, albumin, TBIL, ALB, and GGT according to normal or abnormal LFTs on admission. The ALT, AST, TBIL, ALP, and GGT values in the abnormal LFTs group increased slightly within the first 5 days after admission and trended downwards thereafter, while those values in the normal LFTs group tended upwards for the entire in-hospital duration. The albumin values trended downwards in both groups within the first 5 days of hospitalization and then fluctuated slightly for the entire duration of follow-up.

Figure 2. The liver function variations. (A) Longitudinal back-to-back violin plots showing the variations of ALT, AST, albumin, TBIL, ALP, and GGT during follow-up stratified by presence or absence of abnormal liver function tests on admission. Circles and triangles indicate medians. The black vertical bars have lengths equal to one-half the length of the 95% confidence interval for the difference in medians. When this bar does not touch the circles and triangles, there is a significant difference in medians at the 0.05 level. (B) Smooth trajectories of mean ALT, AST, albumin, TBIL, ALP, and GGT by disease severity with 95% confidence band based on locally weighted scatterplot smoothing stratified by presence or absence of abnormal liver function tests on admission. ALT, alanine aminotransferase; AST, aspartate transaminase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; TBIL, total bilirubin abnormal.

When stratified according to the severity of COVID-19 (mild vs. severe/critical), the dynamic curves of LFTs showed downward trends of ALT, AST, TBIL, ALP, and GGT and a upward trend of albumin in both mild and severe/critical groups (Supplementary Figure 2). Furthermore, the values of ALT, AST, TBIL, ALP, and GGT were higher and albumin was lower in patents with the outcomes of death, ICU admission, and mechanical ventilation compared those without in most time-points (Supplementary Figures 3–5).

Predictors of Peak (Nadir) Value of Liver Function Test During Hospitalization in COVID-19

The cumulative probability model revealed the association between baseline characteristics and hospital treatment on peak ALT, AST, TBIL, ALP, GGT levels, and nadir albumin levels in the entire cohort (Supplementary Figure 6 and Figures 3, 4). Younger age, male gender, use of antibiotics, increased hemoglobin, increased C-reactive protein, and increased lactate dehydrogenase were factors positively associated with elevated ALT levels. Male gender, diabetes, higher C-reactive protein, and increased lactate dehydrogenase were the leading factors positively associated with elevated AST levels. Total bilirubin levels rise were tightly associated with male gender, decreased creatinine, decreased platelet count, increased C-reactive protein, and increased lactate dehydrogenase. Older age, male gender, antiviral, antibiotics, systemic corticosteroids use, hemoglobin reduction, C-reactive protein, and lactate dehydrogenase elevation were main factors positively correlated with decreased albumin levels. Alkaline phosphatase levels were closely linked with older age, male gender, platelet count, C-reactive protein, and lactate dehydrogenase elevation. Male gender, white blood cell, platelet count, hemoglobin, C-reactive protein, and lactate dehydrogenase increase were identified as factors positively associated with elevated GGT levels. C-reactive protein, lactate dehydrogenase platelet count, hemoglobin, and male gender were common factors positively associated with ALT, AST, TBIL, ALP, GGT elevation, and albumin reduction during hospitalization. To predict the peak (nadir) value of these LFTs, nomograms that incorporated the significant risk factors were established.

Figure 3. Factors and nomogram for predicting the peak values of ALT, AST, and TBIL during hospitalization. (A, C, E) Multivariable analysis of factors associated with the peak values of ALT, AST, and TBIL during hospitalization. The non-linearity of continuous variables were considered and analyzed with restricted cubic splines. (B, D, F) Nomogram for predicting the peak values of ALT, AST, and TBIL during hospitalization. To use the nomogram, first draw a vertical line to the top points row to assign points for each variable; then, add the points from each variable together and drop a vertical line from the total points row to obtain the median, mean values of peak ALT, AST, and TBIL during hospitalization as well as the probability of above the 1-, 2-, 3-time upper limit of normal of these parameters.

Figure 4. Factors and nomogram for predicting the nadir albumin and peak ALP, GGT during hospitalization. (A, C, E) Multivariable analysis of factors associated with nadir albumin and peak ALP, GGT during hospitalization. The non-linearity of continuous variables were considered and analyzed with restricted cubic splines. (B, D, F) Nomogram for predicting the peak values of nadir albumin and peak ALP, GGT during hospitalization. To use the nomogram, first draw a vertical line to the top points row to assign points for each variable; then, add the points from each variable together and drop a vertical line from the total points row to obtain the median, mean values of nadir albumin and peak ALP, GGT during hospitalization as well as the probability of above the 1-, 2-, 3-time upper limit of normal of these parameters. ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase.

Associations Between Abnormal Liver Function Test on Admission and Clinic Outcomes

During a median 13 (IQR: 8–19) days of hospitalization, 61 patients (2.1%) died, 106 patients (3.6%) admitted or transfer to ICU, and 75 patients (2.6%) required mechanical ventilation (Table 2 and Supplementary Figure 7). The 30-day cumulative incidences of death was significantly higher in patients with abnormal LFTs on admission compared with those with normal LFTs (abnormal vs. normal: 3.3 vs. 0.47%; HR 8.32, [95%CI 3.79 −18.26]; p < 0.001, Figure 5A). Similarly, patients with abnormal LFTs on admission had a higher 30-day cumulative incidences of ICU admission (5.9 vs. 1.2%; HR 5.18 [95%CI 3.12–8.60]; p < 0.001; Figure 5C) and mechanical ventilation requirement (4.2 vs. 0.8%; HR 5.14 [95%CI 2.82–9.34]; p < 0.001, Figure 5E). This pattern persisted after adjusting for potential confounders, with the adjusted HRs of abnormal LFTs were 3.66 (95%CI 1.64–8.19, p = 0.002, Figure 5B) for death, 3.12 (95%CI 1.86–5.23, p < 0.001, Figure 5D) for ICU admission, and 3.00 (95%CI 1.63–5.52, p < 0.001, Figure 5F) for mechanical ventilation requirement. Furthermore, these effects were homogeneous across the severity of COVID-19 (Pinteraction > 0.1 for all comparisons, Figure 6 and Supplementary Figures 8, 9). Notably, chronic liver disease was not associated with an increased risk of either of these adverse outcomes (Figures 5, 6 and Supplementary Figures 8, 9).

Figure 5. Outcome analysis according to admission abnormal vs. normal liver function tests (LFTs). (A) Cumulative incidence of death in patients with abnormal vs. normal LFTs on admission. (B) Independent effect (hazard ratio with 95% confidence intervals) of admission abnormal vs. normal LFTs on all-cause mortality adjusted for potential confounders using the Cox multivariable regression models. (C) Cumulative incidence of ICU admission in patients with abnormal vs. normal LFTs on admission based on competing risk approach (the Fine and Gray method) with death being the competing events. (D) Independent effect (hazard ratio with 95% confidence intervals) of admission abnormal vs. normal LFTs on ICU admission adjusted for potential confounders using the Cox multivariable regression models. (E) Cumulative incidence of mechanical ventilation in patients with abnormal vs. normal LFTs on admission based on competing risk approach (the Fine and Gray method) with death being the competing events. (F) Independent effect (hazard ratio with 95% confidence intervals) of admission abnormal vs. normal LFTs on mechanical ventilation adjusted for potential confounders using the Cox multivariable regression models. Comorbidities include hypertension, cardiovascular disease, diabetes, chronic pulmonary diseases, cerebrovascular disease, malignancy, and autoimmune disease. Chronic liver diseases include hepatitis B virus infection, hepatitis C virus infection, and autoimmune liver disease. LFTs, liver function tests; ICU, intensive care unit.

Figure 6. Cumulative incidence of death according to admission abnormal vs. normal liver function tests (LFTs) and severity of COVID-19 infection. (A) Cumulative incidence of death in patients with abnormal vs. normal LFTs on admission and mild COVID-19 infection. (B) Cumulative incidence of death in patients with abnormal vs. normal LFTs on admission and severe/critical COVID-19 infection. (C) Forest plot showing the interaction test of the LFTs (normal vs. abnormal) and severity of COVID-19 infection (mild vs. severe/critical) on death after adjustment for potential confounders using the Cox multivariable regression models. Pinteraction = 0.521, showing a homogeneous effect of LFTs on death across the severity of COVID-19 infection. Comorbidities include hypertension, cardiovascular disease, diabetes, chronic pulmonary diseases, cerebrovascular disease, malignancy, and autoimmune disease. Chronic liver diseases include hepatitis B virus infection, hepatitis C virus infection, and autoimmune liver disease. COVID-19, coronavirus disease 2019; LFTs, liver function tests.

The relationship between the baseline ALT, AST, albumin TBIL, ALP as well as GGT and death rate during hospitalization was depicted in Figure 7. The increased ALT, AST, TBIL, ALP, GGT, and decreased albumin on admission had a non-linear positive association with the risk of death, which was homogeneous across the severity of COVID-19. Similar results were observed for the secondary endpoint of ICU admission (Supplementary Figure 10) as well as mechanical ventilation requirement (Supplementary Figure 11).

Figure 7. Patient distribution and death rate according to baseline liver function tests Patient distribution and death rate according to baseline ALT, AST, albumin, TBIL, ALP, and GGT (A) in entire cohort and (B) by severity of COVID19 infection (mild vs. severe/critical). Restricted cubic splines were generated using logistic regression models. ALT, alanine aminotransferase; AST, aspartate transaminase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; TBIL, total bilirubin abnormal.

When stratified according to different levels of LFTs, abnormal levels of baseline AST, albumin, TBIL, ALP, and GGT were significantly associated with the risk of death, ICU admission, and mechanical ventilation (Figure 8 and Supplementary Figures 12, 13). Among them, AST over three-fold ULN and albumin <30 g/L had the highest risks of death, ICU admission, and mechanical ventilation. The elevation of ALT tended to be associated with increased risks of those outcomes. Nevertheless, the difference did not reach significance.

Figure 8. Mortality during hospitalization in patients with different level of baseline liver function tests. (A) Cumulative incidence of death in patients with different level of liver function test on admission. (B) Death rate in patients with different level of liver function test on admission, the unadjusted adjusted effect of liver function test at different level on the mortality during hospitalization. Adjusted HRs are derived from multivariate Cox regression models, adjusted for age, gender, comorbidities (hypertension, cardiovascular disease, diabetes, chronic pulmonary diseases, cerebrovascular disease, malignancy, autoimmune disease) and chronic liver diseases (hepatitis B virus infection, hepatitis C virus infection, autoimmune liver disease). ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; CI, confidence interval; GGT, gamma-glutamyltransferase; HR, hazard ratio; TBIL, total bilirubin.

Associations Between

De novo Abnormal Liver Function Test During Hospitalization and Clinic Outcomes

Among the 1,498 patients with normal LFTs upon admission, 368 patients (24.6%) developed de novo abnormalities of LFTs (Supplementary Table 3). Univariable and multivariable logistic regression analysis showed that lymphocyte count (OR 1.13, 95%CI: 1.03–1.25, p = 0.007), use of quinolones (OR 1.48, 95%CI: 1.10–1.98, p = 0.010), and cephalosporins (OR 4.80, 95%CI: 1.58–14.59, p = 0.006) were independently were associated with de novo abnormalities of LFTs (Supplementary Figure 14 and Figure 9). Compared with those without de novo abnormal LFTs, patients with de novo abnormal LFTs had higher risk of death, ICU admission as well as the mechanical ventilation requirement. The trends persisted after adjusting for potential confounders, but the differences were not significant (Supplementary Table 4 and Figure 10).

Figure 9. Multivariable analysis of factors associated with de novo abnormal vs. normal liver function tests (LFTs) during hospitalization.

Figure 10. Outcome analysis according to de novo abnormal vs. normal liver function tests (LFTs) during hospitalization. (A) Cumulative incidence of death in patients with de novo abnormal vs. normal LFTs during hospitalization. (B) Independent effect (hazard ratio with 95% confidence intervals) of de novo abnormal vs. normal LFTs during hospitalization on all-cause mortality adjusted for potential confounders using the Cox multivariable regression models. (C) Cumulative incidence of ICU admission in patients with de novo abnormal vs. normal LFTs during hospitalization based on competing risk approach (the Fine and Gray method) with death being the competing events. (D) Independent effect (hazard ratio with 95% confidence intervals) of de novo abnormal vs. normal LFTs during hospitalization on ICU admission adjusted for potential confounders using the Cox multivariable regression models. (E) Cumulative incidence of mechanical ventilation in patients with de novo abnormal vs. normal LFTs during hospitalization based on competing risk approach (the Fine and Gray method) with death being the competing events. (F) Independent effect (hazard ratio with 95% confidence intervals) of de novo abnormal vs. normal LFTs during hospitalization on mechanical ventilation adjusted for potential confounders using the Cox multivariable regression models. Comorbidities include hypertension, cardiovascular disease, diabetes, chronic pulmonary diseases, cerebrovascular disease, malignancy, and autoimmune disease. Chronic liver diseases include hepatitis B virus infection, hepatitis C virus infection, and autoimmune liver disease. LFTs, liver function tests; ICU, intensive care unit.

Associations Between Peak (Nadir) Liver Function Test During Hospitalization and Clinic Outcomes

Overall, 1,782 patients (61.2%) had abnormal LFTs during hospitalization in the entire cohort. Peak ALT, AST, TBIL, ALP, and GGT above ULN was observed in 855 (29.4%), 321 (11.0%), 103 (3.5%), 166 (5.7%), and 642 (22.0%) patients, respectively. Nadir albumin <35 g/L was observed in 1,114 (38.3%) patients during hospitalization. The baseline characteristics of patients grouped according to LFTs abnormalities during hospitalization are shown in Supplementary Table 5. Compared with those with normal liver function impairment during hospitalization, patients with abnormal LFTs had severer COVID-19 disease and more common of respiratory and digestive symptoms. Similar to baseline LFTs abnormality, abnormal LFTs during hospitalization, peak AST, TBIL, ALP, GGT, and nadir albumin but not peak ALT were significantly (or a trend toward) associated with adverse outcomes of COVID-19 (Figures 11–13, Supplementary Tables 6, 7, and Supplementary Figures 15–19).

Figure 11. Outcome analysis according to abnormal vs. normal liver function tests (LFTs) during hospitalization in entire cohort. (A) Cumulative incidence of death in patients with abnormal vs. normal LFTs during hospitalization in entire cohort. (B) Independent effect (hazard ratio with 95% confidence intervals) of abnormal vs. normal LFTs during hospitalization on all-cause mortality adjusted for potential confounders using the Cox multivariable regression models. (C) Cumulative incidence of ICU admission in patients with abnormal vs. normal LFTs during hospitalization based on competing risk approach (the Fine and Gray method) with death being the competing events. (D) Independent effect (hazard ratio with 95% confidence intervals) of abnormal vs. normal LFTs during hospitalization on ICU admission adjusted for potential confounders using the Cox multivariable regression models. (E) Cumulative incidence of mechanical ventilation in patients with abnormal vs. normal LFTs during hospitalization based on competing risk approach (the Fine and Gray method) with death being the competing events. (F) Independent effect (hazard ratio with 95% confidence intervals) of abnormal vs. normal LFTs during hospitalization on mechanical ventilation adjusted for potential confounders using the Cox multivariable regression models. Comorbidities include hypertension, cardiovascular disease, diabetes, chronic pulmonary diseases, cerebrovascular disease, malignancy, and autoimmune disease. Chronic liver diseases include hepatitis B virus infection, hepatitis C virus infection, and autoimmune liver disease. LFTs, liver function tests; ICU, intensive care unit.

Figure 12. Patient distribution and death rates according to peak (nadir) liver function test in entire cohort. Patient distribution and death rate according to peak ALT, peak AST, nadir albumin, peak TBIL, peak ALP, and peak GGT during hospitalization (A) in entire cohort (B) by severity of COVID-19 infection (mild vs. severe/critical). Restricted cubic splines were generated using logistic regression models. ALT, alanine aminotransferase; AST, aspartate transaminase; ALP, alkaline phosphatase; COVID-19, coronavirus disease 2019; GGT, gamma-glutamyltransferase; TBIL, total bilirubin.

Figure 13. Mortality during hospitalization in patients with different level of peak (nadir) liver function test in entire cohort. Cumulative incidence of death during hospitalization in patients with different level of peak ALT, peak AST, nadir albumin, peak TBIL, peak ALP, and peak GGT during hospitalization. ALT, alanine aminotransferase; AST, aspartate transaminase; ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; TBIL, total bilirubin abnormal.

Discussion

In this observational study of 2,912 hospitalized patients with COVID-19, we present the patterns and trajectories of LFTs as well as depict their clinical significance. The major findings were: (i) the derangement of liver function was generally mild (1–2 time of ULN) in non-severe patients but more frequent and to a greater extent in patients with severe/critical COVID-19 infection; (ii) Pattern of LFTs abnormality is predominantly hepatocellular rather than cholestatic; (iii) abnormality of LFTs was transient and tended to resolve over time; (iv) common factors associated with the peak (nadir) LFTs were C-reactive protein, lactate dehydrogenase, platelet count, hemoglobin, and male gender; (v) abnormal LFTs (AST, albumin, TBIL, ALP, and GGT but not ALT) were independently associated with increased risks of mortality, ICU admission, and mechanical ventilation requirement, which was homogeneous across the severity of COVID-19 infection. The strengths and novelties of the current study lie in: (i) use of a death-based primary endpoint, which is an objectively assessed and clinically relevant endpoint; (ii) a large sample size which allow providing estimates with narrow CIs; (iii) multivariate and subgroup analysis, which permitted adjustment for potential confounding factors and explore the effect homogeneity; (iv) adopting not only categorized but continuous LFT analysis; (v) comprehensive liver function parameters and outcomes analyses; (vi) differentiation between baseline and in-hospital elevations of liver enzymes; (vii) significant amount of data on pre-existing liver disease and therapies used during hospitalization.

In our cohort, 48.6% had abnormal liver biochemistries at admission and 61.2% had liver biochemistries derangement during hospitalization, which was slightly higher than what has been reported in the literature (34, 35). Disparity may be attributed to the diverse definition of abnormality of LFTs. Indeed, the liver enzymes (ALT, AST, ALP, and GGT) elevation observed here is similar to those in previous cohorts (11–27). Nevertheless, the hypoalbuminemia was considered as part of abnormal LFTs in our definition while it was not included in most previous studies. As in other reports (11–27), liver enzyme elevations in COVID-19, even in the severe COVID-19 category, are mild-to-moderate in most of the cases, and the pattern of abnormal liver biochemistries was characterized by slight increases in hepatocyte-related enzymes, including ALT and AST, with accompanying GGT elevation. Pure cholestatic alterations characterized by ALP elevation were rare, and an increase in TBIL was less commonly observed (36, 37). However, significant hypoalbuminemia was observed, particularly among patients with severe COVID-19 disease. The possible explanation might be that albumin is a negative acute phase reactant rather than a manifestation of a hepatic synthetic dysfunction.

Furthermore, when stratifying according to disease severity of COVID-19 infection, we found that the AST, TBIL, ALP, and GGT were elevated more frequently and to a greater extent in patients with severe COVID-19 compared to those with mild disease. However, ALT elevation was not significantly higher in the severe/critical patients. This observation may be related to the mechanism of LFTs abnormality. Available evidence suggests that hepatic involvement in COVID-19 could be related to the direct cytopathic effect of the virus, an uncontrolled immune reaction, sepsis, or drug-induced liver injury (2, 11, 37, 38). The postulated mechanism of viral entry is through the host angiotensin-converting enzyme 2 (ACE2) receptors (39, 40). However, the ACE2 receptor is much more heavily expressed in cholangiocytes than in hepatocytes. Furthermore, the concentrations of serum ALP was normal in most patients with COVID-19, suggest the most common mechanism of liver damage is not due to a direct cytopathic effect of the SARS-CoV-2 virus. Our analysis showed that peak (nadir) liver function markers were commonly correlated with the direct or indirect markers of inflammation (C-reactive protein, lactate dehydrogenase, platelet count, hemoglobin at baseline), which support the point that most cases of liver derangement may reflect sepsis related cholestasis and inflammatory changes, or hepatotoxicity from concomitant medications (41, 42). Furthermore, studies have confirmed increased NETosis, a form of non-apoptotic and highly immunogenic cell death causing bystander damage and coagulation changes, accompanies disease severity (42, 43). It can be imagined that the alteration of immune balance occurs with increased severity of COVID-19, thus explaining why increases in serum AST, ALP, and TBIL levels but not ALT tend to parallel the severity of pulmonary disease, in an analogous fashion to patterns seen in sepsis (44). Lymphocyte count, use of quinolones and cephalosporins were independently were associated with de novo abnormalities of LFTs during hospitalization, suggesting drug-induced liver injury should not be overlooked in patients with COVID-19. With further analysis of longitudinal patterns, we found that the abnormality of LFTs manifested as transient elevation in most cases and liver involvement tended to resolve during prolonged disease course, indicating that supportive care alone might be sufficient to achieve liver recovery. Therefore, we advise checking baseline LFTs in all patients on admission and monitoring of LFTs throughout the hospitalization, particularly in patients undergoing drug therapy for COVID-19 with potential hepatotoxicity.

Our results showed that abnormalities of LFTs on admission as well during hospitalization were associated with death, ICU admission and mechanical ventilation requirement in COVID-19 patients. More importantly, these associations were independent from the most commonly described predictors of the evaluated outcomes in multivariable analysis. Furthermore, the effects of LFTs on the evaluated outcomes were homogeneous across the severity of COVID-19, suggesting the impact of LFTs on the evaluated outcomes were not modified by the severity of COVID-19. Several studies have reported on the association between the abnormal LFTs and severity of disease or outcomes, with conflicting results (11–27). Most of them reported the results of univariate analyses without appropriately adjust for potential confounders. Thus, it is unclear whether the influence of abnormal LFTs on the prognosis was real or mediated by its association with other co-existing diseases. A large multicenter study of 5,771 Chinese individuals showed that peak liver biochemistries (AST, ALT, ALP, and TBIL) predicted mortality, after adjusting for age, gender, and comorbidities in Cox regression model (18). Similarly, an Italian study with 565 inpatients showed that abnormality of LFTs (ALT, AST, ALP, GGT, and TBIL) observed at admission was independently associated to a composite endpoint of transfer to the ICU or death (24). In contrast, another Italian study by Ponziani et al. (22) suggested baseline liver test (AST, ALT, and GGT) abnormalities were associated with increased risk of ICU admission but not with mortality. The discrepancy might be due to the somewhat low incidence of death in the latter study, which may reduce the likelihood of association between LFTS and mortality of COVID-19, with a wide CI of the HR. Thus, patients with abnormal LFTs should be closely followed up due to the potential worse outcomes.

In our study, while AST, albumin, TBIL, ALP, and GGT were significantly associated with adverse outcomes, no such an association were observed in ALT. This was in agreement with the study by Hao et al. (27) showing no differences in the severity, discharge rate, and median hospitalization time between patients with and without ALT elevation. However, this finding is in contrast with two previous studies where higher peak ALT values were significantly associated with increased risk of mortality or discharge to hospice (OR = 1.14 or 1.43) (18, 19). The main reason for the discrepancy was not clear. Nevertheless, it should be noted that the association between ALT and death was not so strong (18, 19), and our patients were generally healthier compared with previously published cohorts.

The prevalence of chronic liver disease in our cohort was 2.3%, which is within the range (2–11%) reported in recent data from other cohorts (45–48). Previous studies showed that those with chronic liver disease are more likely to have more adverse outcomes and mortality when compared to those without (49–52). In our study, however, the presence of chronic liver disease was not significantly associated with disease progression and mortality, which may be due in part to the overall low numbers of patients with these disease entities. Another possible explanation may be that the severity of chronic liver disease in our patients is generally mild, with no patient having cirrhosis. Indeed, the term “chronic liver disease” constitutes a spectrum of patients with varying prognosis ranging from chronic hepatitis, cirrhosis, decompensated cirrhosis to acute-on-chronic liver failure that may differentially affect outcomes (53).

Our study has several limitations. First, the single-center nature may limit its representativeness. However, quality control was ensured because all the diagnostic and therapeutic algorithms were uniform. Second, potential bias in the selection of samples is inherent to its retrospective design. Nevertheless, we included all consecutive patients with confirmed COVID-19 admitted to the hospital, which minimizes the risk of selection bias. Third, although multivariate regression analyses were conducted to adjust for potential confounders, our findings may be biased due to unidentified confounding. Fourth, liver biochemistries and other important laboratory markers were not assessed daily on every patient because this was not required for clinical decision making. Fifth, our study patients represent an exclusively inpatient population. Therefore, this information may not be generalizable to outpatients. Sixth, this is an observational study. Thus, the association should not be regarded as causal effect. Seventh, alcohol abuse and hepatotoxic drug intake prior to development of COVID-19 have not been considered. Finally, with only a few cases of incompletely characterized chronic liver disease in this cohort, we cannot draw conclusions about hepatic impairment and other outcomes for those patients.

In conclusion, abnormal liver function was common and associated with adverse clinical outcomes in COVID-19 patients. Thus, clinicians should keep close monitoring of liver biochemistries and cautiously use appropriate medications with least hepatotoxicity in such patients. Due to the nature of such retrospective study, these results should be interpreted with caution and are needed to be confirmed in future large prospective studies.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The studies involving human participants were reviewed and approved by National Health Commission of China and the institutional review board at Huoshenshan Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Author Contributions

Study concept and design: YL and HX, acquisition of data: YL, XZ, YW, JZ, CM, XF, YM, YZ, LY, GH, and HX, analysis and interpretation of data, drafting of the manuscript, and statistical analysis: YL, critical revision of the manuscript for important intellectual content: HX and GH. All authors contributed to the article and approved the submitted version.

Funding

This study was supported in part by grants from Boost program of Xijing Hospital (XJZT19ML15), Clinical Applied Research Subject of Military Medicine (XJGX15Y0) for HX, Boost Program of Xijing Hospital (XJZT18H02) for GH, and China Postdoctoral Science Foundation (2019TQ0134) for YL.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.639855/full#supplementary-material

Abbreviations

ACE2, angiotensin converting enzyme 2; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; CI, confidence interval; COVID-19, coronavirus disease 2019; GGT, gamma-glutamyltransferase; HR, hazard ratio; ICU, intensive care unit; LFTs, liver function tests; SARSCoV-2, severe acute respiratory syndrome coronavirus 2; TBIL, total bilirubin; ULN, upper limit of normal.

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Tests for Liver Disease

A small amount of blood may be taken and tested for one or more of the following:

  • AFP (alpha fetoprotein). This is a protein made by the liver. A high level in the blood can be a sign of liver cancer or liver injury and regeneration in adults.

  • Albumin. This is a liver function test. It measures a protein made by the liver. When a person has liver disease, the level of albumin in the blood (serum albumin) is often low.

  • Alk phos (alkaline phosphatase). This is an enzyme that is mostly made in the liver and bones. It’s measured with a blood test. A high level suggests a problem with the bile ducts in the liver.

  • ALT (alanine aminotransferase). ALT is an enzyme made by the liver. When the liver is damaged, ALT leaks into the blood. If a blood test finds a high level of ALT, this can be a sign of liver problems such as inflammation, scarring, or a tumor.

  • Ammonia. This is a liver function test that shows when a harmful substance is left behind in the blood after digestion. Normally the liver removes ammonia from the blood and turns it into urea. This leaves the body with urine. If a blood test shows that the ammonia level is too high, this process isn’t happening as it should. This test is very inaccurate for liver function and should rarely be used.

  • AST (aspartate aminotransferase). AST is another enzyme made by the liver as well as by other organs such as muscle. It too is measured with a blood test. High levels of AST may be a sign of liver injury, especially if the ALT level is also high.

  • Bilirubin. This is a liver function test. It measures the yellow substance made when the body breaks down red blood cells. Bilirubin is collected by the liver to be sent out of the body with stool. When something is wrong with the liver or bile ducts, bilirubin may build up in the body. This causes yellowing of the skin and the whites of the eyes (jaundice). Two measurements may be taken from this test: total bilirubin and direct bilirubin. A high bilirubin level may be the result of liver disease or a blockage in the bile ducts. A high indirect bilirubin can mean a condition called Gilbert syndrome. Only a small portion of people have Gilbert syndrome. Gilbert syndrome is not a sign of disease. A high indirect bilirubin can also be a sign of rapid red blood cell breakdown.

  • CBC (complete blood count). This is a test that measures all the parts of the blood. These are red blood cells, white blood cells, and platelets. Problems with these counts can mean infection or illness. They can also be a sign of a problem with the spleen. The spleen is an organ close to the liver that can be affected by liver disease. A low platelet count is common with advanced fibrosis of the liver. It also happens when the spleen becomes enlarged and begins to absorb platelets.

  • GGT (gamma-glutamyl transpeptidase). This is a liver enzyme that’s often measured along with other enzymes to gauge liver problems. GGT is measured with a blood test. If alk phos and GGT are both higher than normal, it may be a sign that the bile ducts in the liver may be diseased or blocked. It also can be a sign of fatty liver or alcohol damage.

  • Glucose. This is a sugar in the blood and the body’s most important source of energy. A healthy liver helps the body maintain a normal glucose level. If a blood test shows that glucose is low, this may mean the liver is not working properly.

  • Infectious hepatitis. This is a disease and can be found with antibody and antigen tests for Hepatitis A, B, C, D, and E.

  • PT (prothrombin time) or INR (international normalized ratio). This checks how long it takes for blood to form clots. The liver makes a protein that helps with clotting. Problems with clotting can be a sign of liver disease. 

  • 5NT (5′-nucleotidase). This is enzyme is made is several organs, but only released into the blood by the liver. A high or low level may be a sign of liver disease.

  • SBA (serum bile acid). This test measures the amount of bile acid in the blood. A high level may mean that bile ducts are blocked or that the liver is unable to excrete bile acid. This test is rarely done.

  • Vitamins A, D, E, and K. These vitamins are stored in the liver and fat and released over time (fat-soluble). They are absorbed by the liver, with help from bile. If a blood test shows that these vitamin levels are low, this could mean the liver is not absorbing them properly.

  • Zinc. This is a nutrient that is absorbed by the liver. If a blood test shows a low zinc level, this could mean the liver isn’t absorbing zinc properly. This can worsen conditions brought on by high levels of ammonia.

  • Several other lab tests may be done to check for specific liver problems once liver damage is found. These include:

    90,000 Increase in ALT and AST in liver diseases

    Alanine aminotransferase (ALT)

    The study of the activity of ALT and AST in the blood serum is extremely important for the diagnosis of liver diseases. The increase in their activity is directly proportional to the degree of liver tissue necrosis.

    The serum ALT activity is the first and most significant change in liver disease.An increase in ALT activity by 1.5-5 times compared to the upper limit of the norm is considered as moderate hyperenzymemia, 6-10 times as moderate hyperenzymemia and more than 10 times as high. The degree of elevation in ALT activity indicates the severity of liver cell necrosis, but does not directly indicate the depth of violations of the liver functions proper.

    In acute hepatitis, regardless of its etiology, ALT activity increases in all patients. At the same time, the ALT level rises 10-15 days before the onset of jaundice in viral hepatitis A, and for many weeks – in viral hepatitis B.In the typical course of acute viral hepatitis, ALT activity reaches its maximum at the 2-3rd week of the disease. With a favorable course, the ALT level is normalized after 30-40 days. Usually, in acute viral hepatitis, the level of ALT activity ranges from 500 to 3000 IU / L.

    A repeated and progressive increase in ALT activity indicates a new necrosis of liver cells or a relapse of the disease. Prolongation of the period of increased ALT activity is often an unfavorable sign, since it may indicate the transition of acute to chronic hepatitis.

    In acute alcoholic hepatitis, AST activity is higher than ALT, but the activity of both enzymes does not exceed 500-600 IU / L.

    Chronic hepatitis is characterized by moderate to moderate hyperenzymemia. In latent forms of liver cirrhosis, an increase in ALT activity may not be observed.

    In patients with toxic hepatitis, infectious mononucleosis, intrahepatic cholestasis, cirrhosis, liver metastases, AST activity is higher than ALT.

    An increase in ALT activity can also be detected in carriers of the hepatitis B surface antigen that do not have clinical manifestations, which indicates the presence of outwardly asymptomatic active processes in the liver.

    Aspartate aminotransferase (AST)

    AST also rises in acute hepatitis and other severe lesions of hepatocytes. A moderate increase is observed in obstructive jaundice, in patients with liver metastases and cirrhosis. De Ritis coefficient, i.e.That is, the ratio of ALT / AST, which is normally equal to 1.33, in liver diseases is lower than this value, and in heart diseases it is higher.

    In case of an increase in the activity of ALT and AST, we recommend that you sign up for a consultation with a hepatologist and undergo a liver examination using the Fibroscan apparatus – Liver elastometry / elastography

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    AST (AST, aspartate aminotransferase)

    AST (aspartate aminotransferase, ACAT) is an intracellular enzyme from the group of transferases, a subgroup of transaminases, which catalyzes the conversion of a-keto acids into amino acids by transferring an amino group.The enzyme catalyzes the reversible reaction of the transition of oxaloacetate to aspartate, transferring the amino group to the first molecule, the second reaction product is a-ketoglutarate. The transamination coenzyme is pyridoxal phosphate (a derivative of vitamin B6). AST is found in cells such as cardiomyocytes, hepatocytes, myocytes, neurons and nephrocytes, a small part of the enzyme is present in the cells of the pancreas, erythrocytes. As a result of cytolysis (destruction of cells), this enzyme enters the bloodstream, which makes it possible to diagnose damage to various organs by laboratory methods.In cells, AST is represented by two isoforms – cytoplasmic (about 1/3 of ACT is localized in the cytoplasm of cells), and mitochondrial (2/3 – in mitochondria). In cardiomyocytes, ACT activity is about 10,000 times higher than in serum in healthy people. In hepatocytes, the mitochondrial form of AST is mainly represented (80% of the total activity).

    An increase in the level of AST in the blood test in myocardial infarction is one of the early markers of damage to the heart muscle, although its specificity is low.If acute myocardial infarction is suspected, the biochemical indicator of AST has a diagnostic sensitivity of 96%, and a diagnostic specificity of 86% 12 hours after the onset of chest pain. Already 6-8 hours after the onset of a painful attack, the level in the AST analysis in the blood serum increases several times, the concentration peak falls at 18-24 hours, and on the 4-5th day after the onset of the disease, the AST level decreases to normal values. in the heart muscle and the level in the analysis of ACT in serum there is a direct relationship.The increase in the level of AST in dynamics indicates the expansion of the boundaries of the focus of myocardial necrosis. An increase in the level in the blood test of AST by 4-5 times in an elderly person, as a rule, indicates an acute myocardial infarction, an increase in the level in the blood test of AST by 10-15 times is an unfavorable prognostic sign. At the same time, if the increase in AST is less significant, but the activity of the enzyme persists on day 3, the prognosis is also unfavorable. Also, an increase in AST activity in myocardial infarction may indicate the involvement of other organs and tissues in the process, for example, the liver or pancreas.With myocardial infarction, the de Ritis coefficient (AST / ALT ratio) increases sharply, since, compared with AST, ALT increases insignificantly.

    Measurement of AST is also indicated for the diagnosis, differential diagnosis and monitoring of diseases of the hepatobiliary system, and injuries of skeletal muscles. The AST level often rises 20-50 times in viral hepatitis and liver diseases, accompanied by liver tissue necrosis. An increase in the level of AST in the biochemical blood test is observed with dermatomyasitis and muscular dystrophy and can reach eight times the upper limit of the norm.In other muscle diseases (for example, with a neurogenic source), the concentration of AST remains within the reference values. Pulmonary embolism can lead to an increase in the level of ACT in serum by a factor of 2-3. An increase in activity 2-5 times from the upper limit of the norm is observed in hemolytic diseases (AST activity in erythrocytes is about 15 times higher than in serum), gangrene, acute pancreatitis, muscle damage during trauma. A slight increase in the level of AST in the blood test can be observed with increased muscle load.There are certain sex differences in the level of ACT activity, the activity of the enzyme in the blood serum in women is slightly lower than in men.

    General practitioner, surgeon, pediatrician, gastroenterologist, hepatologist, cardiologist, therapist.

    Alanine aminotransferase, ALT, ALT, Transaminases in Moscow inexpensively

    Alanine aminotransferase is produced by cells of the human body to catalyze metabolic processes. The largest amount of the enzyme is formed in the liver and is normally almost completely involved in reactions.With various pathologies, the level of ALT in the blood rises. As a result, the study of alanine aminotransferase is used to diagnose acute and chronic diseases: hepatitis, diseases of the cardiovascular system, gastrointestinal tract, skeletal muscles – and to evaluate the effectiveness of the stages of their therapy.

    Analysis of the transaminase index and identification of the size of the deviation from normal values ​​is carried out in conjunction with ultrasound data, studies of markers of viral hepatitis, other indicators of biochemistry: total bilirubin, G-GTP, AST, ALP.Indications for testing are symptoms of lesion or situations of increased risk of liver damage, chronic alcoholism, previous contacts with patients with viral hepatitis, hereditary diseases, diabetes.

    Determination of alanine aminotransferase

    Transferases, which include alanine aminotransferase, or glutamate pyruvate transaminase, are involved in protein-carbohydrate metabolism – in cyclic reactions of conversion of amino acids into keto acids, transamination.The ALT enzyme exhibits high activity in the tissues of the kidneys and liver, comparatively less in the tissues of the spleen, myocardium, lungs, skeletal muscles, and pancreas. An increase in the amount of the enzyme in the bloodstream occurs when the cells of these organs are damaged: nephorones, hepatocytes, cardiomyocytes, myocytes.

    Indications for analysis ALAT

    The study of the ALT indicator is prescribed in the presence of symptoms of liver dysfunction: loss of appetite, nausea, vomiting, fatigue and weakness, pain in the right hypochondrium, yellowness of the whites of the eyes or skin, staining of feces in a light color, darkening of urine.

    Analysis of blood biochemistry for ALT is carried out to confirm the diagnosis of the following liver diseases:

    • hepatitis of a viral, autoimmune, toxic nature;
    • cirrhosis;
    • steatosis;
    • malignant neoplasms.

    Overweight patients taking drugs that are toxic to the liver, abuse alcohol, with diabetes or a history of hereditary predisposition to hepatic pathologies are also prescribed blood biochemistry with ALT determination.

    In addition, testing of alanine aminotransferase parameters is performed in the following situations:

    • diagnostics of pathologies of skeletal muscles, pancreas, kidneys, gall bladder, spleen;
    • examination of contacts for viral hepatitis;
    • examination of blood donors;
    • monitoring of medication intake;
    • inflammation, soft tissue damage: trauma, burns;
    • in the presence of shock.

    ALT study is prescribed as part of a comprehensive examination for the detection of viral infections, malignant tumors, diseases: myocardial infarction, pericarditis, myocarditis, hypothyroidism, hemolytic anemia, myopathy

    Analysis for the level of alanine aminotransferase is carried out in patients with chronic diseases before starting drug therapy. Further in the course of treatment, testing is carried out in order to control the dynamics, the tolerance of drugs, the state of the liver are checked.

    Identification of pathologies and their features by the value of transaminase

    To a large extent, the activity of the enzyme increases with medicinal and viral hepatitis. There is a proportional relationship between its amount in the bloodstream and the severity of the disease. For the diagnosis of pathologies, it is important that the ALT level exceeds the norm even before the onset of the jaundice stage. Alanine aminotransferase also increases already in the early stages of infectious and toxic hepatitis and, with favorable development, gradually decreases over several weeks.In case of liver damage due to alcohol exposure, the excess from the reference intervals is not so significant.

    Natural causes also affect the amount of transaminase in the blood. The enzyme level increases due to factors affecting the condition of the muscles, such as multiple intramuscular injections, intense exercise. Enzyme production is affected by liver-depressing drugs, dietary supplements, excessive consumption of alcoholic beverages, and food intake containing many food additives.

    Causes of deviations in the level of alanine aminotransferase from the norm

    A significant increase in the level of alanine aminotransferase can be observed in case of poisoning with potent drugs, lead, carbon tetrachloride, while taking narcotic analgesics, as well as in diseases:

    • infectious mononucleosis;
    • hepatitis, cirrhosis, cholestasis, liver cancer;
    • fatty hepatosis;
    • acute myocardial infarction;
    • pericarditis;
    • myocarditis;
    • renal, heart failure;
    • destructive pancreatitis;
    • myodystrophy;
    • myositis;
    • acute cholecystitis;
    • gallstone disease;
    • 90,059 extensive soft tissue lesions.

    An increase in the number of ALT in most cases indicates damage to hepatocytes and disruption of their normal functioning. Metabolic pathologies cause liver infections, autoimmune processes, neoplasms, diseases that provoke ischemia, circulatory disorders, the use of substances toxic to the liver.

    Hepatotoxic drugs: alcohol, food additives, psychotropics, anabolic steroids, COCs, immunosuppressants, antibiotics, anesthetics.

    Reasons for a decrease in the level of alanine aminotransferase:

    • liver necrosis;
    • decompensated cirrhosis;
    • deficiency of vitamin B₆ in the body.

    Extensive liver damage leads to a decrease in the number of hepatocytes and, as a result, to a decrease in the level of ALT in the tissues of biological fluids of the body. Vitamin B₆, along with ALAT, is involved in transamination, therefore, for the normal activity of the enzyme, its intake with food should be sufficient.

    Treatment of pathologies causing abnormal ALT levels

    Deciphering the result of the analysis of biochemistry for ALT is carried out in conjunction with the results of complex biochemistry, data on aspartate aminotransferase.The following specialists are involved in the therapy of diseases that cause an increase or decrease in the level of transaminase in the blood: hepatologists, cardiologists, gastroenterologists, endocrinologists, nephrologists, infectious disease specialists, therapists.

    Treatment is aimed at eliminating the causes of pathological processes. Medicines are combined with dietary food. For liver diseases, drugs are prescribed that improve digestion, choleretic, hepatoprotectors. Most of the prescriptions are plant foods rich in vitamins, especially vitamins B₆ and D.The amount of salt and animal fats is limited. It is important to exclude nicotine, alcohol, hepatotoxic substances, the intake of which is not agreed with the doctor.

    Symptoms of heart muscle damage associated with an increase in alanine aminotransferase require the consultation of a cardiologist. In this case, the doctor additionally prescribes echocardiography, electrocardiography (ECG), blood tests for troponin I, MV-CPK. Clarification of the diagnosis of damage to the musculature of the skeleton is carried out by a rheumatologist. In addition to ALT, the level of the enzyme creatine kinase is studied.

    Preparation for analysis

    There are no contraindications to the study of ALT, but taking a biomaterial is not recommended without performing a set of preparatory measures. Blood is drawn from a vein in the morning on an empty stomach. The last meal with limited fat and no alcohol should be 8-14 hours before manipulation. During the period of abstinence, it is allowed to drink non-carbonated water. In the hour interval preceding the procedure, smoking, emotional and physical stress are excluded.Data on the intake of medications relevant for testing are reported to the doctor. Biochemistry is not performed after massage, physiotherapy, X-ray and ultrasound studies. It is allowed to take the analysis in the daytime if the previous meal was lightweight.

    Donate blood biochemistry for alanine aminotransferase

    We invite you to take a biochemical blood test for ALT in one of our medical centers within walking distance of the metro ring stations. Our clinics are equipped with high-tech equipment and professional staff.We offer accurate blood sampling, accurate testing, low prices. Contact us!

    GENERAL RULES FOR PREPARATION FOR BLOOD ANALYSIS

    Blood is taken from a vein. General recommendations must be followed:

    • blood is donated in the morning on an empty stomach or not earlier than 2–4 hours after a meal;
    • it is allowed to use water without gas;
    • on the eve of the analysis, alcohol should be abandoned, physical and emotional overstrain should be excluded;
    • to quit smoking 30 minutes before the study;
    • It is not necessary to donate blood during the period of taking medications, unless the doctor has prescribed otherwise.

    Biochemical analysis AST | Donate blood for alanine aminotransferase to the “LABOR MEDICINE CENTER”

    1. When is the AST test prescribed?

    As already noted, aspartate aminotransferase is found in all tissues of the body. The highest concentration of this enzyme is observed in the liver, heart, erythrocytes, the lowest in the skin, kidneys, and pancreas. Changes in the content of aspartate aminotransferase in the test samples and differences in the detected values ​​from the norm may indicate pathologies.

    With the help of the AST analysis, the following are most often diagnosed:

    1. Liver diseases. The concentration of aspartate aminotransferase in the tissues of this organ is high, therefore, when cells are destroyed, the enzyme begins to be released into the bloodstream. As a result, its concentration in the blood rises sharply.

    Important!
    Changes in ALT and AST levels in viral hepatitis and a number of other liver pathologies appear earlier than common visual symptoms: yellowing of the skin, sclera.

    In addition to hepatitis, the AST analysis allows us to suspect and timely diagnose liver cirrhosis, various formations (benign and malignant, primary and metastatic), toxic liver damage due to the intake of drugs or other substances.

    2. Heart disease. Increased AST activity is one of the earliest indicators of myocardial infarction. The enzyme content in these cases increases and can exceed the norm by 10-15 times.It is also important that the activity of aspartate aminotransferase is directly related to the size of the necrosis focus in the heart muscle.

    In addition to myocardial infarction, AST analysis can be used indirectly to help diagnose myocarditis, severe congestive heart failure, and heart muscle injuries.

    3. Muscle diseases. These include, for example, progressive muscular dystrophy and dermatomyositis. In these cases, the AST analysis is used as an additional diagnostic method.

    4. Diseases of the biliary tract. Changes in the content of aspartate aminotransferase make it possible to suspect and diagnose cholelithiasis, tumors and kinks of the biliary tract.

    AST analysis in progress:

    • as part of regular preventive screening;
    • for planned hospitalization;
    • before surgery;
    • to monitor the effectiveness of treatment.

    It is also prescribed for patients who plan to become blood donors.

    AST analysis can be carried out both separately and in combination with other types of diagnostics. Most often it is carried out together with ALAT. Based on the results of these studies, the de Ritis coefficient is calculated, which is important for the diagnosis of diseases.

    2. How to prepare for the procedure?

    There are several guidelines to follow before visiting a medical center:

    1.AST analysis is taken on an empty stomach. It is preferable to do this in the morning. At the same time, at least 8 hours should pass from the moment of the last meal. There are no restrictions on water intake.

    Important!
    In some cases, doctors are allowed to take the test 4-6 hours after a light meal. The decision on the possibility of such an approach is made by the doctor.

    2.At least 1 day before contacting the laboratory, you should change the diet. All alcoholic beverages should be excluded from it. You should also give up sweets.

    3. At least 1 hour before the analysis, you should reduce to a minimum physical activity and stop smoking.

    Compliance with these requirements ensures the highest accuracy of the study and allows you to exclude the main reasons that increase or decrease the content of AST in the blood.

    3. How long does the procedure take?

    Collecting samples for testing usually takes a few minutes. After that, they are sent to our laboratory, where experienced doctors study them. The patient receives the results of the AST analysis within 1 day.

    4. How to ensure the most accurate result?

    The concentration of AST in the blood, even in healthy people, can be influenced by various factors:

    1. Physical and psychological stress.They can lead to elevated AST levels and should be avoided.
    2. Diagnostic and therapeutic procedures. The concentration of AST can be affected by X-ray studies, including fluorography, as well as a number of other physiotherapeutic procedures. If you took them shortly before contacting the medical center, be sure to inform your doctor about it.
    3. Drinking alcohol and smoking. They should be discarded 1 day and 1 hour before the procedure, respectively.
    4. Taking medications. For example, antibiotics, oral contraceptives, anti-inflammatory and antineoplastic agents can change the level of AST in the blood. If you are taking ANY medications, be sure to tell your doctor. If possible, they should be canceled before analysis.
    5. Important!
      Consult your healthcare professional before making any changes to your medication program.

    6. Postponed heart surgery. The doctor should be notified about their implementation.

    5. How is the procedure going?

    For AST analysis, blood samples are taken from a vein. The collection process takes a few minutes. After that, the samples are sent for testing to the laboratory. Usually, doctors simultaneously determine the content of ALT and AST, and also calculate their ratio (de Ritis coefficient).The patient receives the results in person and / or by email.

    Age, gender AsAT, U / l
    <5 days <97
    5 days – 6 months <77
    6-12 months <82
    1-3 years <48
    3 years – 6 years <36
    6 – 12 years old <47
    Women 12-17 years old <25
    Women > 17 years old <31
    Men 12-17 years old <29
    Men > 17 years old <29

    The ratio of AST and ALT (de Ritis coefficient) is normally from 0.91 to 1.75.

    The content of aspartate aminotransferase in the blood varies depending on the sex and age of the patient. This is taken into account when calculating the normal values. If the deviation from the norm is small, therapy is not prescribed. However, the doctor may recommend that the patient make lifestyle changes, such as adjusting their diet or limiting alcohol consumption.

    Important!
    Interpretation of test results is not a diagnosis.The information obtained after the examination is intended for the attending physician. It should not be used for self-diagnosis and treatment. The attending physician should determine the disease and develop a therapy program based on the analysis and results of the entire set of studies.

    7. What should be done in case of significant deviations of AST indices from the norm?

    There are two main types of deviations:

    1.The AST level is significantly below normal. Low values ​​may indicate serious necrotic processes in the liver. They can occur as a result of the terminal stage of cirrhosis or other pathology. Low AST values ​​are also observed after repeated hemodialysis, as well as with a lack of vitamin B6 in the body.

    2. An increased level of aspartate aminotransferase is usually observed at

    • myocardial infarction;
    • congestive heart failure, cardiac liver fibrosis;
    • viral and toxic hepatitis;
    • formations of the liver and bile ducts;
    • acute pancreatitis;
    • ischemic or hemorrhagic stroke.

    Indicators exceeding the norm are also noted

    90,058 90,059 in pregnant women;

  • when taking drugs that cause cholestasis.
  • 8. Additional research

    If the results of the analysis do not correspond to the norm for the sex and age of the patient, you should consult a hepatologist, gastroenterologist, therapist.You can make an appointment with a specialist in our center. If necessary, you can also get advice from doctors of a related profile.

    Patients with abnormal AST levels are usually prescribed additional types of diagnostics:

    1. 1. Blood test for other indicators.
    2. 2. Blood test for viral hepatitis.
    3. 3. Ultrasound of the abdominal organs.

    You can undergo all the necessary types of diagnostics in our medical center.

    90,000 ALT with up to 50% discount

    Deadline

    Analysis will be ready in
    within 1 day, excluding the day of collection.
    The term can be extended by 1 day if necessary.You will receive the results by email. mail immediately when ready.

    Deadline: 2 days, excluding Saturday and Sunday (except for the day of taking the biomaterial)

    Preparation for analysis

    In advance

    Do not take a blood test immediately after radiography, fluorography, ultrasound, physiotherapy.

    The day before

    24 hours before blood sampling:

    • Limit fatty and fried foods, do not drink alcohol.
    • Avoid strenuous physical activity.

    From 8 to 14 hours before donating blood, do not eat, drink only clean non-carbonated water.

    On the day of donation

    Before taking blood

    • No smoking for 60 minutes,
    • Be quiet for 15-30 minutes.

    Analysis Information

    Indicator

    ALT is a test that is used to assess liver function. An increase in ALT in the blood in a certain proportion with another enzyme, AST may also indicate a previous heart attack.

    Appointments

    As a rule, it is necessary after prolonged use of medications, interaction with toxic substances (including alcohol), in the diagnosis of hepatitis, suspicion of pancreatitis.

    Specialist

    It is prescribed both in a complex of biochemical analyzes, and separately, by a therapist or hepatologist.

    Important

    The results of the analysis are very noticeably influenced by food intake, therefore it is important to strictly abstain for 12 hours before taking blood.

    Research method – UV kinetic test

    Material for research
    – Blood serum

    Composition and Results

    ALT

    Find out more about biochemical blood tests:

    Do’s and don’ts before a blood test?

    How to decipher general and biochemical blood tests?

    Biochemical blood tests – meaning and importance

    ALT is an enzyme from the aminotransferase group that is responsible for amino acid metabolism and is produced intracellularly.Normally, the level of ALT in the blood is negligible, and the highest level of the enzyme is observed in the liver cells. Therefore, with an increase in the concentration of ALT in the blood, the first suspicion falls on asymptomatic lesions of this particular organ. As a rule, this analysis is necessary after prolonged use of medications, interaction with toxic substances (including alcohol), in the diagnosis of hepatitis, suspicion of pancreatitis.

    An increase in ALT in the blood in a certain proportion with another enzyme, AST (aspartate aminotransferase) may also indicate a heart attack.The results of the analysis are very noticeably influenced by food intake, therefore it is important to strictly abstain for 12 hours before taking blood.

    ALT (alanine aminotransferase, ALAT) is an intracellular enzyme from the group of transferases, a subgroup of transaminases, which catalyzes the conversion of a-keto acids into amino acids by transferring amino groups. Normally, only a small part of this enzyme is lost into the blood. The enzyme is present mainly in the cytoplasm of hepatocytes, but it is also found in the cells of skeletal muscles and myocardium.The biochemical activity of ALT in the liver is almost 10 times higher than in the myocardium and skeletal muscles, therefore, an increase in the level of ALT in the blood is considered mainly as an indicator of damage to the liver parenchyma. When liver cells are damaged, the integrity of their membrane is disrupted and ALT enters the bloodstream. ALT has a greater diagnostic sensitivity in diseases of the hepatobiliary system than AST.

    If the biochemical blood test ALT (ALAT) showed an increase in ALT activity 50 times or more, then this can mainly be due to acute impairment of hepatic perfusion, acute necrosis of hepatic cells caused by exotoxins, including paracetamol and carbon tetrachloride, viral hepatitis, infectious mononucleosis.An increase in the concentration of ALT in the blood is diagnostically significant, since its level increases even before the appearance of other clinical symptoms of liver diseases (jaundice, etc.). In viral hepatitis, an increase in enzyme activity occurs at a very early time – in the prodromal period (observed in 50% of patients – 5 days, in 90% – 2 days before the clinical manifestation of the disease).

    High ALT and AST values ​​in the results of a biochemical blood test are also observed in toxic hepatitis, especially in severe cases.A moderate increase in transaminases is observed with alcoholic liver damage. Depending on the stage of the cirrhotic process, the levels of ALT and AST can be either at the upper limit of the norm, or in 4-5 times increase from the upper limit (the level of AST is higher than ALT). In patients with primary or metastatic liver carcinomas, an increase in the activity of transaminases by 5-10 times is observed, however, there are cases when their level remains within the normal range, mainly in the early stages of malignant organ infiltration.The level in the blood test ALT (ALAT), exceeding more than 15 times the upper limit of the norm, is always an indicator of acute hepatocellular necrosis of toxic, viral or circulatory origin.

    An increase in the level in the analysis of ALT is also observed in myocardial infarction, since this enzyme is also contained in the heart muscle, however, its increase compared to AST is insignificant, since the activity of ALT in cardiomyocytes, in contrast to AST, is low. In uncomplicated myocardial infarction, ALT (ALAT) levels in the blood test remain within normal limits or a slight increase is observed.An increase in the concentration of the enzyme in serum during myocardial infarction may indicate the development of congestion in the liver.

    You can take a biochemical blood test for ALT and AST enzymes in the Lab4U online laboratory at prices with a discount of up to 50%.

    ALT (ALT, Alanine aminotransferase, alanine transaminase, SGPT, Alanine aminotransferase)

    Study material
    Blood serum

    Method of determination
    Kinetic UV test (optimized, standardized by DGKC).

    Intracellular enzyme involved in the exchange of amino acids.

    Catalyzes the transfer of the amino group of alanine to alpha-ketoglutaric acid to form pyruvic acid and glutamic acid. Transamination occurs in the presence of a coenzyme – pyridoxal phosphate – a derivative of vitamin B6.

    The highest ALT activity is detected in the liver and kidneys, the lowest – in the pancreas, heart, skeletal muscles.The enzyme activity in women is slightly lower than in men. ALT is an intracellular enzyme; its content in the blood serum of healthy people is low. But when cells rich in ALT (liver, heart muscle, skeletal muscles, kidneys) are damaged or destroyed, these enzymes are released into the bloodstream, which leads to an increase in their activity in the blood.

    In viral hepatitis, the increase in ALT activity is usually proportional to the severity of the disease. In acute cases, the activity of the enzyme in the blood serum may exceed normal values ​​by 5-10 times or more.In viral hepatitis, an increase in the activity of the enzyme occurs at a very early date – even before the onset of jaundice.