Home Medicine Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
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Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review

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Published/Copyright: June 12, 2023
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From the journal Open Medicine Volume 18 Issue 1

Abstract

Tusanqi-induced hepatic sinusoidal obstruction syndrome (HSOS) is caused by exposure to pyrrolizidine alkaloids (PAs) and manifests as abdominal distension, liver pain, ascites, jaundice, and hepatomegaly. Pathologically, hepatic congestion and sinusoidal occlusion are observed in HSOS. We summarized the clinical characteristics of 124 patients with HSOS caused by Tusanqi in China between 1980 and 2019, along with those of 831 patients from seven English case series. The main clinical manifestations of PA-HSOS included abdominal pain, ascites, and jaundice. Common imaging features included characteristic heterogeneous density, slender hepatic veins, and other nonspecific changes. The acute stage is primarily manifested as hepatic sinus congestion and necrosis. Meanwhile, the persistence of hepatic sinus congestion and the onset of perisinusoidal fibrosis were observed during the repair stage. Finally, the persistence of hepatic sinusoidal fibrosis and resultant central hepatic vein occlusion were observed in the chronic stage. The new Nanjing standard for PA-HSOS incorporates the history of PA consumption and imaging features and eliminates weight gain and the serum total bilirubin value. Preliminary clinical validation of the Nanjing standard for PA-HSOS diagnosis revealed a sensitivity and specificity of 95.35 and 100%, respectively.

Keywords: hepatic sinusoidal obstruction syndrome; pyrrolizidine alkaloid; Tusanqi; drug-induced liver injury

1 Introduction

Herb and dietary supplement-induced liver injury (HILI) is the main cause of drug-induced liver injury (DILI) in China, with an incidence rate of 23.8 cases per 100,000 residents, which is higher than that in Western countries [1]. Diagnosing DILI, especially HILI, is challenging because of the lack of characteristic clinical features and specific tests for this condition. Among the different hepatotoxic herbs, the pyrrolizidine alkaloid (PA)-containing herb [2], Gynura japonica or Tusanqi, can cause abdominal distension, liver pain, ascites, jaundice, and hepatomegaly. Recent studies have suggested that the pathophysiologic mechanism of Tusanqi is related to that of hepatocellular carcinoma [3]. The symptoms observed are mainly because of sinus endothelial injury, congestion, and hepatic sinusoidal obstruction syndrome (HSOS). This review describes the clinical and pathological features of PA-HSOS and discusses its diagnosis based on case studies.

2 Epidemiology

Exposure to PAs has been identified as one of the two major causes of HSOS [1,4]. PAs are common plant toxins that are widely distributed in up to 13 distantly related angiosperm families in the plant kingdom, including approximately 3% of flowering plants [5]. Humans are exposed to PAs through direct consumption of PA-containing plants [6,7] used as herbal medicines, herbal teas, and dietary supplements or through the ingestion of PA-contaminated foods [8,9], such as milk, tea, and honey. The earliest case of PA-induced HSOS was reported in 1920 and was caused by the ingestion of PA-contaminated wheat [10]. Since then, over 15,000 PA poisoning cases have been recorded in several countries and regions, including Afghanistan, Britain, China, Germany, Hong Kong (China), India, Jamaica, South Africa, Switzerland, and the United States [11]. In China, the main cause of HSOS is the ingestion of PA-containing herbal medicine (Gynura japonica, Tusanqi), which accounts for 50–89% [12] of the reported HSOS cases [13–18]. Between 1980 and 2019, a total of 2,156 Tusanqi-induced HSOS cases were reported in China: (1) 91 Tusanqi-induced HSOS case reports, involving 124 patients; (2) 87 Tusanqi-induced HSOS case series, involving 1,645 patients; and (3) 24 case series of Tusanqi-related HSOS (caused by mixed etiologies, including Tusanqi), involving 387 patients [19].

3 Pathogenesis

PA is mainly composed of senilin and senilic acid and can be classified into two types: unsaturated and saturated PA. Saturated PA is generally considered to be non-hepatotoxic. However, unsaturated PA is genotoxic, carcinogenic, and hepatotoxic in humans and animals [20]. The prototype compound of unsaturated PA is less toxic as it is oxidized, nitroxidized, and demethylated to dehydropyrrolizidine alkaloids (DHPAs) by CYP3A (P450 cytochrome) in the liver and then hydrolyzed to dehydropyrrole and dehydroretronecine (DHR) [21,22], both of which bind to proteins to form pyrrole–protein adducts (PPAs) [23,24] that damage sinusoidal endothelial cells (SECs). SEC’s damage marks the beginning of PA-HSOS; thus, the protection of SECs can prevent the development of PA-HSOS [25,26]. The initial damage to SECs can be attributed to F-actin depolymerization caused by the covalent binding of PA-reactive metabolites to F-actin. Some studies have suggested that overexpression of thrombospondin 1 plays an important role in early SEC injury [27]. Since actin has a major role in maintaining the normal morphology of SECs, its depolymerization makes SECs more rounded and induces the release of matrix metalloproteinase-9 (MMP-9) [28,29]. Upregulation of MMP-9 leads to extracellular matrix (ECM) degradation in the space of Disse between the SECs and hepatocytes [30]. Morphological changes in endothelial cells and degradation of the ECM result in disruption of the liver sinusoidal barrier and efflux of red blood cells into the discharge space. Subsequent SEC necrosis, shedding, and obstruction of the hepatic sinusoids lead to PA-HSOS. In addition, the vascular endothelial growth factor (VEGF) upregulates the expression of MMP-9 by activating SECs [31]. The upregulation of MMP-9 is also associated with persistent extracellular regulated protein kinase 1/2 phosphorylation and decreased hepatic venous nitric oxide concentration [32]. The inhibition of MMP-9 production may be used as a target for the prevention and treatment of PA-HSOS. It has been reported that MMP-9 inhibitors can prevent PA-HSOS induced by monocrotaline in animal models [33]. In addition, distinct hepatic endothelial cell populations (Kupffer cells, SECs, and hepatic stellate cells) are required for complete microvascular function. SECs are unique endothelial cells that function as scavenger cells, removing circulating waste molecules and antigens. Under the synergistic effect of Kupffer and hepatic dendritic cells, they may also be involved in the immune regulatory function of the liver [34]. When SECs are damaged, their associated functions are no longer performed, contributing to the pathogenesis of PA-HSOS. After unsaturated PAs enter the human body, they can form electrophilic DHPA and DHR mediated by CYP3A. These proteins bind to form PPAs, which then damage SECs, thereby initiating PA-HSOS. Under the action of PA-reactive metabolites, F-actin depolymerization and MMP-9 upregulation damage the SECs shed and block hepatic sinusoids, exacerbating PA-HSOS. SEC’s dysfunction also further aggravates PA-HSOS. Besides, PAs damage hepatocytes through cytoskeleton necrosis and collapse [35] and induction of apoptosis [36] contributing to the development of PA-HSOS as shown in Figure 1.

Figure 1 Pathogenesis of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome (PA-HSOS). DHR: dehydroretronecine, DHPA: dehydropyrrolizidine alkaloids, PPA: pyrrole–protein adducts, MMP-9: matrix metalloproteinase-9, VEGF: vascular endothelial growth factor, NO: nitric oxide.
Figure 1

Pathogenesis of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome (PA-HSOS). DHR: dehydroretronecine, DHPA: dehydropyrrolizidine alkaloids, PPA: pyrrole–protein adducts, MMP-9: matrix metalloproteinase-9, VEGF: vascular endothelial growth factor, NO: nitric oxide.

4 Clinical manifestations

We summarized the clinical characteristics of 124 patients with HSOS caused by Tusanqi in China between 1980 and 2019 [19], along with those of 831 patients from seven English case series [12,37–42] (Table 1). The data of 124 patients from 74 institutions across 20 provinces and regions in China were analyzed. The clinical features of patients with Tusanqi-induced HSOS ranged from asymptomatic to severe. Symptoms usually appeared a few days to several years after ingestion of Tusanqi. The most common clinical features were typical HSOS symptoms, including ascites, hepatomegaly, and jaundice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and total bilirubin (TBIL) were measured. Some patients presented with mildly decreased serum albumin (ALB) levels and a prolonged prothrombin time (PT). Most patients underwent ultrasonography and computed tomography (CT) to diagnose HSOS. Meanwhile, liver biopsies were not universally performed.

Table 1

Demographic information, clinical manifestation, and laboratory tests of PA-induced HSOS

Reference Zhu et al. [19] Wang et al. [37] Zhuge et al. [51] Song et al. [38] Wang et al. [39] Zhang et al. [40] Peng et al. [41] Kan et al. [42]
Number (n) 124 117 108 116 84 86 249 71
Gender (male/female) 68/56 78/39 66/42 78/38 45/39 49/37 148/101 48/23
Age (year) 54.16 ± 21.52 63 (52.5–69)1 61 (55–69)1 56.92 ± 12.392 52.97 ± 15.282 65 (60–75) 64 56.48 ± 11.84
Clinical manifestation
Ascites 100% (124/124) 99.1% (116/117) 98% (50/51) 100% (79/79) 100% (83/83) 100% (86/86) 100% (249/249) 100% (71/71)
Hepatomegaly 64.8%(79/124) 70% (82/117) 92% (47/51) 75.95% (60/79) 65.1% (54/83) 88.4% (220/249 78.87 (56/71)
Abdominal distention 98.3% (115/117) 99.1% (107/108) 98.3% (113/115) 99.2% (247/249) 100% (71/71)
Jaundice 57.4% (70/124) 39.8% (43/108) 52.9% (54/102) 57.8% (48/83) 40.1% (100/249)
Right upper quadrant pain 19.7% (23/117) 36.4% (40/110) 34.1% (85/249) 61.97% (44/71)
Edema 41.0%(50/124) 39.3% (46/117) 39.5% (43/109) 37.3% (31/83) 36.62% (26/71)
Weight gain 18% (21/117) 15.5% (16/103) 11.59% (8/69)
Laboratory tests
Variable Mean ± SD Median (25–75th percentiles) Median (25–75th percentiles) Mean ± SD Mean ± SD Median (25–75th percentiles) Mean ± SD Mean ± SD
ALT (U/L) 236.59 ± 385.08 49 (25.0–152.5) 52.6 (26.8–125) 134.50 ± 154.89 216.83 ± 235.78 40.9 (25.98–70.88) 132.09 ± 181.72 132.24 ± 155.83
AST (U/L) 222.15 ± 329.27 75 (39.0–158.5) 69.6 (42.4–115) 146.31 ± 156.30 221.15 ± 221.70 56.7 (38.25–91) 129.04 ± 184.08 148.00 ± 161.18
ALP (U/L) 180.50 ± 112.19 122 (86.8–191.3) 130 (105–178) 170 ± 106.89 183.48 ± 59.96 166.66 ± 80.49 177.91 ± 119.59
γ-GT (U/L) 131.96 ± 138.93 100.7 (61.8–164.8) 120 (72.4–170) 160.52 ± 114.56 155.70 ± 99.45 172.27 ± 128.21
TB (μmol/L) 64.72 ± 91.08 33.3 (19.7–47.0) 39.7 (28.3–62.4) 65.07 ± 78.83 52.96 ± 45.95 33.7 (22.38–46.2) 39.94 ± 28.87 69.81 ± 69.16
ALB (g/L) 32.25 ± 6.31 30.6 (27.7–33.6) 32.1 (29.8–34.7) 30.71 ± 5.50 32.02 ± 4.51 33.15 ± 4.31 30.76 ± 6.05
PT (s) 17.93 ± 7.51 14.8 (12.7–17.0) 15.1 (14.2–16.7) 17.43 ± 2.64 18.08 ± 4.12 14.55 (13–16.93) 16.01 ± 3.97 17.58 ± 2.87
PLT (109/L) 113 (78–153) 95 (74–134) 114.06 ± 63.48 99.5 (72.5–133.25) 115.32 ± 49.01 117.67 ± 64.60

ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; γ-GT: γ-glutamyl transpeptidase; TB: total bilirubin; ALB: albumin; PT: prothrombin time; PLT: platelet.

5 Imaging features

Imaging features establish the diagnosis of PA-HSOS and are thus necessary for the examination of patients with this condition. Typical two-dimensional ultrasonography findings of PA-HSOS included [17]: diffuse hepatomegaly; hepatic parenchyma echogenicity showing thickening, increased density, and uneven distribution, with “patch-like” areas of reduced echogenicity along the hepatic veins; and ascites. Color Doppler ultrasonography showed normal portal and splenic vein diameters and reduced blood flow (<25 cm/s) [43]. Contrast-enhanced ultrasonography showed uneven enhancement during the arterial phase and slow filling of the portal vein and hepatic artery, in addition to prolonged arterial–hepatic vein transit time [43].

Typical CT findings included the following [42,44]: (1) diffuse hepatomegaly and non-uniformly reduced liver parenchyma density were observed on the plain scan; (2) liver parenchyma during the venous and equilibrium phases was characterized by a “map-like appearance,” “mottling-like” uneven enhancement, and low-density edema around the portal vein called the “halo sign”; (3) the caudate and left lateral lobes of the liver were slightly affected, liver parenchyma around the hepatic vein showed a high degree of enhancement, exhibiting the characteristic “clover sign,” lumen of the hepatic vein was narrow or unclear, and hepatic segment of the inferior vena cava was compressed and thinned out; and (4) extrahepatic signs, such as ascites, pleural effusion, gallbladder wall edema, and gastrointestinal wall edema, were also seen in combination. Patients in the acute stage had less complications, such as splenomegaly and esophagogastric varices, than those in later stages.

Typical magnetic resonance imaging (MRI) findings included [45] an enlarged liver and massive ascites on the plain scan, uneven liver signals, and slender or unclear hepatic veins. T2-weighted imaging also showed patchy high signals forming a “cloud” shape. An MRI dynamic enhanced scan showed uneven enhancement during the arteriovenous phase, forming a “piebald” shape, and enhancement was more evident during the delayed phase.

6 Clinical staging

Based on their clinical symptoms, the disease was divided into acute, subacute, and chronic stages. The staging criteria were as follows: (1) In the acute stage, early manifestations included weight gain, hepatomegaly, tenderness, and abnormal liver function. Patients also manifested abdominal distension, ascites, and jaundice. (2) In the subacute stage, persistent hepatomegaly, recurrent ascites, and liver dysfunction due to mild-to-severe or acute injury were observed. (3) In the chronic stage, the disease involved progression to liver cirrhosis, occurrence of hypersplenism, development of esophagogastric varices, and persistence of ascites.

7 Histopathological findings

A systematic description of pathological changes in the liver in PA-HSOS is lacking. One reason is that PA-HSOS has a high risk of puncture during the acute stage, and coagulation parameters and degree of ascites affect the decision to perform a liver biopsy. Although percutaneous or transjugular liver biopsy can reduce the risk of liver hemorrhage, technical difficulties preclude its use as a routine procedure. Besides, the diagnosis of PA-HSOS does not depend on liver pathology results. A study of 16 patients from a single center in China described pathological changes in the liver caused by PA-HSOS [46].

In the early stage, hematoxylin–eosin (HE) staining showed that hepatic sinusoids were dilated and congested at the center of the hepatic lobule. CD31 immunohistochemical staining showed that sinusoidal endothelium was incomplete, and reticular fiber staining showed numerous slender reticular fibers interspersed between red blood cells. Meanwhile, hepatic sinusoids without reticular fibers were narrowly compressed. In mild cases, a greater number of hepatic plates and sinusoids remained. In cases of severe hemorrhage, sinusoidal endothelium was completely destroyed, perisinusoidal space and sinusoids were not easily distinguished, and many hepatic sinusoids were interspersed with reticular fibers. Red blood cells obstructed the sinus cavity, most of the hepatic plate in the central lobular zone was necrotic and disappeared, and the hemorrhage fused into a sheet. In severe cases, two zones or even one may be involved. CD34 staining showed that the central vein endothelium was either partially or completely lost. Subendothelial hemorrhage, edema, and many red blood cells were also observed. The lumen of the blood vessels was either narrow or occluded.

In the middle stage, erythrocytes in the hemorrhagic zone were lysed, reticular fibers were collapsed and dense, collagen fibers were gradually deposited, lacunae with blood flow were congested and expanded, and some lacunae were covered with sinus endothelial cells (CD31 positive, CD34 negative). A portion of the ischemic liver plate gradually atrophied and underwent necrosis; thus, blood supply remained sufficient. These findings were observed in adjacent rows. Some hepatic sinusoids around the bleeding zone underwent compensatory dilatation and lacunar enlargement. Red blood cells within the endothelium of the central vein disappeared, and the subendothelial filling was massive. Reticular fibers progressed from edematous stenosis to fibrous stenosis. Although most of the lumen was completely occluded, the growth of a few small blood vessels was observed.

In the late stage, a large amount of collagen was deposited into the hemorrhagic zone. The remaining liver plate was gradually repaired by widening and regeneration in zones of light hemorrhage. In severe cases, large areas of fibrous scar form and can be seen lining the vascular endothelium (CD34 positive) of most dilated cavities. Hepatocytes in the marginal zone regenerated in adjacent rows and were gradually incorporated into the fibrous septum. The subendothelial collagen in the central vein became dense, and the lumen recanalized and gradually enlarged.

Counting and staging of hemorrhagic zones showed that the same patient can simultaneously have early, middle, and late hemorrhagic zones and that the changes in hepatic sinusoids and central veins are synchronized. Patients with a high proportion of fresh hemorrhagic lesions have a relatively short disease course. In contrast, fibrotic lesions are characterized by late bleeding; thus, patients with a high proportion of fibrosis had a relatively long disease duration.

Findings also varied depending on the degree of lobular hemorrhagic injury. In cases of mild injury, central lobular atrophy and narrowing of the hepatic plate were observed, and hepatic plates were continuous or mostly discontinuous. In moderate injury, central lobular atrophy was observed, and the hepatic plate disappeared but zone 2 expansion did not occur. In severe cases, the hepatic plate atrophied, the central lobular band disappeared, and expansion to zone 2 or even zone 1 occurred.

8 Case analysis

8.1 Case 1

A 52-year-old man ingested “Tusanqi powder” at a dose of 5 g one to two times daily because of an injury sustained from a fall. Eight days later, he developed fatigue, abdominal distension, and abdominal pain. His coagulation indices were as follows: PT: 19.0 s, prothrombin activity (PTA): 42%, and international normalized ratio (INR): 1.87. On biochemical testing, his results were as follows: estimated value of the glomerular filtration rate: 98.47 mL/min/1.73 m2, TBIL: 108.9 µmol/L, direct bilirubin (DBIL): 65.4 µmol/L, ALB: 26.0 g/L, globulin: 33.4 g/L, ALT: 645 U/L, AST: 477 U/L, ALP: 148 U/L, and GGT: 251 U/L. The CT scan showed that the density of the liver parenchyma was unevenly reduced. The liver parenchyma in the arterial and venous phases showed a characteristic “map-like” appearance and uneven enhancement, and the hepatic veins were thin and unclear. Enlarged lymph nodes in the porta hepatis were observed. A liver biopsy was performed on the 10th day of the disease. Early pathological changes were observed in the specimen of the patient who underwent liver biopsy during the acute stage. Hepatocytes exhibited hemorrhagic necrosis and were fused into sheets. As hepatocytes separated, numerous red blood cells infiltrated the perisinusoidal space, and the perisinusoidal space expanded and compressed the hepatic sinus. The sinus cavity and perisinusoidal space fused and became indistinguishable, and the hepatic sinusoid appeared dilated and congested. Hemorrhagic necrosis was observed on HE staining (Figure 2). After the diagnosis of HSOS was established, treatment with low-molecular-weight heparin combined with warfarin was initiated; however, the condition of the patient continued to deteriorate. Complications, such as hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, occurred, and the patient died on the 30th day of the disease.

Figure 2 CT and pathological features in case 1. (a) CT scan shows diffuse hepatomegaly, heterogeneous density of the liver parenchyma, unclear delineation of the hepatic vein, and ascites (*). (b) Histopathology results reveal congestion, hemorrhage (white arrow), and coagulation-like necrosis (black arrow) in the central area of the liver (HE staining, 10 × 10).
Figure 2

CT and pathological features in case 1. (a) CT scan shows diffuse hepatomegaly, heterogeneous density of the liver parenchyma, unclear delineation of the hepatic vein, and ascites (*). (b) Histopathology results reveal congestion, hemorrhage (white arrow), and coagulation-like necrosis (black arrow) in the central area of the liver (HE staining, 10 × 10).

8.2 Case 2

A 49-year-old man ingested 3 g of “Tusanqi powder” three times daily for 2 months. Subsequently, the patient developed fatigue, abdominal distension, and abdominal pain. The laboratory findings were as follows: TBIL: 34.6 µmol/L, DBIL: 18.73 µmol/L, ALB: 34.2 g/L, ALT: 446 U/L, AST: 543 U/L, ALP: 116.0 U/L, GGT: 103 U/L, PT: 14.0 s, PTA: 77.8%, and INR: 1.13. CT showed diffuse hepatomegaly and unevenly reduced density of the liver parenchyma. The liver parenchyma during the arterial and venous phases showed a characteristic “map-like” appearance and uneven enhancement. The hepatic veins were unclear, and ascites were present. After admission, the patient was diagnosed with HSOS and treated with low-molecular-weight heparin and warfarin. After 1 month of treatment, the patient’s clinical symptoms disappeared and biochemical indices and imaging findings returned to normal. Warfarin was administered orally and monitored weekly to achieve an INR between 2.0 and 2.5. Three months after the patient was treated, a liver biopsy revealed that most liver tissues did not exhibit obvious inflammation and necrosis. Only a few areas still showed congestion in the hepatic sinus, with patchy and band-like inflammation and necrosis. Fibrotic embolism was observed in the central vein, and perisinusoidal fibrosis was also noted (Figure 3c and d).

Figure 3 CT and pathological features in case 2. (a) CT scan shows heterogeneous density of the liver parenchyma, unclear clover-like enhancement of the hepatic vein, and ascites (*). (b) In the third month of the disease course, the CT scan shows homogenous density of the liver parenchyma and clearly exposed hepatic veins (black arrow). (c) Histopathology results show hepatic sinus congestion (black arrow) and inflammatory cell infiltration in a bridge-like pattern (black arrow) (HE staining, 10 × 10). (d) Mild fibrosis is seen around the sinus (black arrow) (Masson staining, 20 × 10).
Figure 3

CT and pathological features in case 2. (a) CT scan shows heterogeneous density of the liver parenchyma, unclear clover-like enhancement of the hepatic vein, and ascites (*). (b) In the third month of the disease course, the CT scan shows homogenous density of the liver parenchyma and clearly exposed hepatic veins (black arrow). (c) Histopathology results show hepatic sinus congestion (black arrow) and inflammatory cell infiltration in a bridge-like pattern (black arrow) (HE staining, 10 × 10). (d) Mild fibrosis is seen around the sinus (black arrow) (Masson staining, 20 × 10).

8.3 Case 3

A 52-year-old woman intermittently ingested 3 g of “Tusanqi powder” one to two times a day. Fatigue, abdominal distension, and abdominal pain occurred after 15 days of using the drug. Her blood coagulation indices were as follows: PT: 15.0 s, PTA: 83%, and INR: 1.07. Biochemical test results were as follows: TBIL: 45.9 µmol/L, DBIL: 30.4 µmol/L, ALB: 31.0 g/L, ALT: 1142 U/L, AST: 1076 U/L, ALP: 118 U/L, and GGT: 296 U/L. Liver ultrasonography showed diffuse enlargement, liver parenchyma echogenicity with increased coarse density, uneven distribution, and visible “patch-like” areas of reduced echogenicity along the hepatic veins. A small amount of peritoneal effusion was also present. A CT scan showed an uneven reduction in liver parenchyma density, a characteristic “map-like” appearance of the liver parenchyma during the arterial and venous phases with uneven enhancement, and thin and unclear hepatic veins. Enlarged lymph nodes in the porta hepatis were also observed. After HSOS was diagnosed, treatment with low-molecular-weight heparin was initiated. After 30 days of treatment, the symptoms of the patient improved, and her biochemical indices and CT findings were close to normal (Figure 4a and b). The patient was readmitted for abnormal liver function in the 8th month of the disease and underwent a liver biopsy. Pathological features included mild inflammation in the central area, obvious dilatation of the hepatic sinus, mild fibrosis around the sinus, fibrosis deposition in the sinus, and an embolism in the central vein. Anticoagulant therapy with rivaroxaban tablets was then initiated for the patient (Figure 4c and d).

Figure 4 CT and pathological features in case 3. (a) CT scan shows diffuse hepatomegaly, heterogeneous density of the liver parenchyma, unclear delineation of the hepatic vein, and ascites (*). (b) In the eighth month of the disease course, the CT scan shows clearly exposed hepatic veins (black arrows) and homogenous density of most liver regions with the persistence of heterogeneity in a few remaining areas. (c) Histopathology results show central vein fibrosis (black arrow), absence of peripheral hepatocytes, infiltration of inflammatory cells, and hepatic sinusoidal dilatation (white arrows) (HE staining, 20 × 10). (d) Central venous occlusion (black arrow) and hepatic sinusoidal dilatation (white arrows) are observed (Masson staining, 10 × 10).
Figure 4

CT and pathological features in case 3. (a) CT scan shows diffuse hepatomegaly, heterogeneous density of the liver parenchyma, unclear delineation of the hepatic vein, and ascites (*). (b) In the eighth month of the disease course, the CT scan shows clearly exposed hepatic veins (black arrows) and homogenous density of most liver regions with the persistence of heterogeneity in a few remaining areas. (c) Histopathology results show central vein fibrosis (black arrow), absence of peripheral hepatocytes, infiltration of inflammatory cells, and hepatic sinusoidal dilatation (white arrows) (HE staining, 20 × 10). (d) Central venous occlusion (black arrow) and hepatic sinusoidal dilatation (white arrows) are observed (Masson staining, 10 × 10).

9 PA-HSOS diagnostic criteria: “Nanjing standard”

There are no unified criteria for diagnosing PA-HSOS, and its diagnosis is typically established using the modified Seattle and Baltimore criteria (Table 2). However, PA-HSOS and hematopoietic stem cell transplantation (HSCT)-HSOS have several differences in epidemiology, etiology, clinical features, and underlying diseases [12]. Thus, the use of the modified Seattle and Baltimore criteria for the diagnosis of PA-HSOS has significant limitations. In 2017, the “Expert Consensus Opinions on the Diagnosis and Treatment of PA-Related HSOS (2017, Nanjing)” proposed the “Nanjing standard” for the diagnosis of PA-HSOS (Table 2) [12], which preliminarily unified the criteria for PA-HSOS. In the Nanjing standard, the primary diagnostic criterion for HSOS is the use of PA-containing plants. In recent years, the incidence of PA-HSOS has increased. However, because the history of PA exposure is easy to miss, its incidence appears sporadic. The clinical manifestations of patients with HSOS are usually nonspecific; therefore, they are often misdiagnosed as acute or subacute severe hepatitis, decompensated liver cirrhosis, Budd–Chiari syndrome, or other diseases, affecting the timing of diagnosis and treatment of the disease and causing progression to severe or multiple organ failure with high mortality rates [47,48].

Table 2

Revised Seattle, Baltimore, and European Society for bone marrow transplantation (EBMT) diagnostic criteria for hepatic sinus obstruction syndrome

Standard Definition
Revised Seattle standard At least 2 of the following manifestations occurred within 20 days after HSCT: bilirubin >2 mg/dL, hepatomegaly with right upper abdominal pain, fluid retention, weight gain ≥ 2% of baseline weight
Baltimore standard At least 2 of the following manifestations occurred within 21 days after HSCT: bilirubin >2 mg/dL, hepatomegaly with right upper abdominal pain, fluid retention, weight gain ≥ 5% of baseline weight
Nanjing standard Have a clear history of taking plants containing PA, meet the following three items or be confirmed by pathology, and exclude liver injury caused by other known causes. ① Abdominal distension and/or liver pain, hepatomegaly, and ascites. ② Elevated serum total bilirubin or other abnormal liver function. ③ Typical enhanced CT or MRI findings

Note: HSCT: hematopoietic stem cell transplantation; PA: pyrrolizidine alkaloid; CT: computed tomography; MRI: magnetic resonance imaging.

10 Advantages of the “Nanjing standard”

The primary criterion in the “Nanjing standard” is a history of ingesting PA-containing plants. PA-HSOS is a DILI; therefore, obtaining a medication history is important. Domestic reports of HSOS are often higher than those of consumption of PA-containing plants. PA-containing plants are widely distributed. Approximately 3% of the flowering plants (more than 6,000 species) in the world contain PA, including comfrey (all genera), Compositae (ragwort and lycopi), and leguminous pig feces beans; however, Tusanqi is the most widely used PA-containing plant in China [47,49]. Many studies have reported the detection of PA in various foods, including honey, milk, salad, tea, and mutton [50].

Second, the “Nanjing standard” changed the criterion “serum bilirubin ≥ 34.2 μmol/L” to “elevated serum TBIL or other abnormal liver functions.” A recent review on PA-HSOS described four cohorts of 117, 108, 116, and 80 patients [22,37,39,51] with TBILs of 33.3 (19.7–47.0), 39.7 (28.3–62.4), 65.07 ± 78.83, and 52.96 ± 45.95 (μmol/L), respectively. Elevated bilirubin was not the main clinical feature of PA-HSOS, as approximately one-third of the TBIL levels of the patients were lower than 34.2 μmol/L. If the modified Seattle and Baltimore criteria were used to diagnose PA-HSOS, this finding may be missed. Therefore, the “Nanjing standard” no longer provides specific quantitative requirements for the elevation of serum TBIL.

Additionally, compared with the modified Seattle and Baltimore criteria, the “Nanjing standard” no longer incorporates weight gain as a criterion. Compared with patients with HSCT-HSOS whose body weights are regularly monitored during hospitalization, patients with PA-HSOS have sporadic presentations, and changes in their body weight are usually difficult to trace. The increase in their body weight is mainly due to the excess production of pleural fluid and ascites. In our summary of the clinical characteristics of PA-HSOS, we also found that only a few cohorts collected data on patient weight parameters (Table 1).

Importantly, imaging manifestations were added to the “Nanjing standard.” Patients with PA-HSOS share typical imaging characteristics that are valuable in the diagnosis of HSOS [52,53]. CT findings include ascites on the plain scan, uneven reduction of liver parenchyma density, characteristic “geographic” and “piebald” uneven enhancement, and varying degrees of abnormal liver patch enhancement associated with clinical severity. MRI findings include heterogeneous patchy enhancement of the liver parenchyma during the portal venous and delayed phases and poor filling of the hepatic lobe and segmental veins by the contrast medium [54]. A recent single-center retrospective study [42] validated the diagnostic value of contrast-enhanced CT among patients with PA-HSOS (n = 71), Budd–Chiari syndrome (n = 57), and liver cirrhosis (n = 165). In patients exhibiting patchy enhancement, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of PA-HSOS were 92.96, 92.79, 80.49, 97.63, and 91.83%, respectively. Contrast-enhanced CT showed ideal diagnostic performance and can therefore be used as an effective, simple, and noninvasive method for diagnosing PA-HSOS.

11 Verification of the “Nanjing standard”

The diagnostic performance of the “Nanjing Criteria” lacks systematic evaluation and verification. A recent clinical study [40] conducted preliminary clinical validation of the “Nanjing standard.” This study retrospectively analyzed consecutive patient data from multiple hospitals (ID: ChiCTR1900020784), including 86 patients with PA-HSOS and 327 patients with other liver diseases. The diagnostic performances of the Nanjing standard and simplified Nanjing standard were evaluated and validated. The sensitivity and specificity of the Nanjing standard for the diagnosis of PA-HSOS were 95.35% and 100%, respectively. However, this was a single-center retrospective study, and selection bias was present because of the small sample size and a small number of patients with certain diseases (such as acute liver injury and Budd–Chiari syndrome). Therefore, further research with multicenter and large-sample clinical trials is required to validate the “Nanjing standard” for the diagnosis of PA-HSOS.

In conclusion, PA-HSOS is a DILI that has been rising in recent years and has a high mortality rate, if not treated early. Early diagnosis is the key to initiating early treatment and obtaining a good prognosis. Understanding the key features of this disease enables early diagnosis. A clear history of PA use, characteristic clinical features, such as abdominal distension, abdominal pain, and ascites, that are significantly more severe than those in other liver diseases (such as viral hepatitis and alcoholic hepatitis), and characteristic imaging findings support the diagnosis of PA-HSOS. Although pathology is the gold standard for diagnosis, its invasiveness precludes its routine use. The “Nanjing standard” may also be valuable in the diagnosis of PA-HSOS.

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  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Funding information: This study was supported by the Chinese Federation of Public Health Foundation (GWLM202002).

  3. Author contributions: YW Tan and SN Zheng contributed equally to the research with SN Zheng responsible for literature retrieval and YW Tan responsible for literature analysis, research design, and writing. All authors participated in the revision of the manuscript and agreed to its publication.

  4. Conflict of interest: The authors have no conflicts of interest to declare for this study.

  5. Data availability statement: Data are available from the corresponding author upon reasonable request.

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Received: 2023-01-18
Revised: 2023-05-05
Accepted: 2023-05-25
Published Online: 2023-06-12

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0737
Keywords for this article
hepatic sinusoidal obstruction syndrome; pyrrolizidine alkaloid; Tusanqi; drug-induced liver injury
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
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  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
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  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
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  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
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  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
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  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
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  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
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  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
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  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
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  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
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  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
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  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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