Stevens-Johnson syndrome and acute vanishing bile duct syndrome after the use of amoxicillin and naproxen in a child.

Introduction

Cholestasis and skin lesions are common results of drug toxicity. Recently, the number of patients with drug-induced vanishing bile duct syndrome (VBDS) has increased, and VBDS has also gained more attention. Although rare, over 30 drugs have been reported to cause VBDS, and even if treatment is interrupted, VBDS can still occur.[1] Stevens–Johnson Syndrome (SJS) is an immune complex-mediated hypersensitivity reaction involving the skin and mucosa, which is also usually induced by drugs. Both of VBDS and SJS are rare diseases. To the best of our knowledge, there have been almost no similar reports to date. We present the case of a pediatric patient who developed SJS and VBDS after oral amoxicillin and naproxen intake.

Case report

A 6-year-old male patient was admitted to our hospital with an unknown cause of high jaundice and an old vesiculobullous rash. Our hospital was the third hospital that the patient attended. The patient’s medical history revealed that the rash developed after ingesting amoxicillin and naproxen (2 months before he was admitted to our hospital), which, within 2 days, spread rapidly throughout his body. He had been treated with a conventional pediatric dose of amoxicillin and naproxen because of fever. The patient had no history of any allergic diseases, immunodeficiency, or hereditary metabolic liver disease. The patient’s family history was unremarkable. The patient’s earlier medical history indicated that he had lesions on lips and eyes (Figure 1a,b). At the other two hospitals, no suspicious pediatric drugs had been used. When the patient was admitted to our hospital, a physical examination revealed severe jaundice, hepatomegaly, and an annular old vesiculobullous rash, which spread across his entire body. Skin lesions were present on >10% of his body (Figure 1c), and he was diagnosed with SJS caused by the use of amoxicillin and naproxen.[2,3] There is currently no other diagnosis, and the patient’s symptoms have been considered to be differentiated from those of Alagille syndrome, but the child had no previous history of liver disease (these are the first symptoms), and there were no abnormalities in the heart, bone, face, and eye. The patient was negative for JAG1 and NOTCH2 gene expression, and there are similar published reports about this child’s situation.[4]

Figure 1.

(a,b) The vesiculobullous rash spread to the entire body. (c) Regression of lesions after treatment.

The patient’s laboratory results from the provincial Hospital Affiliated to Shandong University, China were as follows: white blood cell (WBC) count, 4.0 × 09/L; hemoglobin (Hb), 120 g/L; neutrophilic granulocyte percentage, 68.4%; platelet count, 231 × 09/L; alanine aminotransferase (ALT), 942 U/L (N: 9–50 U/L); aspartate aminotransferase (AST), 804 U/L (N: 15–40 U/L); alkaline phosphatase (ALP), 318 U/L (N: 45–125 U/L); gamma-glutamyl transferase (GGT), 150 U/L (N: 10–60 U/L); total bilirubin (TBil), 51.63 μmol/L; direct bilirubin (DBil), 32.88 μmol/L; total bile acid (TBA), 201.44 μmol/L; and total cholesterol (CHO), 3.03 mmol/L (N: <5.18 mmol/L). The prothrombin time (PT) was 12.5 s (N: 9.9–12.8 s), prothrombin activity (PTA) was 85% (N: 80%–120%), and international normalized ratio (INR) was 1.10. The patient’s renal function and electrolyte levels were within normal limits.

The herpes simplex virus IgG antibody result was positive, the IgM antibody result was negative, and the remaining viral indicators were negative for IgG and IgM. and CMV and EBV DNA were also negative. The patient had negative results for hepatotropic and non-hepatotropic viruses caused by hepatitis disease (cytomegalovirus, rubella, herpes simplex, Epstein–Barr virus, and parvovirus infections), and antinuclear antibodies, anti-neutrophil cytoplasmic antibodies, anti-smooth muscle antibody, and liver and kidney microsomal antibody results were all negative. The urine copper level and serum ceruloplasmin level were in the normal range.

At the first hospital, the patient was treated with a dose of methylprednisolone for 15 days (2 mg/kg per 12 hours, intravenously, for 16 days), plasma exchange (total of five exchanges), and supportive care. After 16 days of treatment, the patient’s skin lesions started to improve (Figure 1c), but the cholestasis continued. The patient was discharged from the hospital and attended the Beijing Children’s Hospital for further treatment.

The patient’s laboratory results from the Beijing Children’s Hospital, Capital Medical University are as follows: ALT, 658.9 U/L (N: 9–50 U/L); AST, 407.4 U/L (N: 15–40 U/L); ALP, 536.0 U/L (N: 45–125 U/L); GGT, 980.9 U/L (N: 10–60 U/L); TBil, 188.49 μmol/L (N: 5–21 μmol/L); DBil, 145.75 μmol/L (N: <7 μmol/L); TBA, 143.3 μmol/L (N: 5–21 μmol/L); and CHO, 13.63 mmol/L (N: <5.18 mmol/L). Coagulation function and blood test results were normal. Renal function and electrolyte levels were within normal limits. However, findings from the patient’s abdominal ultrasound included hepatomegaly, and magnetic resonance cholangiopancreatography showed an obstruction in the bile duct.

At the second hospital, Beijing Children’s Hospital, the patient continued to be treated with methylprednisolone for a total of 6 weeks (2 mg/kg per day, first intravenously and then orally, which was gradually tapered), ursodeoxycholic acid (UDCA; 15 mg/kg per day, orally), traditional Chinese medicine, and supportive care. After 6 weeks of treatment, cholestasis marker levels (TBil, GGT, ALP, TBA, and CHO) had steadily increased. Thus, a liver biopsy was performed 6 weeks after admission. After the liver biopsy, the patient attended our hospital.

At our hospital, we analyzed the pathological images. The biopsy specimen revealed lobular structures, the interlobular bile duct was visible only in three portal areas, the remaining portal areas did not contain a interlobular bile duct, and there was marked degeneration of the interlobular bile duct epithelium. There was no obvious inflammation in the mesenchyme and no peripheral bile duct reaction, some liver cells around CK7 were immune-staining positive, there were lobular capillary bile plugs, and hepatocyte cholestasis was present with liver cell necrosis, which suggests VBDS (Figure 2a–d). We increased the dose of UDCA (40 mg/kg per day, orally), S-adenosyl-L-methionine (1000 mg per day, intravenously), alprostadil (10 μg per day, intravenously), and Pien Tze Huang (traditional Chinese medicine), and placed the patient on a low fat diet with supportive care. After 3 months of treatment at our hospital, the patient’s overall condition was improving, and the cholestasis marker levels (TBil, GGT, ALP, TBA, and CHO) were steadily decreasing. The patient was discharged and followed up at the outpatient clinic for treatment with UDCA and Pien Tze Huang. After 5 months of treatment, the patient’s jaundice had completely resolved, and his laboratory results were normalized as follows: ALT, 11 U/L; AST, 30 U/L; TBil, 17.3 μmol/L; GGT, 54.5 U/L; ALP, 209.7 U/L; and CHO, 5.35 mmol/L. Coagulation function was normal. The patient’s follow-up test results showed that the liver synthetic function and clinical findings had returned to normal. Table 1 shows the change in liver function test results in this patient.

Figure 2.

Liver histology results show the destruction of interlobular bile ducts, and some liver cells around CK7 were immune-staining positive. Lobular capillary bile plugs, hepatocyte cholestasis, and liver cell necrosis were also observed (magnification, ×200).

Table 1.

Clinical and laboratory findings.

Time (week)	AST (U/L)	ALT (U/L)	TBil (μmol/L)	DBil (μmol/L)	ALP (U/L)	GGT (U/L)	TBA (μmol/L)	CHO (mmol/L)	Other Interventions
Day 2	Amoxicillin and Naproxen stopped
1	421	272	77.9	48.5	207	178	62.4	–	Hospitalization
2	663	384	173	103	549	772	148	–
3	659	407	189	146	536	981	143	13.6
4	83.5	203	349	276	491	463	631	23.5
6	24.2	112	274	202	451	326	437	24.9	Liver biopsy
8	22.5	180	252	210	360	193	187	26.4
10	31.8	188	212	173	452	277	238	30.9
12	28.2	174	144	121	507	505	169	32.9
14	33.0	201	93.1	75.5	946	847	45.6	35.2
16	23.7	128	49.9	44.1	615	584	32.0	24.9
18	15.5	45.5	30.8	26.2	389	229	24.1	16.1	Outpatient
22	11.0	30.0	17.3	12.5	209	54.5	11.2	5.35

ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBil, total bilirubin; DBil, direct bilirubin; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; TBA, total bile acid; CHO, total cholesterol.

Discussion

Drug-induced SJS and accompanying VBDS have rarely been observed in children. In this case report, liver dysfunction and skin lesions were induced by amoxicillin and naproxen, which are widely used in rural private clinics in China. The patient’s medical history did not show any evidence of pre-existing liver and biliary tract disease. Both amoxicillin and naproxen can cause drug-related VBDS.[4] Similar to VBDS, drug-related VBDS mainly includes fatigue, pruritus, jaundice, gastrointestinal symptoms, hyperlipemia, and dystrophy. The laboratory examination showed an obvious elevation of ALP and GGT, which can be accompanied by high DBil and transaminase. Magnetic resonance cholangiopancreatography (MRCP) in patients with a high degree of bile duct injury can indicate that the intrahepatic and extrahepatic bile ducts are slender. Liver biopsy results showed that over 50% of the interlobular bile ducts had disappeared. With inflammation, there is fibrosis, lobular central hepatocyte necrosis, and obvious destruction of bile duct epithelium.[5] The mechanism of VBDS bile duct epithelial injury and the disappearance of intrahepatic bile ducts has not been fully elucidated. The drugs may act as a hapten against keratin on the surface of the bile duct epithelial cells, and the autoantibodies can damage bile duct epithelial cells and cause the bile ducts to disappear. The percentage of bile ducts that disappear and the persistence of the disease depend on the severity of bile duct injury.

Generally, there are two possible outcomes of drug-related VBDS: progressive failure and irreversible reduction of bile ducts that leads to widespread disappearance of bile ducts and cholestatic cirrhosis; or the gradual regeneration of the bile duct epithelium resulting in clinical recovery in some patients. Existing bile ducts disappear, but liver biochemistry and cholestasis can gradually improve and, after several months, return to normal.[6] Unfortunately, there are no clear ways to induce bile duct regeneration, and thus, symptomatic treatment is important. Discontinuing drugs that damage the liver and administering UDCA and immunosuppressants may be helpful. Patients with chronic cholestasis may present with fat-soluble vitamin deficiency, osteoporosis, cholelithiasis syndrome, and hyperlipidemia, in addition to the complications of cirrhosis and portal hypertension.[7] Studies have found that extremely high doses of UDCA (45 mg/kg per day) enable improvement of VBDS induced by amoxicillin and clavulanate potassium.[8] In our patient, the liver histopathology results were consistent with VBDS. We treated the patient with high doses of UDCA (40 mg/kg per day) and other drugs that promote bile excretion. After 5 months of treatment, the patient’s jaundice had completely resolved, and the patient’s laboratory results returned to normal. Based on these findings, the patient was diagnosed with amoxicillin and naproxen-induced VBDS.

SJS is an immune complex-mediated hypersensitivity reaction involving the skin and mucosa, which is usually induced by drugs, sometimes leading to systemic symptoms. It is a serious and potentially life-threatening disease. For SJS, the incidence varies from 1 to 6 cases per million people per year, the mortality rate is about 5%, and the most common complications are liver damage, kidney damage, hypoalbuminemia, and secondary infection.[9,10] Nonsteroidal anti-inflammatory drugs (NSAIDs), penicillin, sulfonamides, allopurinol, and anticonvulsants are most commonly implicated in this disease. In our case, the patient had taken two of these types of drugs (amoxicillin and naproxen). Currently, there is no definite treatment for SJS.[11,12] In China, glucocorticoids and intravenous immune globulin (IVIG) are the two main drugs that are used as the treatment. Our patient was treated with glucocorticoids, IVIG, and plasma exchange. After 16 days of treatment, the patient’s skin lesions started to regress.

Amoxicillin and NSAIDs are commonly used in rural private clinics in China, causing a certain incidence of liver damage.[13,14] Currently, there are few reports about the cholestasis caused by naproxen. The pattern of liver injury is typically hepatocellular, but it can be mixed or cholestatic.[15] Several cases have been reported on the progress to biliary cirrhosis, severe cholestasis, and acute liver failure,[16,17] and liver transplantation is the only treatment that can fundamentally improve liver function. Currently, there are few reports of children with VBDS combined with SJS in China or in other countries. To the best of our knowledge, this is the ninth reported case of drug-induced skin lesions and VBDS and the first reported case of amoxicillin and naproxen-induced SJS/VBDS in children.

In conclusion, amoxicillin and NSAIDs are commonly used in children, especially in China. These two types of drugs have been known to induce SJS and VBDS in rare cases. Therefore, their use should be considered carefully. For patients who develop a rash and jaundice after ingesting the two kinds of drugs, the medication should be stopped immediately, and treatment should be initiated as soon as possible.