This should not be included in the list of inclusion criteria: Cases with a clear cause of toxic hepatitis, such as viral hepatitis, drugs, or occupational toxic hepatitis. Many cases were excluded because the patients had used steroids to treat their respiratory symptoms, consumed alcohol, or were carriers of the hepatitis B virus (HBV). The three patients presented in this case series had no major causative factors of hepatitis (Table 1)

Case 1 was a five-year-old female without any underlying diseases. The patient was born via cesarean section with a birth weight of 4.00 kg. “Findings during pregnancy and birth were normal. The child was exposed to HD for one year and three months (January 2002 – April 2003). During about 90% of the total exposure period, she was exposed to PHMG as an HD ingredient, and the remaining 10% was to chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). Her parents stated that the humidifier was used 24 hours a day and the distance between the humidifier and the patient was less than 0.5 meters.

The patient went to the hospital due to fever, general weakness, epigastric pain, anorexia, and nausea. Symptoms had begun three days earlier. The patient had a confirmed body temperature over 39°C and hepatomegaly. At admission, her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were confirmed to be 268 and 118 units/L, respectively (Fig. 1). Her hepatic enzyme levels increased to 3,000 units/L. Gastric bleeding was observed on the third day after admission. The patient’s blood test results and general condition continued to deteriorate. She was transferred to a general hospital. After the transfer, gastric bleeding, hematemesis, and melena were continuously observed. Gastrointestinal bleeding did not improve after a transfusion. Viral tests were all negative. The patient was diagnosed with acute fulminant hepatitis of unknown cause. After intubation due to dyspnea, symptomatic treatment continued in the intensive care unit (ICU). However, the patient’s mental status was drowsy. She died of multiple organfailure due to disseminated intravascular coagulation one day after transfer to the general hospital.

Case 2 was a four-month-old male patient without an underlying disease. His birth weight was 3.06 kg, with normal findings during pregnancy and birth. He was exposed to HD containing 100% PHMG from birth for 24 hours per day. The distance between the humidifier and the patient was two meters.

The patient visited the clinic due to a fever and persistent cough. His AST and ALT levels were confirmed to be 2,061 and 2,245 units/L, respectively (Fig. 2). He was admitted to the hospital for elevated hepatic enzymes. The doctor suspected cytomegalovirus infection and prescribed medications. Viral testing confirmed negative immunoglobulin M and positive immunoglobulin G. The patient was transferred to a general hospital for further medical examination.

The patient had a cough and rhinorrhea with normal body temperature. There was no evidence of infection at evaluation. The patient was discharged upon improvements in symptoms and hepatic enzyme levels. Follow-up testing showed increased hepatic enzyme levels. Hepatomegaly was still observed.

Case 2 patient also experienced respiratory symptoms, such as cough, after exposure to HD, and was treated for pneumonia and rhinitis several times. He was diagnosed with attention deficit hyperactivity disorder (ADHD). He still complains of unrecovered fatigue and lethargy.

Case 3 was a 41-year-old female exposed to HD since the age of 38 (November 2007 to April 2010). During about 45% of the total exposure period, PHMG was used as an HD ingredient, and during the remaining 55%, CMIT/MIT was used. The patient stated that she was exposed to HD for an average of 11 hours per day in a residential space.

The patient reported upper respiratory symptoms and dyspnea. A pulmonologist began treatment based on the suspicion of asthma. After six months of asthma treatment, prednisolone was tapered due to improvement in symptoms. However, sore throat, cough, sputum, and chest discomfort suddenly recurred. Auscultated rhonchi lung sounds were heard by the pulmonologist. The doctor prescribed prednisolone to improve the symptoms. However, the patient was admitted to the hospital with a worsening cough and elevated hepatic enzymes after one week. Approximately 17 days after hospitalization, her hepatic enzyme level increased from 250 to 4,000 units/L (Fig. 3). Her symptoms persisted, and the fever remained uncontrolled. The patient was transferred to a general hospital.

In the general hospital, the medical staff tried to determine the cause with hepatotoxicity of unknown origin. Granulomatous hepatitis was found on liver biopsy. The liver biopsy results are as follows:

After the symptoms were controlled, the patient was discharged from the hospital. She voluntarily stopped using HD. Her asthma symptoms persisted. Treatment was continued as her forced expiratory volume in one second (FEV1) decreased to 27%. Prednisolone was continued, and toxic hepatitis has not recurred.

We observed the mitochondria of two patients (except case 1) by transmission electron microscopy (TEM) and found decreases in the size of the mitochondria. They were distorted with blurred cristae. The ring of the mitochondria was not clear, and the boundary was blurred in both patients (Figs. 4 and 5). Damage to the mitochondrial inner membrane, outer membrane, and cristae indicates that the mitochondrial electron transport chain is disrupted, resulting in impaired ATP production [4,5]. This article is a human case series study that supports prior knowledge that hepatotoxicity can occur through HD inhalation. Alcohol consumption, HBV, and hepatitis C virus (HCV) are known as the major causes of hepatotoxicity. Obesity, diabetes, and some drugs can also induce hepatotoxicity [6]. The highly suspect hepatotoxic drugs include antihypertensive, antirheumatic, analgesic, anticonvulsant, and antimicrobial agents. In particular, minocycline and nitrofurantoin have been reported as major causes of drug-induced hepatotoxicity [7]. Accordingly, the patient’s medical history is important when determining the hepatotoxic cause. We confirmed that there were no underlying factors that could induce hepatitis in the three patients through an interview and medical records. In Oriental culture, herbal medicines have been reported as a major cause of toxic hepatitis. In this regard, all patients denied using herbal medicines.