Over the course of 40 years, the distribution of liver diseases has changed dramatically with changes in the environment and diet, and with advances in medicine. The hepatitis C virus (HCV) was discovered in 1989. During 1980-2000, HCV was the major etiology of hepatocellular carcinoma (HCC) in Japan. However, its assay method has been established and anti-direct viral drugs have been developed, because of which, HCV is being eradicated. Conversely, fatty and alcoholic liver diseases have been increasing in Japan because of the westernization of eating habits and increasing female drinkers. Recently, these liver diseases have become the major causes of HCC. We have identified clinical features of nonalcoholic fatty liver disease-HCC and the genomic background of its occurrence and progression. We should pay attention to changes in disease distribution and research its pathogenesis for application in treatments.

Recent studies have elucidated the pathophysiology of the common placental disorders. It is believed that gestational hypertension, also known as preeclampsia, is a two-stage disease. Inadequate migration of the trophoblasts induces defective remodeling of the uterine spiral arteries. The poorly perfused and re-perfused placenta (Stage 1) produces antiangiogenic factors that cause maternal endothelial dysfunction (Stage 2). It has been hypothesized that a luck of fetomaternal immune tolerance leads to insufficient trophoblastic differentiation.

Another placental disorder is chronic villitis or villitis of unknown etiology. The diagnosis of severe chronic villitis is important to the clinician because it causes intrauterine growth restriction, fetal death, and neonatal neurological impairment. These lesions could be of immune origin. It has been reported that the pathogenesis of chronic placentitis is the maternal anti-fetal cellular and antibody-mediated rejection.

Disorders of gestational immune tolerance underlie these two placental diorders.

Hepatic disorder consists of acute and chronic hepatitis. Most patients with acute hepatitis are cured without transitioning to chronic hepatitis. Chronic hepatitis progresses to liver cirrhosis and can even lead to hepatocellular carcinoma, irrespective of the etiology. Liver cirrhosis is classified into compensated and decompensated cirrhosis. Patients develop no symptoms until they progress to decompensated cirrhosis, a reason why the liver is called the silent organ. Jaundice, ascites, portal hypertension, and encephalopathy are symptoms of liver failure. It is important to start treatment before progression to cirrhosis. One such chronic liver disease that can lead to cirrhosis is hepatitis B. Carriers of hepatitis B are diagnosed by a positive result on the HBs antigen assay. If nucleic acid analog treatment is started at an appropriate time, chronic hepatitis B does not progress. One characteristic of hepatitis B virus infection that clinicians must keep in mind is that immune-suppression treatment or chemotherapy causes the virus to repopulate, thereby resulting in severe hepatitis. Hepatitis C virus infection was once the main cause of post-transfusion hepatitis. After the discovery of hepatitis C virus, 99.9% of new infections after blood transfusion were eliminated. Now, over 95% of patients can be cured by oral drug treatment. Fatty liver disease consists of alcoholic and nonalcoholic fatty liver disease that results from obesity and metabolic syndrome. In Japan, obesity and metabolic syndrome have become major health problems, leading to dramatic increases in the prevalence of fatty liver disease. Nonalcoholic fatty liver disease has become the most rapidly increasing cause of cirrhosis and hepatocellular carcinoma. As a result, nonalcoholic fatty liver disease has become a major public healthcare concern at the national level.

Two topics, insulin autoimmune syndrome and early-onset diabetes care, have been selected for the final lecture in the Tokyo Women's Medical University (TWMU).

Insulin autoimmune syndrome (IAS), or Hirata's disease, first described by Hirata in 1971, is characterized by fasting hypoglycemia without evidence of exogenous insulin administration, high concentration of total serum immune reactive insulin, and the presence of high titer autoantibodies against native human insulin in serum. Other characteristics associated with IAS are the high frequencies of HLA-DR4 positivity, the prevalence of IAS in Japan, and the intake of drugs containing sulfhydryl compounds before IAS onset. We found that IAS showed a strong association with HLA-DR4 (mostly with DRB1*04:06, less frequently with DRB1*04:03 or DRB1*04:07), which encode glutamate at position 74 in the HLA-DR beta molecules, and is presumed to be essential to the production of polyclonal insulin autoantibodies in IAS.

As part of a physicians' professional duty of care for early-onset diabetes patients, the staff at our clinic aim to provide high-quality care for these patients with early-onset DM to improve treatment outcomes. Patients with type 1 diabetes were found to have a better prognosis compared to those attending other clinics, which suggests an improved care system at TWMU diabetes center.