Clinical features of acute attacks, chronic symptoms, and long-term complications among patients with acute hepatic porphyria in Japan: a real-world claims database study.

BACKGROUND: Acute hepatic porphyria (AHP) is a family of rare genetic diseases, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and delta-aminolevulinic acid dehydratase-deficient porphyria. The objective of this retrospective cohort study was to provide information on the clinical features of AHP in Japan-including acute attacks, chronic symptoms, and long-term complications. METHODS: Patients with AHP between April 2008 and June 2020 were selected from Japan's Medical Data Vision claims database. Patients with AHP were matched 1:10, by sex and age, to patients without AHP. The outcomes were evaluated overall, for patients age ≥ 55 years, and for the matched population. RESULTS: A total of 391 patients with AHP were included from the Japanese Medical Data Vision database. During the observation period (April 2008-June 2020), 18.2% (71/391) of patients experienced 1 acute attack and 10.5% (41/391) experienced ≥ 2 attacks. Chronic symptoms with rates ~ 10% or higher in the AHP population compared with the matched population included neurotic, stress-related, and somatoform disorders (21.7% vs. 6.7% [15.0% difference]); sleep disorders (23.0% vs. 9.9% [13.1% difference]); other and unspecified abdominal pain (13.6% vs. 3.7% [9.9% difference]); and nausea and vomiting, excluding chemotherapy-induced emesis (17.9% vs. 8.1% [9.8% difference]). Long-term complications with higher incidence rates in the AHP population compared with the matched population included fibrosis and cirrhosis of liver (15.9% vs. 3.0% [12.9% difference]), polyneuropathies and other disorders of the peripheral nervous system (20.5% vs. 7.9% [12.6% difference]), liver cancer (16.9% vs. 4.7% [12.2% difference]), renal failure (16.4% vs. 4.3% [12.1% difference]), and hypertension (26.1% vs. 18.8% [7.3% difference]). Among AHP patients age ≥ 55 years, the most common long-term complications were hypertension, kidney failure, and liver cancer. CONCLUSIONS: In Japan, patients with AHP experience a high clinical burden in terms of acute attacks, chronic symptoms, and long-term complications. The clinical burden related to chronic symptoms and long-term complications was substantially higher in Japanese patients with AHP compared with a matched population without AHP. Recognizing these signs and symptoms of AHP may aid physicians in making an earlier diagnosis, which may help patients avoid attack triggers, implement disease management, and reduce lifetime disease burden.

Clinical features of Japanese patients with acute hepatic porphyria.

Acute hepatic porphyria (AHP) is a family of rare genetic diseases of heme biosynthesis characterized by severe neurovisceral attacks. The clinical characteristics of patients with AHP as well as the prevalence of AHP in Japan are not well understood. The objectives of this study were to describe clinical characteristics of AHP at time of diagnosis in Japanese patients and to estimate the prevalence of AHP. Patients with porphyria were selected from Japan's Medical Data Vision health care claims database between April 2008 and June 2020. Patient characteristics before and at time of AHP diagnosis were evaluated. Prevalence per 100 000 was estimated during the study period. A total of 391 cases of AHP were included. At time of AHP diagnosis, mean age was 44 years, and the most common type was acute intermittent porphyria. Median time to diagnosis was 3 months, but some patients remained undiagnosed for several years. The most common complications included metabolic disorders (54%) and diabetes mellitus (39%). In addition, the well-known complications of AHP, including hypertension (22%) and malignant neoplasms of digestive organs (22%), were observed. About 10% of patients received medications that may have aggravated porphyria attacks. The estimated prevalence of AHP in Japan during the study period was 1.18 cases per 100 000 population. At time of diagnosis, many patients with AHP in Japan are already experiencing a high burden of disease-related complications. Raising AHP awareness may aid physicians in providing an earlier diagnosis and reducing lifetime disease burden.

Evaluation of the Implementation of Additional Risk Minimization Activities in Europe, the USA, and Japan.

BACKGROUND: Risk minimization activities are planned and conducted as part of a drug's risk management plan; additional risk minimization activities are implemented as needed in consideration of the regulations and medical environment in each country/region, as well as drug-specific factors. OBJECTIVE: The present study was conducted with the aim of investigating the status of implementing additional risk minimization activities in Europe, the USA, and Japan and understanding the characteristics of such activities commonly conducted in these countries/regions. METHODS: For new drugs approved between 2013 and 2017, the status of implementing the additional activities was investigated based on the information published on each of the regulatory agencies' websites. Next, we identified drugs approved in all three countries/regions and investigated drug-specific factors such as indications and safety concerns. Furthermore, the contents of the activities were analyzed from the viewpoint of whether they intended risk mitigation or risk prevention. RESULTS: The status of implementing additional activities was 26.4% (42/159 drugs) in Europe, 7.6% (15/197 drugs) in the USA, and 64.8% (92/142 drugs) in Japan. Forty-five drugs that were approved in all three countries/regions were identified. Many drugs with additional activities displayed novel mechanisms of action in therapeutic areas such as oncology. Common additional activities were implemented for only three drugs and for two of these drugs, "teratogenicity" was identified as a safety concern subjected to additional activities. CONCLUSIONS: Risk minimization activities were considered to be largely influenced by differences in regulatory thinking, medical systems, such as the number of healthcare providers per patient and the insurance system, and cultural differences. For drugs with a risk for teratogenicity and those with side effects that differ from conventional therapies, there was a tendency to commonly implement additional activities.

Clinical utility of transthoracic echocardiography for screening abdominal aortic aneurysm: a prospective study in a Japanese population.

BACKGROUND: The aim of the present study was to evaluate the clinical utility of transthoracic echocardiography (TTE) for screening abdominal aortic aneurysm (AAA) and to identify important TTE indices associated with AAA in a Japanese population. METHODS: We prospectively studied 1912 patients who were referred for TTE. AAA was defined as ≥ 30 mm in size. RESULTS: The abdominal aorta was visualized in 95.1% (1818/1912) by TTE. AAA was identified in 2.6% (47/1818). The aortic root size was significantly larger in patients with AAA than those without (36.0 ± 4.1 vs. 31.7 ± 4.2 mm, p < 0.001). The aortic root size had a fair correlation with abdominal aortic size (r = 0.31, p < 0.001). The aortic root size of ≥ 34 mm was predictive of AAA by receiver operating characteristic curve analysis (area under the curve = 0.78, p < 0.001). Multiple logistic regression analysis revealed that aortic root size (Hazard ratio 1.23, p < 0.001) and age (Hazard ratio 1.05, p = 0.013) were the independent predictors of AAA. CONCLUSIONS: The feasibility of the abdominal aortic visualization during TTE was excellent. The aortic root size measured by TTE was the independent predictor of AAA. Screening for AAA during TTE appeared to be useful especially in the older patients with a large (≥34 mm) aortic root.

Involvement of the change in chromatin structure in thymocyte apoptosis induced by phosphorylation of histones.

The inhibitors of protein phosphatase such as calyculin A and okadaic acid induced thymocyte apoptosis. DNA fragmentation was increased in the nuclei from thymocytes treated with calyculin A, which accelerated phosphorylation of histones. Judging from the circular dichroism analysis, the structure of soluble chromatin was changed by the treatment with calyculin A. These results suggest that the change in chromatin structure may be one of the molecular mechanisms of internucleosomal DNA fragmentation.