Long‐lived Werner syndrome patient autopsy report: The presence of liver cirrhosis

Dear Editor, Werner syndrome (WS) is an autosomal recessive disorder known as progeria. Although it has recently been reported that patients with WS have extended lifespans, many die by the age of 60 years from various causative disorders, such as malignant tumors, ischemic heart disease and infectious diseases. This time, we report a long-lived WS patient with liver cirrhosis. The patient was a man who was diagnosed with WS when aged in his 40s, and genetic analysis confirmed an abnormality in the compound heterozygous mutations of the WRN gene (the type 1 mutation: c.3913C>T/6 mutation: c.1105C>T). This patient had three siblings, he is the youngest, and his older brother had previously been diagnosed with WS at Osaka University and died at the age of 68 years. He had one son, who had no clinical features of WS, and lived with his son’s family. The patient had gray hair in his 30s and began losing hair in his 40s, and he underwent cataract surgery in his 40s. He had the WS-characteristic bird-like face, skin atrophy, abnormal voice (hoarseness) and calcification of the Achilles tendon. Although diabetes with insulin resistance existed, glycated hemoglobin was controlled to approximately 6.5% by pioglitazone and dipeptidyl peptidase-4 inhibitor. Although the patient’s physique was of short stature with low body mass (height 154 cm, weight 42.5 kg at the age of 60 years; body mass index 17.9 kg/m), computed tomography (CT) of the abdomen showed accumulation of visceral fat. He had been suffering from intractable ulcers of the sole and Achilles tendon since his 40s. He had a meningioma resected at the age of 63 years. Imaging findings carried out around the age of 70 years were fatty liver, blunt liver edge, suspected chronic liver damage, and mild-to-moderate splenomegaly on abdominal CT and ultrasonography. An upper gastrointestinal endoscopy was carried out at the age of 73 years, and the presence of esophageal varices (Li, F1, Cb, RC [−]) was specified. Although his intellectual level was normal, his cognitive decline began to appear around the age of 70 years, and he died at Nagoya university hospital at the age of 76 years due to osteomyelitis and sepsis. Autopsy findings showed atrophy of the liver (851 g), blunt edges and nodule formation on the surface with a slightly yellowish liver parenchyma on the cut surface (Fig. 1a,b). Histological observation of the liver showed an image of liver cirrhosis with regenerated nodules (Fig. 1c), and some fat deposits remained (Fig. 1d), suggesting the presence of fatty liver disease. The dilation of veins in the lower esophagus and mild splenomegaly were also observed. Advanced atherosclerosis with calcification was observed in the aorta and the coronary arteries, but no significant stenosis was observed. In this case, a slight increase in aspartate transaminase and alanine transaminase was observed for many years, but it did not reach three digits. Hepatitis B virus antigen and hepatitis C antibody were negative, and the patient did not have a drinking habit. Therefore, considering the findings of histopathology, CT and ultrasonographic findings, non-alcoholic steatohepatitis (NASH) due to fatty liver for many years was assumed to be the cause of his liver cirrhosis. Hashizume et al. reported three WS patients around the age of 30 years who were diagnosed with NASH based on liver biopsy and images. As far as we know, liver cirrhosis in WS patients has only been reported from India in a 35-year-old man, and a histological diagnosis was not made, but only by symptoms and CT imaging. According to a systematic review of Japanese WS patients by Tsukamoto et al., fatty liver was found in 12 of 44 patients with WS, many of whom were not obese, but reported an association with high triglyceride and low high-density lipoprotein cholesterol levels. Similarly, the present case was not accompanied by obesity, and no increase in blood low-density lipoprotein cholesterol was observed, but a moderate increase in triglyceride ( 200 mg/dL) and low high density lipoprotein cholesterol levels ( 30 mg/dL) were observed. Visceral fat accumulation, insulin resistance, the presence of diabetes, aging and dyslipidemia have been reported as risk factors for non-alcoholic fatty liver disease/NASH. Furthermore, it has been reported that the progression of liver fibrosis in nonalcoholic fatty liver disease/NASH patients is associated with aging. It is possible that WRN gene mutations promoted aging in the liver and, coupled with the presence of NASH, contributed to the development of liver cirrhosis in this patient. Although patients with WS who lived longer than the present patient have been reported, in the present WS patient, arteriosclerosis had progressed, as evidenced by autopsy findings, but the possible reason for this patient’s longevity was that he did not develop a fatal myocardial infarction and lifethreatening malignant tumors. In addition, cataract surgery carried out performed in his 40s, and the onset of WS symptoms might be slower than usual. The reason might be related to the mutation patterns in the WRN gene, as this case was compound heterozygous. Although the previous report showed that there is no difference in major clinical signs and symptoms between homozygotes and compound heterozygotes, the effect of the mutation patterns on the onset and severity of each symptom is unknown, and requires further investigation. The current case suggests that fatty liver in WS patients is a risk factor for developing cirrhosis through NASH, and requires early appropriate intervention for liver damage.