Clinicopathological Features of He Shou Wu-induced Liver Injury

This Ancient Anti-aging Therapy Is Not Liver-friendly

Yan Wang; Lan Wang; Romil Saxena; Aileen Wee; Ruiyuan Yang; Qiuju Tian; Jiping Zhang; Xinyan Zhao; Jidong Jia

Disclosures

Liver International. 2019;39(2):389-400. 

In This Article

Discussion

He Shou Wu, also known as Polygonum multiflorum Thumb (PMT), is a popular Chinese herb that has been used as an anti-aging agent and a "cure-all" panacea tonic for various conditions including alopecia and graying of hair, cancer, diabetes, atherosclerosis, sleep disorders, and neurodegenerative diseases.[24]The root of PMT was first recorded in the herbal "Kaibaobencao" issued by the Imperial Court of the Song Dynasty (973–974 AD). Because herbs, including He Shou Wu, are often assumed to be natural and safe, growing numbers of individuals consume herbal products worldwide. However, increasing numbers of patients with He Shou Wu-induced liver injury have been reported in recent years. Review of the published reports in Pubmed and CNKI databases showed that by 2016, 612 cases of liver injury associated with He Shou Wu had been reported (most in Chinese), including reports of cirrhosis, liver transplantation, and death.[8,9,25]

In our study, the number of women affected by He Shou Wu was larger than that of men. Middle-aged women also appeared to be more liable to He Shou Wu-induced liver injury. One possibility is that middle-aged women are more likely than men to procure herbal products. On the other hand, gender-based biological differences may also be a confounding factor. Jaundice is the presenting feature in most cases; other common symptoms include fatigue and nausea. The pattern of injury is hepatocellular, based on both, the R-value (>5) and the histological findings of moderate to severe hepatitis with areas of necrosis. Almost half of the patients also have increased TB >100 μmol/L (5.8 mg/dL), with a quarter of them having serum TB >171 μmol/L (10 mg/dL). Those with persistently high TB have more severe disease and longer duration of hospitalisation.

Histological manifestations of He Shou Wu-induced liver injury have been reported; however, the major histopathological injury pattern has yet to be determined. Our biopsies show that the findings appear to be related to the timing of biopsy with the onset of symptoms and severity of disease. In early disease or more severe disease, the pattern is that of a moderate to severe hepatitis. The inflammatory infiltrate is present in both portal tracts and the lobular parenchyma, and is composed mostly of lymphocytes. Interface hepatitis is moderate to severe. Areas of necrosis are found, either around the central veins or scattered randomly in the parenchyma. Canalicular cholestasis may be prominent. In patients with less severe disease or when the biopsy is taken later in the course, the inflammation tends to be mild and is overshadowed by canalicular cholestasis. The interlobular bile ducts do not appear to be targets of injury and although mild and focal biliary epithelial injury may be seen, bile duct loss was not seen in our series. It thus appears that liver injury induced by He Shou Wu is primarily inflammatory in nature. As the inflammation subsides, canalicular cholestasis becomes apparent in the absence of significant bile duct injury or loss.

Our results concur with other studies in that most patients with He Shou Wu-induced liver injury manifest with jaundice and markedly increased TB, ALT and AST levels and that most of these patients recover fully.[11,13,16,17,26–31] We found that 27.6% of patients (8/29) were ANA positive (1:160 or 1:320), indicating that immunological disturbances may be involved in the pathogenesis of liver injury, in addition to direct toxicity. In other words, He Shou Wu-induced liver injury is idiosyncratic rather than intrinsic. This hypothesis is further supported by marked CD8 T lymphocytic infiltration (data not shown) and moderate to severe interface activity in most of our biopsied cases. Patient 20, whose liver injury persisted after cessation of He Shou Wu, achieved complete remission of disease with immunosuppressive therapy. At most recent follow-up, she has been on continuous prednisone therapy for the last 12 months. We are therefore unable to conclude whether this patient represents (autoimmune hepatitis) AIH-like DILI, drug-induced AIH, or typical AIH unmasked by the DILI episode. Disease course after cessation of prednisone will ultimately shed light on the correct diagnosis.

Twenty-five of the 29 patients recovered fully at various intervals after cessation of He Shou Wu. Although most patients recovered, one died of liver failure and three had persistent chronic HILI. Combining our data with previous studies, eight patients have died, four undergone liver transplantation, and four progressed to cirrhosis, underscoring that He Shou Wu can induce severe and fatal liver injury that requires careful monitoring and intensive care. Liver transplantation should be considered in patients with persistently high TB who are unresponsive to conventional therapy. Although cases of cirrhosis due to He Shou Wu have been previously reported in literature, none of our patients progressed to cirrhosis. Interestingly, 18 out of 29 patients satisfied Hy's Law;[32] amongst these, one patient had a fatal outcome. The mortality ~10%, which suggests that Hy's Law can be applied to He Shou Wu induced liver injury to predict outcome.

The present study only includes those patients with He Shou Wu-induced HILI who were sick enough to be hospitalised. Asymptomatic patients or those with mild liver disease are not included; thus, the entire spectrum of liver injury from this extremely popular herbal compound in the general population remains unknown. Furthermore, whereas all studied patients had ingested He Shou Wu, the majority had taken compounds with complex ingredients that also included He Shou Wu. The present study shares these two drawbacks with other previously reported series on He Shou Wu toxicity.

The main bioactive ingredients of He Shou Wu are believed to be anthraquinones, especially, emodin and 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside. The mechanisms may be associated with arresting the cell cycle and inducing apoptosis, necroinflammation, and steatosis.[33] The exact mechanism of He Shou Wu-induced injury remains to be defined.

Finally, there is an urgent need for public education on the harmful effects of He Shou Wu. Liver chemistries should be monitored regularly during and after consumption, and the drug withdrawn with the first signs of symptoms. Furthermore, governments should adopt stricter regulations or require that specific warnings be posted on herbal products containing He Shou Wu.

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