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

Results

Characteristics of Patients With He Shou Wu-induced Liver Injury

From August 2005 to August 2017, there were 547 individuals with discharge diagnoses of DILI. Of the 547 patients, 316 (57.8%) cases had DILI due to Traditional Chinese Medicine (TCM), 156 (28.5%) due to prescription medication, 60 (11.0%) due to both prescription medication and TCM. The remaining cases were attributed to dietary supplements [9 (1.6%)], chemical poisons [4 (0.7%)], combination of prescription medication and dietary supplements [1 (0.2%)], or the combination of TCM and chemical poisons [1 (0.2%)] (Figure 1 and Figure 2). Twenty-nine patients suffered liver injury due to ingestion of He Shou Wu. The median age was 53 years (range 15–74) and 75.9% (22/29) were women (Table 1). The most common symptom was jaundice (79.3%), followed by fatigue (55.2%), nausea (48.3%), abdominal distension (27.6%), itching (24.1%), fever (20.7%), and abdominal pain (10.3%). The median time to onset of disease after consuming He Shou Wu was 40 days (range: 4–300) and median duration of herb consumption was 30 days (range: 1–300) (Table 2). The median follow-up was 33.0 months (1.5–93.0). Liver biopsies were available for review in nine (Cases 7, 18–20, 23–26, 28) of these 29 patients. Five had taken pure He Shou Wu, while the remaining 25 had taken compounds containing He Shou Wu.

Figure 1.

Flow chart of the retrospective study of 547 hospitalised patients diagnosed with DILI. Of the 316 patients who had consumed traditional Chinese medicines (TCM), 29 were attributed to He Shou Wu with 9 undergoing liver biopsies

Figure 2.

Categories of drugs implicated in the 547 patients who were discharged with a diagnosis of DILI. TCM: Traditional Chinese Medicine

Biochemical Features of He Shou Wu-induced Liver Injury

All 29 patients showed (Table 2, Supporting information Table S1) marked increases in ALT (median: 995.0, range: 308.0-2052.0 U/L) and AST levels (median: 585.0; range: 260.6-1500.0 U/L), whereas ALP (median: 165.0, range: 75.2-440.0 U/L) and gamma-glutamyl transferase (GGT) levels (median: 200.0, range: 29.7-693.0 U/L) were only moderately increased. Because of the marked increase in ALT and moderate increase in ALP, R ratios of all patients were >5, indicating hepatocellular injury. Interestingly, 79.3% (23/29) of the study cohort showed serum elevations of TB (median: 103.3, range: 11.5-527.4 μmol/L), direct bilirubin (DB), (median: 68.8, range: 2.6-396.8 μmol/L), and total bile acid (TBA) (median 112.8, range: 2.2-388.3 μmol/L). Prolonged coagulation [international normalised ratio (INR) >1.5] was noted in three patients. Sixty-five percent (19/29) of the patients were negative or borderline positive (1:80) for antinuclear antibody (ANA), 20.7% (6/29) were moderately positive (1:160), and 6.9% (2/29) strongly positive (1:320). The serum ANA levels are tested by indirect immunofluorescence and the positive cut-off value is 1:80 rather than 1:40 in our hospital, which may be different from other medical centers. Furthermore, 21 of the 29 patients who were tested for antibodies to smooth muscle actin, soluble liver antigen, anti-liver-kidney microsomal-1 and anti-liver cytoplasmic antigen-1, were negative. IgG was increased (>1.1 ULN) in five patients.

Patient Characteristics According to Severity of He Shou Wu-induced Liver Injury

According to well-defined criteria, seven patients (24.2%) had mild liver injury, 13 (44.8%) moderate, six (20.7%) moderate-severe, two (6.9%) severe, and one (3.4%) fatal. Table 2 provides a comparison of patients' characteristics according to severity of liver injury. Age, sex, and clinical symptoms were similar in these three groups, as were peak ALT, AST, ALP, and GGT levels. As expected, patients with moderate, moderate-severe, severe, and fatal liver damage were more likely to have jaundice than those with mild liver injury. Furthermore, peak TB, DB, TBA and INR values at onset were significantly higher in the moderate-severe and fatal than the mild liver injury group. The interval between peak TB and 50% peak was significantly longer in those with severe disease than in other groups. The AST/ALT ratio was higher in the severe and fatal (median: 1.2; range: 1.1-1.4) than mild (median: 0.7; range: 0.4-1.2), moderate, and moderate-severe groups (median: 0.7; range: 0.4-1.4); however, these differences were not significant. IgG was also higher in the severe and fatal (median: 2590.0; range: 672.0-2790.0 mg/dL) than mild (median: 1110.0; range: 855.0-1,900.0 mg/dL) and moderate and moderate-severe groups (median: 1240.0; range: 900.0-2310.0 mg/dL); however, these differences were not significant, possibly because there were so few patients with severe disease. The proportion of ANA positivity was similar among the groups.

Histopathological Injury Patterns of He Shou Wu-induced Liver Injury

Nine of the 29 patients with He Shou Wu injury had liver biopsies. The median time from onset of symptoms to liver biopsy was 30 days (range: 6–37 days). There were no significant differences in major clinical and biochemical variables at onset between those who had had liver biopsies and those who did not (Supporting information Table S2). Patients whose TB declined slowly were more likely to have undergone biopsy than those whose TB recovered quickly, perhaps reflecting the clinical need to rule out bile duct damage and loss.

Predominant histological pattern was moderate to severe hepatitis with (4 cases) or without cholestasis (3 cases). It was seen in seven biopsies, and was characterised by a moderate to severe portal and lobular inflammation. The inflammatory infiltrate consisted mostly of lymphocytes; some cases contained a few intermingled eosinophils; but plasma cells were not excessive. The patient who improved only after administration of prednisone showed moderate to severe interface activity with septal fibrosis (Figure 3A). Perivenultitis characterised by variable degrees of inflammation and necrosis around central veins was seen. (Figure 3B-C). Some of these areas of necrosis were replaced by clusters of pigment-laden macrophages (Figure 3D). Ballooning of hepatocytes was also seen. There was no significant steatosis or demonstration of cholate stasis or hemosiderosis.

Figure 3.

He Shou Wu-induced liver injury showing. A, Moderate portal inflammation and interface hepatitis (Case 20) (H&E, ×400). B, Central perivenulitis with hepatocyte dropout and surrounding lobular inflammation (Case 20) (H&E, ×400). C, Centrilobular hepatocyte necrosis and dropout (Case 19) (Reticulin, ×400). D, Clusters of PAS-positive diastase-resistant ceroid-laden macrophages. (Case 24, PAS-D, ×400). E, Prominent hepatocellular and canalicular cholestasis (Case 26) (H&E, ×400), and (F) Brisk ductular reaction at the portal interface. The interlobular bile duct is preserved (Case 18) (cytokeratin 19 immunostain, ×200)

The predominant finding in Cases 26 and 28 was severe canalicular cholestasis (Figure 3E). Portal and lobular inflammation was only mild and consisted predominantly of lymphocytes. There was no interface hepatitis. The canalicular cholestasis in these two cases was out of proportion to the degree of inflammation and hepatocellular damage. Ductular reaction (Figure 3F) and sinusoidal lymphocytic infiltration were observed in seven cases. None of the biopsies showed any obvious inflammation of interlobular bile ducts or bile duct loss, apart from focal bile duct tortuosity and the ductal epithelium exhibiting either reactive changes or minimal cytoplasmic damage. Detailed scores for each patient are shown in Table 3.

Comparison of Patients who had Taken He Shou Wu Alone Versus Compounds Containing He Shou Wu

Five of the 29 patients had taken He Shou Wu alone and the remaining 24 compounds containing He Shou Wu. Supporting information Table S3 provides a comparison of patients who had taken pure He Shou Wu and those who had taken herbal compounds containing He Shou Wu. Interestingly, these two groups did not differ significantly in age, sex, clinical symptoms, or laboratory findings, including peak ALT, AST, AST/ALT ratio, ALP, GGT, peak TB, DB, TBA, INR, IgG, and ANA positive ratio. The latency, duration of drug consumption, time taken for ALT and TB to decrease to 50% and to normal levels was also similar between the groups, suggesting that He Shou Wu was the chief culprit of liver injury. Details of the components of those herbal compounds are listed in Supporting information Table S4.

Clinical Course and Outcomes of He Shou Wu-induced Liver Injury

The 29 patients were followed up for a median of 33.0 months (range: 1.5-93.0). Details of follow-up duration and final outcomes are shown in Table 1. Most of the patients (25/29) recovered completely in a median time of 45 days (range 10–138 days) for ALT/AST normalisation (Figure 4A,B) and 46 days (range 0–551 days) for TB/ALP normalisation (Figure 4C,D). Patients with moderate and moderate-severe liver injury took significantly longer to recover than the those with mild disease (median: 57; range: 17–551 days) vs. (median: 0; range: 0–38 days), P < 0.001). Of those who recovered, there were four cases of note comprising (a) Case 11 was rechallenged with He Shou Wu, (b) Case 20 with autoimmune features responded to corticosteroids, (c) Case 21 had another episode of HILI due to TCM, and (d) Case 24 had another episode of DILI due to antibiotic treatment for Helicobacter pylori infection.

Figure 4.

Liver chemistry test results which normalised in 25 patients. A, ALT; B, AST; C, TB; D, ALP. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TB, total bilirubin; ULN: upper limit of normal

There were four patients with poor outcomes, namely (a) Case 25 had a protracted clinical course with three episodes of liver injury (two attributed to He Shou Wu and one to other herbs; Figure 5A), (b) Case 26 had persistent cholestasis11 months after stopping He Shou Wu (Figure 5B), (c) Case 27 had chronic liver injury with possible autoimmune features but had not received any steroid treatment (Figure 5C), (d) Case 29 died of liver failure (Figure 5D).

Figure 5.

Changes in liver chemistries in three patients with poor outcomes and one with eventful clinical course. A, Case 25: Relapses due to rechallenge with He Shou Wu and another episode of TCM-induced DILI before eventual recovery after 35 months. B, Case 26: Developed chronicity after another episode of TCM-induced DILI in the 5th month of follow-up. C, Case 27: Progressed to chronicity by 10 months. D, Case 29: TB increased despite cessation of drugs and the patient eventually died. ALT, alanine aminotransferase; ST, aspartate aminotransferase; ALP, alkaline phosphatase; TB, total bilirubin; TCM, Traditional Chinese Medicine; ULN: upper limit of normal

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....