As shown in Fig. 3, this comprehensive search yielded 26 results from PubMed, 29 from Wanfang Data, and 146 from CNKI. To ensure data integrity and relevance, we meticulously refined the dataset. We initially excluded 22 duplicate results, followed by the elimination of 70 results that did not pertain to case studies. In addition, according to the inclusion and exclusion criteria, 108 articles were excluded. Subsequently, we selected 23 articles that met our inclusion criteria. From these articles, we synthesized a dataset comprising 1437 cases of Haff disease associated with crayfish consumption in China spanning the years 2000 to 2020(Table 3).

Fig. 3

Identification of studies via databases and registers

Table 3 Outbreaks of Haff disease after eating crayfish

In China, the onset of Haff disease due to crayfish consumption was initially observed in Beijing in 2000. Subsequently, there was a recurrence of cases in Nanjing in 2010, followed by incidences reported in various regions, including Jiangsu, Hebei, Shanghai, Anhui, Hubei, Guangdong, and Hong Kong over the subsequent decade. As depicted in Fig. 4, the majority of cases were concentrated in the middle and lower reaches of the Yangtze River Basin. Notably, the crayfish implicated in the Guangdong incident were traced back to the Yangtze River basin.

Fig. 4

The provinces of China where Haff disease caused by crayfish has been reported from 2000 to 2020

Causes of Haff disease were reported almost every year from 2010 to 2020, with outbreaks concentrated in the summer and a significant higher number of female patients than male patients. As shown in Fig. 5, the age distribution of patients ranged from 4 to 70 years old. As shown in Table 4, almost all patients had abnormal muscle pain (96.4%), and some patients showed changes in urine color (10.9%), abdominal pain (15.4%) and chest pain (26.6%).

Fig. 5

Patient’s age gender and symptom chart

Table 4 Symptoms and incidence rate of Haff disease

It shows clearly that the number of cases increased significantly in 2016, and there are studies that point out that the outbreak was related to the flooding that occurred in the Yangtze River basin in 2016 (Fig. 6). For example, during 2016 and 2017 in Tongling, Anhui Province, it was found that the number of cases decreased greatly in 2017. An outbreak of Haff disease also occurred in Wuhan, Hubei in 2014. These cases indicates that the outbreak may be related to flooding [24, 25].

Fig. 6

Number of Haff disease in three main province from 2013 to 2017

Li identified an aggregated outbreak of Haff disease in the Yangtze River in 2016, notably in Nanjing, Jiangsu Province, Wuhu, Anhui Province, and Maanshan, Anhui Province [28]. They determined that consuming crayfish roe and alcohol were risk factors for the disease, with a higher consumption of crayfish roe significantly increasing the risk.

In 2016, an outbreak of Haff disease occurred in Guangdong Province. Huang conducted investigations and mouse experiments and revealed that the disease-causing crayfish originated from the Yangtze River [31]. Only 18.9% of patients consumed crayfish meat alone, while others consumed various crayfish parts. Animal experiments corroborated epidemiological findings, indicating variability in infectivity among individuals.

Zha studied Haff disease cases in Maanshan city, Anhui Province, in 2016. They found that a small percentage of crayfish came from farms (5%), while the majority were either wild-caught (79%) or suspected to be wild-caught (16%) [24]. Additionally, consuming more than ten crayfish significantly increased the risk of Haff disease.

Li investigated Haff disease cases in Hubei Province from 2013 to 2017 [23]. They discovered that the number of confirmed cases exceeded the number of reported cases in the Hubei Foodborne Disease Surveillance System, suggesting potential underreporting or limitations in the surveillance system.

Pei analyzed Haff disease outbreaks in Wuhan, Hubei Province, Maanshan, Anhui Province, in 2019, and in Guangzhou, Guangdong Province, in 2020 [30]. The majority the crayfish processed at home (82.22%), and most of the crayfish had an unknown origin (71.11%), with 92.31% of crayfish with clear origins originating from wild catches. Their case-control study highlighted that consuming crayfish roe significantly increased the risk of RM, and each additional crayfish consumed escalated the risk.

The consumption of crayfish may lead to Haff disease, which has a range of clinical manifestations mainly due to rhabdomyolysis

Therefore, we attempted to identify the possible causes of Haff disease starting from the etiology of rhabdomyolysis. There are many causes of RM, the main ones being illicit drugs, alcohol abuse, medical drugs, trauma, viral myositis, and strenuous exercise, in addition to the presence of an underlying disease. The outbreak of Haff disease caused by crayfish has led to research on its causes, which has previously been conducted in the following areas.

RM may be associated with heavy metals, pesticides and antibiotics but the association was not significant

Because of the industrialization of human society, heavy metal pollution is prevalent in nature, and the pathogenicity of crayfish may be related to heavy metal pollution [32]. Crayfish have a strong ability to survive, grow and reproduce in environments with excessive levels of heavy metals, enriching heavy metals in their bodies through sediments and biological chains, and posing a risk to human health [16, 33]. The main heavy metals that are enriched in crayfish are cadmium (Cd), arsenic (As), lead (Pb) and so on. Among them, Cd can have adverse effects on teeth, bones, kidneys, etc [34]. As is carcinogenic [35]. Pb is a chronic poison that affects the mental health of children and causes mental retardation [36]. Excessive intake of heavy metals may lead to symptoms such as acute kidney damage in humans, so it is necessary to state whether heavy metals are the cause of the outbreak of Haff disease [37]. The average heavy metal concentrations in farmed crayfish were lower than those in wild crayfish [38]. An assessment of the association between trace element enrichment in crayfish and health risks in China revealed that crayfish consumption was associated with cancer risk in some provinces, and the risk was greater in children than in adults [39]. The hepatopancreas of crayfish is the tissue with the highest concentration of heavy metals, followed by the gills, exoskeleton, and muscle. The Pb and Cd contents of wild crayfish are slightly higher than the limits for human consumption recommended by the World Health Organization (1989), the U.S. Environmental Protection Agency (2000) and China’s national safety standards [40]. Hubei Entry-Exit Inspection and Quarantine Bureau through the filing of crawfish farming waters in Hubei Province, reported that the detection of heavy metals such as hydrargyrum (Hg), Pb, As, Cd and other heavy metals in crawfish did not exceed the maximum allowable residues in China and other countries and organizations. The average residue level is low and the risk to human health is relatively small. The results for other provinces are basically the same [41, 42]. Consumption of farmed crayfish has a very low effect on RM syndrome.

The development of agriculture and animal husbandry has introduced pesticide contamination into the natural environment, which can ultimately find its way into the human food chain through bioconcentration [43]. Crayfish have demonstrated the ability to thrive and reproduce in environments with pesticide residues, leading to numerous studies exploring the health risks associated with crayfish grown in pesticide-contaminated settings [16]. Many pesticides, including herbicides, insecticides, and fungicides, can potentially induce RM in humans [44]. Generally, when pesticides enter the natural environment, they have the potential to degrade, and when used responsibly, they are less likely to result in excessive pesticide residues in animals [45]. However, it’s crucial to note that severe pesticide contamination, such as the presence of chlordecone, can lead to persistent pesticide residues throughout various parts of crayfish. In these instances, these residues may not clear naturally in the short term, potentially contributing to the development of conditions such as prostate cancer [16, 46]. Consequently, while the impact of pesticides on crayfish consumption-related RM is generally low, the consumption of crayfish subjected to severe pesticide contamination can significantly affect human health.

With the advent of aquaculture, antibiotics have become a widespread tool for disease prevention and treatment [47]. Antibiotics primarily enter aquatic animals through their feed, with only a small portion being absorbed, while the majority remains in the environment [48, 49]. The excessive use of antibiotics, particularly unapproved antibiotics, poses risks to human health, aquatic animal production, and environmental safety [50]. Researchers conducted examinations of antibiotic levels in crayfish from Xuyi, Jiangsu Province, revealing a detection rate of 62% in 2017 and 63% in 2018. The highest furacilin content was found in crayfish shells and heads, while crayfish meat contained the lowest furacilin content. Notably, the detected antibiotic levels complied with relevant international regulations [51]. Studies have indicated a significantly higher incidence of RM when antibiotics like DAP are combined with statins, compared to when statins alone are used [52]. Furthermore, research has demonstrated that Maduramicin can induce RM in mice, suggesting a potential risk of Maduramicin entering the natural environment [53]. Antibiotics are commonly detected in the global farming industry, indicating that antibiotics are a plausible factor contributing to Haff disease [49, 54,55,56].

No relationship between RM and the use of crayfish wash powder

To make the color of crayfish more vibrant and easier to sell, there are many unscrupulous merchants use crayfish washing powder to clean the crayfish. Currently, the main components of crayfish washing powder is oxalic acid, citric acid, sulfites, etc., and consumers are prone to heart failure and fatal arrhythmias and life-threatening after long-term intake of oxalic acid [57].The oxalic acid content in crayfish can be determined by ion chromatography, and the researchers have concluded that the oxalic acid component can be detected in crayfish after cleaning them with crayfish washing powder [58]. As research progressed, researchers found that crayfish wash powder is readily soluble in water and that citric acid and sulfite are permitted food additives whose toxic effects do not cause RM but may lead to liver damage, apoptosis and obesity [59,60,61].

Some viruses appear in aquatic products, and some toxins in the crayfish may cause Haff disease

Since all of the cases reported so far have been due to the consumption of cooked crayfish, the scientific community generally agrees that there is a heat-stable toxin that causes RM [13]. At the time of the outbreak of Haff disease cases in the United States, the U.S. Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) analyzed known aquatic toxins including: ciguatoxin, saxitoxin, brevetoxin, tetrodotoxin. palytoxin, domoic acid, okadaic acid, and two blue-green algal or cyanobacterial toxins, microcystin and nodularin, but unfortunately all the samples tested were negative [8]. Among these toxins, ciguatoxin, saxitoxin, and tetrodotoxin belong to sodium channel blockers, which do not cause rhabdomyolysis [62]. The earliest literature suggested that a palytoxin or palytoxin-like agent in aquatic products causes RM, and the mechanism of action of palytoxin is almost identical to that of RM [63, 64]. In Japan, palytoxin was detected in the crab and sardines that caused the Haff disease, while no palytoxin toxin was detected when the same batch of crayfish consumed at the time of the Haff disease was tested in China [64,65,66]. Palytoxin mainly causes neurotoxicity, but RM from crayfish consumption is more likely to cause muscle toxicity, and palytoxin is more toxic, so it is thought that the real cause is not palytoxin [64,65,66]. It has also been suggested that crawfish contain cyanotoxin, which causes RM after consumption, but this toxin was not detected in the same batch of crawfish consumed at the time of illness [67,68,69]. Cyanobacteria are often found in the crayfish growing environment, increasing the possibility of toxin accumulation. Some studies have pointed out that crayfish can still survive in the presence of toxic cyanobacteria, and the body produces microalgal cyst toxins. Most toxins are present in the hepatopancreas and intestine, the muscle content is very low. But humans will ingest the entire abdomen, so there is a possibility of microalgal toxin poisoning [70]. Currently, the scientific community believes that there is an unknown thermostable toxin that causes symptoms associated with RM in consumers. More research is needed to identify this thermostable toxin as a means to identify the cause of and prevent the occurrence of Haff disease.