Haff disease is a rare syndrome characterized by unexplained myalgia and rhabdomyolysis, often accompanied by myoglobinuria, usually occurring within 24-72 hours of consuming certain types of freshwater or saltwater fish, or crustacean.
Haff disease has been identified during seasonal outbreaks in Europe, but can also occur sporadically or in small clusters. Most cases are associated with the consumption of cooked freshwater fish, although case clusters have also been reported following with boiled crayfish in Louisiana (2001) and China (2011–2013). A cluster has been identified amongst consumers of cowfish (alternatively known as boxfish) (Umisuzume, Lactoria diaphana), a saltwater fish, in Japan (2008-2009).
The majority of reported cases have been associated with freshwater fish, unlike other seafood-related illnesses such as ciguatera, scombroid, or paralytic shellfish poisoning, which are associated with saltwater fish.
Early epidemics in Europe, Russia and Sweden were associated with the ingestion of the same cooked species of freshwater eel (Anguilla anguilla), pike (Esox spp.) and burbot (Lota lota). Since this time, epidemic and sporadic cases have occurred globally. In the United States, most commonly associated with buffalo fish (Ictiobus cyprinellus), Atlantic salmon (Salmo salar) and boiled Red swamp crayfish (Procambarus clarkii); in China the freshwater pomfret (Colossoma brachypomum); in Brazil the Amazonian freshwater fish (Mylossoma duriventre); and in Japan cooked or raw cowfish (Umisuzume, Lactoria diaphana).
Diagnosis of Haff disease
The US Centre for Disease Control (CDC) case definition for Haff disease is:
Illness in a person with unexplained rhabdomyolysis who had eaten fish in the 24 hours before onset of symptoms. The laboratory marker used to define rhabdomyolysis was a fivefold or greater elevation in creatine kinase (CK) levels, with a muscle/brain (MB) fraction <5%.Buchholz 2000
The CDC case definition for Haff disease is broad, and leaves room for confounding factors, such as vigorous exercise. Careful history taking to identify other causes of rhabdomyolysis is paramount before making a diagnosis of Haff disease, especially in an area in which it has not yet been identified.
Clinical symptoms of Haff disease differ from the other fish-related toxic or bacterial illness. Symptoms of rhabdomyolysis predominate and neurologic features are absent.
Unusual smell or taste does not help identify toxic fish, and normal cooking methods cannot detoxify a fish capable of causing Haff disease. Because Haff disease may occur not only in epidemics but also in small clusters or sporadically, fish consumption should be included in the history of patients with unexplained rhabdomyolysis.Buchholz 2000
Management of Haff Disease
The toxin responsible for Haff disease targets and damages striated muscle and causes rhabdomyolysis with the release of myoglobin, creatine phosphokinase, and other muscle cell enzymes, especially lactate dehydrogenase (LDH). Myoglobin can obstruct renal tubules and cause acute renal failure. This toxin has not yet been identified, and some researchers have theorised that it may be similar to a marine toxin- palytoxin- which is found in saltwater fish and results in neurotoxicity and myotoxicity.
There is no antidote for Haff disease poisoning, and the treatment is entirely supportive, with analgesia, IV hydration to promote myoglobin excretion and the avoidance of nephrotoxic agents being the mainstay of treatment.
A small, retrospective cohort study in China compared the use of activated charcoal and mannitol with standard care in patients presenting with Haff disease. They found a statistically significant reduction in serum CK levels at 24-72 hours after admission. The clinical benefit was marginal, with the only result reaching statistical significance being a reduction in length of hospital stay by half a day and a minor decrease in subjective feelings of anxiety during admission.
History of Haff disease
1924 – First described in 1924 in Königsberg, Germany (now Kaliningrad, Russia) on the Baltic coast among fishermen and residents of the northern part of the Frisches Haff (now Vistula Lagoon), following the consumption of freshwater eel, pike and burbot. The outbreak of an illness characterized by sudden, severe muscular stiffness that was often accompanied by dark-colored urine.
Seit Juli 1924 tritt unter den Fischern und den anderen Anwohnern des frischen Hafts gehauft eine bisher unbekannte Erkrankung auf. Die Erkranknngsziifer ist ausserordentlich gross; bisher sind uber 400 Faille zur Kenntnis der Medizinalbehörden gekommen.
Die Symptome und der Verlauf sind höchst eigenartig: Die Fischer fahren am Abend gesund aufs Haft; gegen Morgen zwischen 2 und 6 Uhr überfällt sie mitten in der Arbeit (beim Rudern, Angelwerfen und Einziehen) ein plötzlicher sehr heftiger Sehmerz im Nacken und Kreuz, etwas später in den Armen und Beinen. Sie stürzen im Boot zusammen und meiden wegen der ausserordentlich heftigen Schmerzen, die krampfartigen Charakter tragen, die geringste Bewegung. Auch jede passive Bewegung ist sehr schmerzhaft. Die Atmung ist erschwert, die Kranken klagen über Luftmangel und starkes frostgefühl an Händen und Fussen. Zunächst besteht Harnverhaltung; nach einigen Stunden wird unter starken Schmerzen im Unterbauch ein dunkelkaffeebrauner oder etwas mehr rötlicher Urin entleert.
In 1-3 Tagen sind die Muskelsehmerzen im allgemeinen verschwunden oder wenigstens erträglich geworden; der 2. oder 3. Urin ist meist wieder hellgelb von normalem Aussehen; in einigen Fällen sind auch diese Harnportionen noch dunkel gefärbt. Tagelang bleibt eine grolsse Mattigkeit zurück, die die Fischer arbeitsunfähig macht. Häufig tritt bei den nächsten Ausfahrten aufs Haff die Erkrankung wieder auf; manche Fischer haben so bis zu 8 Anfälle der geschilderten Art durchgemacht.
Rosenow G, Tietz L. Die Haffkrankheit 1924
Since July 1924, a hitherto unknown disease has been occurring more frequently among the fishermen and other residents of the freshly detained. The incidence of disease is extraordinarily large; so far over 400 cases have come to the knowledge of the medical authorities.
The symptoms and the course are very peculiar: the fishermen go to work in good health in the evening; Towards morning between 2 and 6 o’clock in the middle of her work (rowing, fishing and pulling in) she suddenly felt a very strong feeling of feeling in the neck and lower back, a little later in the arms and legs. They collapse in the boat and avoid the slightest movement because of the extremely violent pains which are convulsive in nature. Any passive movement is also very painful. Breathing is difficult, the patients complain of a lack of air and a strong feeling of frost on their hands and feet. At first there is retention of urine; After a few hours, a dark coffee brown or a little more reddish urine is emptied with severe pain in the lower abdomen.
In 1 to 3 days the muscle fatigue generally disappeared or at least become tolerable; the 2nd or 3rd urine is usually light yellow again with a normal appearance; in some cases these portions of urine are still dark in color. For days a great languor remains, which makes the fishermen unable to work. The disease often reappears on the next trips to the lagoon; some fishermen have gone through up to 8 attacks of the kind described.
Rosenow G, Tietz L. Die Haffkrankheit 1924
1932 – In the autumn months of 1932 and the first few months of 1933 a fresh epidemic occurred
in the same region. Bruno zu Jeddeloh estimated that more than 1,000 cases occurred in the two epidemics.
1942 – Ragnar Berlin reported 11 cases in the 1942/43 epidemic in Sweden in patients following the ingestion of several species of cooked freshwater fish including burbot, pike, freshwater eel, and whitefish
…early in 1942, around the shores of a small lake called Ymsen, situated about one Swedish mile (10 km) south of Mariestad, in the province of Skaraborg. The area in question is a shallow, marshy lake about 8 km long and 3 km wide.
Of the 11 persons who were attacked, two have died, one of uremia, and the other showing signs of sepsis, with evidence of renal affection and moderate hematuria. Both were relatively young men, with fishing as their occupationBerlin, 1948
1965 – Leschchenko et al. in Russia experimentally induced a condition mimicking Haff disease in mice and cats by feeding them fresh fish implicated in a Haff disease outbreak.The responsible agent was thought to be an unknown fat-soluble, heat-stable freshwater algal toxin bio-concentrated in the aquatic food chain.
1984 – First cases of Haff disease in the United States were reported in Texas following the consumption of cooked freshwater, largemouth buffalo fish (Ictiobus cyprinellus), a bottomfeeding freshwater fish similar to carp
1985 – Sidorova et al. reported 10 outbreaks over 60 years in Russia. The periodic clusters of Haff disease in Russia and Sweden were caused by the ingestion of the same cooked species associated with the earliest reports including burbot, pike and freshwater eel.
2000 – Buchholz et al reviewed 12 sporadic cases in the US occurring since 1984. They found that all the patients had eaten buffalo fish before becoming ill; 8 of the 12 patients were California residents, although the buffalo fish was caught in Louisiana or Missouri waters.
2001 – Two more cases of Haff disease were confirmed in North Carolina following the consumption of baked Atlantic salmon (Salmo salar). Nine cases of Haff disease were reported by the Louisiana Office of Public Health in patients who resided within a 30-mile radius of each other in south-central Louisiana. All patients were hospitalized for suspected myocardial infarction with the onset of chest pain, dyspnea, diaphoresis, and nausea after consuming boiled crayfish purchased from the same local seafood vendor.
2009 – Cases of Haff disease reported following the ingestion of cooked and raw boxfish/cowfish (Umisuzume, Lactoria diaphana) in Japan (2008–2009). These cases were all characterized by severe muscle pain, “black” urine consistent with myoglobinuria, elevated CK levels consistent with rhabdomyolysis, and the absence of neurotoxic manifestations. The investigators concluded that the cause was a heat-stable myotoxin, similar to palytoxin, bio-concentrated in marine reef fish feeding on the Zoantharia species corals, such as parrotfish, a common cause of marine palytoxin poisoning in Japan.
2013 – Haff disease associated with the ingestion of the freshwater fish Pacu Manteiga (Mylossoma duriventre) in Brazil
2015 – James Henry Diaz performed a retrospective case-series analysis to (1) identify global seafood vectors of Haff disease; (2) describe and compare the most commonly recurring clinical and laboratory manifestations of Haff disease following crayfish and fish consumption and (3) compare the Haff disease toxidrome with other similar seafood poisoning toxidromes.
Samples of the suspected seafood in 21 cases were tested (CDC or US FDA) as negative for the known aquatic toxins: ciguatoxin, saxitoxin, brevetoxin, tetrodotoxin, palytoxin, domoic acid, okadaic acid, and two blue-green algal or cyanobacterial toxins – microcystin and nodularin
The bioaccumulation of a new heat-stable, fresh, and/or brackish/salt-water algal toxin in seafood, similar to palytoxin, but primarily myotoxic and not neurotoxic, is suspected for causing Haff disease…The mechanism of muscle damage in Haff disease is not via GABA antagonism as in water hemlock or cicutoxin poisoning or sodium channel effects as in palytoxin poisoning…Haff disease is neither cicutoxin poisoning nor palytoxin poisoning; it more closely resembles marine palytoxin poisoning without significant neurotoxicityDiaz, 2015
2016 – Outbreak in Salvador, Brazil. A total of 67 cases were detected, the last case was reported on 5 April 2017. Cases consumed ‘Olho de Boi’ (Seriola spp.) and ’Badejo’ (Mycteroperca spp.). Review of the first 15 cases defined in patients presenting with:
- sudden onset muscle pain in more than two body regions and not related to intense physical activity;
- elevated levels of creatinine phosphokinase (CPK) [>5x upper limit of normal 170 U/L (i.e. 850 U/L) within 24 hours of presentation;
- ingestion of fish or fish products <72 hours prior to symptom onset.
- Haffkrankheit; Haff syndrome
- Myoglobinuria paroxysmalis
- Haff–Iuksov–Sartlan disease; Iuksovsk–Sartlansk disease
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- Berlin R. Haff disease in Sweden. Acta Med Scand. 1948; 129(6): 560-572.
- Leshchenko PD, Khoroshilova NV, Slipchenko LM, Kaznacheĭ RIa. Nabliudenie Gaffsko-Iuksovskoĭ bolezni [Observation of Haff-Uchs disease cases]. Vopr Pitan. 1965 Nov-Dec;24(6):73-6
- Sidorova LD et al. Porazhenie pochek pri alimentarno-toksicheskoĭ paroksizmal’noĭ mioglobinurii (Iuksovsko-Sartlanskoĭ bolezni) [Kidney lesions in dietary and toxic paroxysmal myoglobinuria (Iuksovsk-Sartlansk disease)]. Terapevticheskiĭ arkhiv. 1985; 57(10): 120-3.
- Centers for Disease Control and Prevention (CDC). Haff disease associated with eating buffalo fish–United States, 1997. MMWR Morb Mortal Wkly Rep. 1998 Dec 25;47(50):1091-3
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- Huang X., Li, Y., Huang, Q. et al. A past Haff disease outbreak associated with eating freshwater pomfret in South China. BMC Public Health 2013; 13: 447.
- Tolesani Júnior O, Roderjan CN, do Carmo Neto E, Ponte MM, Seabra MC, Knibel MF. Haff disease associated with the ingestion of the freshwater fish Mylossoma duriventre (pacu-manteiga). Rev Bras Ter Intensiva. 2013 Oct-Dec;25(4):348-51.
- Zhang B, Yang G, Yu X, Mao H, Xing C, Liu J. Haff disease after eating crayfish in east China. Intern Med. 2012;51(5):487-9
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- Chan TY. The Emergence and Epidemiology of Haff Disease in China. Toxins (Basel). 2016 Dec 1;8(12):359.
- Bandeira AC et al. Clinical and laboratory evidence of Haff disease – case series from an outbreak in Salvador, Brazil, December 2016 to April 2017. Euro Surveill. 2017 Jun 15;22(24):30552
- Wu CJ, Zhou HJ, Gu W. Clinical characteristics of patients with Haff disease after eating crayfish. World J Emerg Med. 2019;10(3):156-159.
- Lv Jian et al. Efficacy of Active Charcoal and Mannitol in Patients with Haff Disease Caused by the Consumption of Crayfish (Procambarus clarkii): A Retrospective Cohort Study. Evid Based Complement Alternat Med 2020; 2020: 2983589.
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