Fish Disease Leaflet 79

Systemic Noninfectious Granulomatoses of Fishes


National Biological Service
Leetown Science Center
National Fish Health Research Laboratory
1700 Leetown Road
Kearneysville, West Virginia 25430




Episodes of granulomatosis diseases in intensively cultured fishes are common but somewhat sporadic. They occur most frequently in the Salmonidae, and brook trout (Salvelinus fontinalis) and rainbow trout (Salmo gairdneri) are common victims. In recent years, a systemic granuloma disease has also caused serious losses of cultured gilthead bream (Sparus aurata). Few reports involving other species are known.

Occurrence in Salmonidae

Visceral granuloma of brook trout and nephrocalcinosis of rainbow trout are similar diseases. Both are chronic, degenerative, and inflammatory, and affect primarily the stomach and kidney. Mortality rates are not usually remarkable, and the diseases may pass unnoticed; however, crowding, transporting, or other stresses placed on fish in an advanced stage of these diseases sometimes result in massive mortality.

Clinical Signs

Advanced cases of visceral granuloma are characterized grossly by papillary growths on the surface of the stomach and throughout the visceral fat of brook trout. The kidney may be swollen and show various quantities of whitish streaks and round to oval spots. Because the kidney lesions of visceral granuloma are grossly similar to those of bacterial kidney disease (caused by Renibacterium salmoninarum), and the two diseases may occur concurrently or separately, careful diagnosis is necessary. Lesions of kidney disease contain small gram-positive diplobacilli and have a soft consistency due to caseous necrosis; in contrast, lesions of visceral granuloma contain no such bacteria, and have a tough consistency and gritty texture caused by the presence of calcium salts. Histologically, visceral granuloma lesions are typical granulomas with calcium phosphate concretions and Langhans' giant cells (Dunbar and Herman 1971).

Nephrocalcinosis of rainbow trout is characterized grossly by white to gray streaks and spots on the kidney. As the disease progresses, the kidneys swell. Gastric granulomas similar to those seen in visceral granuloma are present but rarely develop grossly.

Histologically, the kidney shows tubular dilation and degeneration, rather than organized granulomas (Harrison and Richards 1979). In extreme cases, granulomata or mineralized deposits may be found in the skeletal muscle. Concretions, when present, and fluids in the tubules and ureters contain calcium salts (Cowey et al. 1977; Gillespie and Evans 1979; Harrison and Richards 1979).

Cause of the Diseases

Visceral granuloma is associated with diet, although the specific cause has not been determined. Cottonseed meal may be related to the prevalence of the disease, because the signs can be produced by adding cottonseed meal to a chemically defined diet that is not known to produce visceral granuloma. In other studies, individual deletion of the various dry components of a meat and meal diet indicated that each of these components caused the disease to some degree. The omission of cottonseed meal, however, resulted in the greatest reduction in prevalence, from 91% to 5%. Calculations based on average values for feed ingredients indicated a direct relation with phosphorus levels (Dunbar and Herman 1971).

Information now available strongly suggests a basic relation between the nephrocalcinosis of rainbow trout and mineral balance. The disease can be produced experimentally by feeding diets having certain characteristics: magnesium-deficient, high-calcium (Cowey et al. 1977); high ratio of calcium or phosphorus to magnesium (Richardson et al. 1985); high selenium (Hilton and Hodson 1983; Hicks et al. 1984); or high cadmium and calcium (Dzuvic et al. 1986). Carlisle and Ketola (1981) reported nephrocalcinosis in Atlantic salmon (Salmo salar) fed excess phosphorus, but Hilton and Ferguson (1982) showed that the feeding of excess vitamin D3 did not cause the disease.

High concentrations of C02 have been correlated with increased prevalence of nephrocalcinosis (Békési et al. 1984; Smart et al. 1979; Gottschalk 1991). This effect is exacerbated by diets low in calcium and phosphorus (Smart et al. 1979).

Although water chemistry may influence the occurrence of nephrocalcinosis and visceral granulomas in salmonids, an imbalance of dietary calcium, phosphorus, and magnesium is now believed to be the basic cause. A ratio of 1:1:0.1 calcium to phosphorus to magnesium is suggested.

Occurrence in Sparidae

Gilthead bream (Sparus aurata) reared in intensive mariculture around the Mediterranean Sea are subject to a systemic granulomatosis that initially affects the kidney and causes acute mortality. In survivors the disease develops as a chronic inflammation affecting nearly all organs (Paperna 1987).

Clinical Signs

Histological examination of acute cases shows necrosis of kidney tubular epithelium and accumulations of tyrosine crystals, and the formation of epithelial granulomas in response to the tubular necrosis (Paperna et al. 1980).

In advanced cases, granulomas cause hypertrophy of the kidney and spleen and occur with increasing severity in most other organs. Exophthalmia and blindness are common in severe cases (Paperna et al. 1980). Crystalline deposits disappear from the chronic lesions.

Cause of the Disease

Prevalence of systemic granuloma in gilthead bream is correlated with long-term storage of formulated feeds, fish meal, or frozen fish. Alcohol extraction or autoclaving of a disease-producing feed did not affect the production of systemic granulomas. In the acute disease, the levels of tyrosine in the blood are 6-30 times above normal, and those in the kidney are 13-15 times above those in the blood. Related species that do not appear to concentrate tyrosine in this way do not develop systemic granuloma. Tyrosine catabolism does not appear to be at fault and overdosing with tyrosine produces the disease only when it is in practical formulations (Paperna et al. 1984). It thus seems that excess tyrosine is a sign, but not a cause. Colorni and Diamant (1991) list systemic granuloma as a disease of unclear etiology but Baudin-Laurencin and Messager (1991) indicate it is caused by ascorbic acid deficiency as in the Turbot (Scophthalmus maximus) (see below).

Occurrence in Turbot

"Granulomatosis hypertyrosinemia" has been reported from intensive cultured turbot in farms along the coast of France. All ages of animals appear susceptible and mortality can be high.

Clinical Signs

Reduced growth, general melanism, and mortality may be the first indication of the problem. Gross examination of the affected fish reveals ocular lesions, white to orange subcutaneous nodules, and granulomatous nodules in the hypertrophied kidneys. Tyrosine crystal deposits can be found in unfixed tissues, especially in the eyes and kidneys. Histological appearance of the granulomas is typical with central necrosis developing in advance lesions. Hypertyrosinemia may be extreme.

Cause of the Disease

Messager et al (1986) experimentally induced typical granulomatosis hypertyrosinemia in turbot fed diets deficient in ascorbic acid. Coustans et al (1990) confirmed the effect of ascorbic acid deficiency and further showed that the condition is exacerbated by hypovitaminosis of B group vitamins. Tyrosine catabolism is impaired leading to deposition of crystalline tyrosine and subsequent granulomatosis. While collage metabolism is impacted, skeletal deformities do not appear to be associated with this disease.

Occurrence in Other Species

Sporadic cases of systemic granulomatosis have been reported from a variety of species in small culture systems or display aquaria. Hernandez and Fernandez (1986) described seven cases diagnosed in goldfish (Carassius auratus) in Costa Rica, and Noga (1986) reported a case from a private breeder involving several African cichlids. No pathogen was isolated in these cases.

In the cichlids, the stomach was affected first; granulomas appeared in the submucosa and serosa as seen in visceral granuloma of brook trout. Fish with advanced cases showed involvement of the spleen, liver, visceral fat, pancreas, and kidneys. Goldfish showed lesions in the heart and cranial cavity as well as in other internal organs.

After a change of diet, the disease disappeared from the cichlid populations. Noga (1986) further implicated diet as the immediate cause by feeding the suspect diet and a known-quality diet to two groups of fish from a different source. Lesions developed only in fish fed the suspect diet. No more specific cause was sought.

I have seen similar lesions in several species of home aquarium fishes, again without demonstrable etiological agents.

Differential diagnosis in all cases of systemic granuloma must include consideration of infectious granuloma caused by mycobacteria, flavobacteria, or mycoses.


The use of carefully formulated feeds produced from high-quality ingredients and the proper storage of the ingredients and finished feeds should prevent most of the diseases described.



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