Gout, with a section on ocular disease in the gouty

by Llewellyn J. Llewellyn

Inborn Errors of Metabolism

Apart from its intrinsic fascination, the tracing out of analogies, clinical or pathological, between diseases apparently diverse has often proved a fruitful source of enlightenment, for the natural history of disease is such that one disorder trenches upon the clinical territory of another, symptoms overlap and similarity if not community of origin is revealed.

Few will gainsay that gouty individuals are the victims of some inborn defect or eccentricity of metabolism, and instinctively the thought arises, are there no other disorders of like character? Immediately we bethink ourselves of alkaptonuria, cystinuria and pentosuria. Sir Archibald Garrod, as we know, classed these disorders as “chemical malformation” of hereditary origin. In other words, all are the outcome of an abnormality in intermediary metabolism.

In alkaptonuria the metabolic warp concerns the aromatic groups, in cystinuria the sulphur-containing radicles of the protein molecule. On the other hand, in pentosuria the origin of the endogenous pentose is variously ascribed to the nucleo-protein of the cell nuclei or to galactose. Lastly, in gout it is in the metabolism of nucleo-protein, or rather of the nucleic acids of the cell nuclei that the flaw resides.

We see, therefore, that Langdon Brown, discussing gout, is well justified in observing that, “We may look upon a person who is readily poisoned by purins in the same light as the person who has cystinuria, alkaptonuria, or pentosuria, i.e., they all lack a link in the chain of protein katabolism, so that intermediate products appear in the urine instead of the usual end-products.” In other words, they all display a pathological kinship, viz., in that they are all due to inborn errors of metabolism.

Certain broad clinical resemblances also obtain. All members of the group, including gout, display hereditary tendencies. All occur much more often in males than in females. They all alike tend to persist through life. Lastly, their distinctive chemical products, including uric acid, are all apparently of low toxicity.

But when we pass to the realm of their symptomatology, resemblance, if it does not cease, becomes relatively obscured. Cystinuria and pentosuria appear to be “harmless anomalies,” and the same is true of alkaptonuria. The cystinuric, albeit, does suffer with urinary concretions, and we may recall that some authorities hold that gout and uric acid calculi are not unrelated. As to alkaptonuria, it has this attenuated link with gout that in its later stages the victims thereof tend to develop a degenerative type of arthritis, while the frequently associated pigmentary change, ochronosis, has a predilection for deposition in the cartilages of the ears and joints.

But how colourless the clinical features of alkaptonuria, etc., as contrasted with the vivid arresting phenomena of gout! how remote the latter disorder from these “harmless anomalies”!

Apart from this general distinction, before gout could with justice be relegated to the same category of disorders, it would be necessary to prove that uric acid was an intermediary and not a terminal product of metabolism. All modern research, however, tends to indicate that uric acid is an end-product, and, moreover, that there are no uricolytic ferments within the body whereby its destruction can be accomplished. The term “chemical malformation,” therefore, though strictly applicable to alkaptonuria, cystinuria, etc., is inapplicable to gout. In other words, though, for example, the homogentisic acid met with in alkaptonuria is a “chemical malformation,” uric acid cannot be regarded as such. We see, therefore, that though gout may, superficially regarded, appear to have kinship with alkaptonuria and its congeners, yet in reality there is a profound and essential difference between it and this fascinating group of disorders.

CHAPTER VI
NUCLEIN METABOLISM

No hard and fast line can be drawn between the metabolism of protein and that of nuclein. For though, morphologically speaking, the nuclei of cells are sharply differentiated from the circumambient cytoplasm, and exhibit equally distinct staining reactions, yet, chemically, the differences between them are quantitative rather than qualitative.

But while, as far as chemical changes are concerned, nuclein metabolism is comparable with that of protein, nevertheless the former in respect of its “energy” and its bearing upon growth and production, is infinitely more vital, incomparably more active; for it is in nuclear changes that we may best discern evidence of the initiation of oxidation processes and other varieties of enzymatic activity. Moreover, as Walker Hall points out, “the presence of masked iron phosphorus and certain forms of fat in the cell nucleus strengthens this view, and thus we are led to recognise the important part played by the nucleus in the life of the cell, and to appreciate the influence of nuclein heredity in cellular exchanges.”

So much by way of prelude, but the story of the growth of our knowledge of nuclein as opposed to protein is so fascinating as to be worthy of a slight digression.