plasia and DNA aneuploidy? Gastroenterology 1992;102:18771880. 2. Schrumpf E, Elgjo K, Fausa 0, Gjone E, Kolmannskog F, Ritland S. Sclerosing cholangitis in ulcerative colitis. Stand J Gastroenterol 1980;15:689-697. 3. Ohlsson R, Danielsson A, Jlrnerot G, Lindstrijm E, L66f L, Rolny P, Rydhn B-O, Tysk C, Wallerstedt S. Prevalence of primary sclerosing cholangitis in ulcerative colitis. Gastroenterology 1991;5:1319-1323. 4. Wiesner RH, LaRusso NF. Clinicopathologic features of the syndrome of primary sclerosing cholangitis. Gastroenterology 1980;79:200-206. 5. Aadland E, Schrumpf E, Fausa 0, Elgjo K, Heilo A, Akhus T, Gjone E. Primary sclerosing cholangitis: a long-term follow-up study. Stand J Gastroenterol 1987;22:655-664. 6. Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts? Ann lntern Med 1985:102:581-587.
Indian Childhood Uniform Criteria
Dear Sir: I have read with interest the article by Adamson et al.’ There is a great deal of confusion in the literature on Indian childhood cirrhosis (ICC) because of varying diagnostic criteria.’ We have recently published a detailed histopathology of the liver in ICC and its changing spectrum after treatment with penicillamine.3 The diagnostic criteria, currently accepted by the majority of groups working on ICC in India, have been specified in that article. The case reported by Adamson et al. showed distinct micronodules, a concentration of orcein in the periportal zone and in the initial biopsy specimen, and distinct periportal necrosis. There was no distinct neutrophilic infiltration, and there is no mention whether there was diffuse pericellular fibrosis. The features of this case go against a diagnosis of classical ICC. The only overlapping features with ICC in this case were presence of Mallory’s bodies and excess copper. There could be situations other than ICC in which copper accumulates in the liver, and a finding of Mallory’s bodies by itself is nonspecific. Thus, the case could at best be described as atypical ICC, a diagnosis given when all criteria for typical ICC3 are not found by biopsy. We do not know if atypical ICC is a spectrum of ICC or a distinct disease entity. Until this matter is resolved by long-term studies, it is better to classify such cases separately as atypical ICC. We also have no record of biopsy-proven classical ICC converting to conventional cirrhosis without treatment. Thus, it would be advisable not to include this case as a classical ICC case. S.R. BHUSNURMATH Department of Experimental Medicine Postgraduate Institute ofMedical Education and Research Chandigarh-160012, India
Several lists of pathological criteria making the diagnosis of ICC have been published over the years. If we use the six criteria listed by Dr. Bhusnurmath et al. in his recent article,’ our patient clearly satisfies four of these: (a) diffuse degeneration of hepatocytes, (b) absence of regenerative nodules, (c) presence of Mallory’s bodies, and (d) diffuse excess of copper binding protein by orcein staining. A fifth criterion, the presence of pericellular or creeping fibrosis, was not mentioned in our case, but the first biopsy specimen did contain “mild fibrosis” (legend to Figure 1) and the second “dense fibrous tissue” (page 1774, paragraph 2, line 3). Not all specimens need to show all features of ICC at all times, and the pericellular fibrosis might have been present between 22 and 30 months of age in our patient. The final criterion, a predominant neutrophilic exudate in the nodules, was not seen in our patient; rather there was “some lymphocytic infiltration of the parenchymal nodules.” We note that the requirement for a neutrophilic exudate is not included in all other lists of pathological criteria for ICC. We would also point out that the finding of electron-dense aggregates containing copper and sulfur by electron-probe analysis virtually seals the pathological diagnosis. Moreover, our patient’s clinical course was absolutely typical, and his biochemical findings included ceruloplasmin levels and urinary copper levels that were entirely characteristic of ICC. Hence, we would contend that our case represents at least (not “at best”) atypical ICC. Surely the fact that the patient was of Western European background makes him somewhat atypical to begin with. We do agree that future elucidation of the basic defect in ICC will sort out how atypical our patient truly is. Incidentally, Dr. Bhusnurmath’s letter mentions that in the initial biopsy distinct periportal necrosis was found. However, our paper notes that at 22 months of age there was “some septate fibrosis but without prominent periportal necrosis” (pages 17731774). WILLIAM A. GAHL, M.D.,PH.D. Human Genetics Branch National Institute of Child Health and Human Development Room 98242, Building 10 Bethesda, Maryland 20892 ZACHARY GOODMAN Department ofHepatic Pathology Armed Forces Institute of Pathology Washington, D.C. JEAN OLSON Department ofPathology The Johns Hopkins School of Medicine Baltimore, Maryland 1. Bhusnurmath SR, Walia BNS, Singh S, Parkash D, Radotra B, Nath R. Sequential histopathologic alterations in Indian childhood cirrhosis treated with d-penicillamine. Hum Path01 1991;22:653-658.
Adamson M, Reiner B, Olson JL, Goodman Z, Plotnick L, Bernardini I, Gahl WA. Indian childhood cirrhosis in an American child. Gastroenterology 1992;102:1771-1777. L-Carnitine for Treatment of Distal Josh VV. Indian childhood cirrhosis. Perspect Paed Path01 Ulcerative Colitis 1987;11:175-192. Dear Sir: Bhusnurmath SR, Singh S, Devina P, Radotra BD, Walia BNS. I congratulate Sheppach et al.’ for the successful treatment of Sequential histopathologic alterations in Indian childhood cirrhosis treated with d-penicillamine, Hum Path01 1991;22:653- distal ulcerative colitis with retention enemas containing sodium 658. butyrate. The therapeutic rationale is based on the possibility that patients have either reduced levels of colonic short-chain fatty acids (SCFAs; e.g., acetate, propionate, and butyrate) or decreased Reply. We appreciate Dr. Bhusnurmath’s comments concerning capability for mitochondrial oxidation of the fatty acids. Elevated our case of ICC in an American child.
luminal butyrate thus corrects the SCFA shortfall or exerts a “mass-action” effect on mitochondrial oxidation. As noted by the authors, impaired mitochondrial oxidation of SCFAs may be due to decreased levels of coenzyme A. If so, L-carnitine may enhance the effectiveness of butyrate. Transport of fatty acids into the mitochondrion requires carnitine.’ Acyl coenzyme A is transferred into the intermembrane space and exchanges with carnitine to yield acylcarnitine. Transport of acylcarnitine through the inner membrane is followed by acyl transfer back to coenzyme A and initiation of oxidation. LCarnitine has been administered orally to patients with propionic acidemia and other disorders of organic acidemia and aciduria.3 Excess organic acids [e.g., propionate) are eliminated as urinary acylcarnitine. This action appears contrary to the desired enhancement of butyrate oxidation in colonic cells. However, formation of acylcarnitine releases coenzyme A, thus facilitating oxidation of SCFAs such as butyrate. Inclusion of L-carnitine in the butyrate enema is a convenient means of testing therapeutic effectiveness. However, simultaneous presentation of L-carnitine and butyrate to the colonic cell may not be the most effective protocol. Oral administration of L-carnitine to improve overall availability of coenzyme A may be more appropriate. In fact, oral L-carnitine alone may provide therapeutic and prophylactic benefit. The side effects of long-term oral administration of L-carnitine, 2 g/day, are relatively modest4 Nevertheless, initial trials with patients with ulcerative colitis should be conservative. JOHN A. JOHNSON
Section of Dermatology Department of Internal Medicine University of Nebraska Medical Center Omaha, Nebraska 68198-4360 1. Scheppach W, Sommer H, Kirchner T, Paganelli G-M, Bartram P, Christ1 S, Richter F, Dusel G, Kasper H. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 1992;103:51-56. 2. Chalmers RA, Roe CR, Tracey BM, Stacey TE, Hoppel CL, Millington DS. Secondary carnitine insufficiency in disorders of organic acid metabolism: modulation of acyl-Co-A/CoA ratios by L-carnitine in vivo. Biochem Sot Trans 1983;11:724-725. 3. Chalmers RA, Roe CR, Stacey TE, Hoppel CL. Urinary excretion of t.-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of L-carnitine. Pediatr Res 1984;18:1325-1328. 4. Fernandez C. Profile of long-term L-carnitine therapy in cardiopathic patients. In: Ferrari R, DiMauro S, Sherwood G, eds. L-carnitine and its role in medicine: from function to therapy. New York: Academic, 1992337-341.
Renal Insensitivity to Atria1 Natriuretic Peptide in Patients With Cirrhosis and Ascites Dear Sir: We read the paper by Gin& et al.’ with great interest. The authors report no natriuretic response to infusion of pharmacological doses of atria1 natriuretic peptide (ANP) in 11 of 16 patients with cirrhosis and ascites. In 7 nonresponders, infusion of norepinephrine (NE) to increase baseline mean arterial pressure (MAP) to levels comparable with those of responders did not restore sensitivity to ANP. In a previous study from the same unit, using rats
GASTROENTEROLOGY Vol. 103, No. 5
with carbon tetrachloride-induced cirrhosis and ascites, the natriuretic and diuretic effects of ANP were increased by the administration of angiotensin II or norepinephrine.’ Gin&s et al.’ propose that the discrepancy between their two studies might have arisen because of a greater increase in MAP in the rat experiments and suggest the likely mechanism to have been greater renin-angiotensin inhibition. However, the effects of infusions of norepinephrine and angiotensin II on the kidney are complex, because both these agents cause renal vasoconstriction as well as an increase in systemic arterial pressure.3 In addition, norepinephrine has a direct, sodium-retaining effect on the proximal tubule.3 Our work on the isolated perfused kidneys of rats with carbon tetrachloride-induced liver cirrhosir? should be considered in this context. The advantage of the isolated perfused kidney preparation is that it allows study of the effect of increasing perfusion pressure4 or infusion of ANP5 in the absence of confounding external neural and humoral factors. In the first study,4 we report a normal natriuretic response in the isolated kidney of cirrhotic rats (which retained sodium avidly in vivo) to stepwise increases of perfusion pressure from 90 to 150 mm Hg. This finding supports the suggestion of Gin&s et al,’ that anti-natriuretic mechanisms extrinsic to the kidney, such as increased activity of the adrenergic or renin-aldosterone systems, operate in vivo and contribute to impaired sodium excretion in cirrhosis. In the second study, we examined the effect of increasing concentrations of ANP on the isolated kidneys of control and cirrhotic rats at constant perfusion pressure (110 mm Hg). The addition of ANP to the perfusate resulted in a smaller increase in sodium excretion in the isolated kidney of the cirrhotic animals compared with the controls at concentrations of 10, 50, and 200 pmol/L. This finding suggests that, in addition to other anti-natriuretic influences that may exist in vivo, intrinsic renal resistance to the natriuretic action of ANP exists in cirrhosis and may contribute to sodium retention. We agree with Gin&s et al.’ that the likely reason for the difference between their clinical and animal findings is the greater increase in arterial pressure provoked by pressor agents in the animal experiments. Greater suppression of the renin-angiotensin system may have been responsible, but because the response of the isolated kidney to ANP is extremely sensitive to perfusion pressure,” an alternative possibility is that by increasing the arterial pressure sufficiently in their animal model of cirrhosis* they have shown the intrinsic renal natriuretic response to increasing perfusion pressure.4 MARIOS Z. PANOS JOHN D. FIRTH CHRISTOPHER D. GOVE ANTHONY E. G. RAINE ROGER WILLIAMS
Institute of Liver Studies King’s College Hospital London SE 5, England
1. Gines P, Tito L, Arroyo V, Llach J, Salmeron JM, Gines A, Jimenez W, Badalamenti S, Rivera F, Rodes J. Renal insensitivity to atria1 natriuretic peptide in patients with cirrhosis and ascites. Effect of increasing systemic arterial pressure. Gastroenterology 1992;102:280-286, 2. Lopez C, Jimenez W, Arroyo V, et al. Role of altered systemic hemodynamics in the blunted renal response to atria1 natriuretic peptide in rats with cirrhosis and ascites. J Hepatol 1969;9:217-226. 3. Laragh JH, Cannon PJ, Bentzel CJ, Sicinski AM, Meltzer JI. Angiotensin II, norepinephrine, and renal transport of electrolytes and water in normal man and in cirrhosis with ascites. J Clin Invest 1963:42:1179-1191.