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growth factors proposed as regulators of the activity of the extracellular matrix include platelet-derived, Kupffer cell-derived, epidermal, and transforming growth factors (Prog Liver Dis 1990;9:143155). In addition to these growth factors, a number of other cytokines, e.g., interleukin-1, tumor necrosis factor, and interferon y, also may be involved in the control of the extracellular matrix. Noncytokine regulatory substances, such as retinoids and glucocorticoids, also may play a role in the activation of nonparenchymal cells responsible for the production of matrix components. Transforming growth factor J3, (at least five distinct TGF-Bs are now known) and TGF-(Y are structurally unrelated and appear to have distinctive cellular actions (Prog Liver Dis 1990;9:57-71). Transforming growth factor c1 is synthesized in liver as well as in extrahepatic tissues. It has been shown in hepatocytes in regenerating liver of laboratory animals (Proc Nat1 Acad Sci U S A 1989;86: 1558-1562). Transforming growth factor J3, is produced by many extrahepatic cell types (Proc Nat1 Acad Sci U S A 1988;85:15391543). In regenerating liver, it is probably produced by nonparenchymal cells; these include Kupffer cells, endothelial cells, and Ito cells (lipocytes). Transforming growth factor 8, has been shown to enhance the production of specific components of the hepatic extracellular matrix (J Clin Invest 1987;79:1285-1288) the production of enzymes involved in the degradation lular matrix (EMBO J 1987;6:1899-1904). The present study is an important contribution confirms a correlation of hepatic TGF-B, with other

and inhibit of extracelbecause markers

Vol. 101. No. 5

not identified. In addition to the normal nonparenchymal cells found in the livers of patients with chronic hepatitis and cirrhosis, it is possible that TGF-B, is produced by the T lymphocytes that infiltrate the liver in these chronic inflammatory disorders. Another area of interest not directly investigated here is the interaction of TGF-8, with TGF-cx. A growing body of experimental data indicates that such an interaction may occur. For example, in hepatocyte

cultures, TGF-8 appears to inhibit the induction of DNA synthesis by TGF-(Y(Prog Liver Dis 1990;9:57-71). In addition to providing directions for future studies of mechanisms of fibrogenesis and hepatic regeneration in chronic liver disease in human beings, this investigation also draws attention to the biological relationship between hepatic inflammatory disease, the expression of cytokine growth factors, and the role of the latter in regulating the activity of the hepatic extracellular matrix and hepatocyte regeneration. Because the transforming growth factors are not the only likely regulators of hepatic extracellular matrix activity, it may be useful in subsequent studies to measure the expression of other regulatory substances. Undoubtedly, expanded knowledge of these relationships will provide new understanding of the complex biology of hepatic disease and new tools for the assessment of therapy. R. S. KOFF. M.D.

it of

fibrogenesis in human liver disease. Although the correlation does not necessarily imply that TGF-P, is causally linked with the development of excess extracellular matrix in chronic liver disease, these observations support a contributory role for TGF-B, in the development of fibrosis. Because TGF-B, expression was correlated with histological evidence of piecemeal necrosis, lobular injury, and portal inflammation, rather than the presence of fibrosis alone, it is not yet clear which lesion is responsible for the synthesis of the growth factor. Although it is possible that no specific lesion can be implicated, the presence of piecemeal necrosis or portal inflammation may be critical features. The observed correlation of serum procollagen type III peptide with serum ALT levels suggests a relationship of fibrosis to hepatocyte degeneration and necrosis. Because TGF-B, mRNA levels can be measured in tissue obtained by percutaneous needle biopsy, it should be possible in future studies to obtain multiple samples during the course of chronic liver disease to define the earliest increases in growth factor expression that occur during the development of these lesions. Whether this will prove more useful than sequential measurement of serum procollagen type III peptide remains to be established. The current study also provides limited evidence that treatment with interferon alfa may reduce fibrogenesis in patients with chronic hepatitis C with or without cirrhosis. Does this reflect direct antiproliferative actions of interferon alfa, perhaps on the synthesis of TGF-B,, or does it indicate reduced viral load resulting from antiviral or immunomodulatory activity of interferon, secondarily resulting in less hepatocyte necrosis and hepatic inflammation? Many questions remain to be answered. For example, how early in the course of interferon alfa treatment can a change in TGF-8, expression be detected? Does it precede changes in hepatic necrosis or inflammation? Will this reduction in TGF-8, mRNA levels observed in interferon-treated patients persist on follow-up Is the reduction in TGF-8, levels after cessation of treatment? correlated with the disappearance of circulating hepatitis C virus RNA and/or hepatic hepatitis C virus RNA? These are questions that can begin to be answered using current polymerase chain reaction techniques to measure serum and hepatic levels of hepatitis C virus RNA and to correlate interferon alfa-induced changes with alterations in hepatic fibrogenesis and regenerative activity. The cellular source of detectable TGF-6, or TGF-(U in the livers of patients with chronic hepatitis or cirrhosis or in normal liver was

SOMATOSTATIN THERAPY FOR AIDS DIARRHEA: MUDDY WATERS Fanning M, Monte M, Sutherland

LR, et al. (Departments of Medicine, University of Toronto, University of Montreal, University of Calgary, Clinical Research, Sandoz Canada, Inc.; Department of Neuroendocrinology, Clinical Research, Sandoz, Basel, Switzerland). Pilot study of Sandostatin (octreotide) therapy of refractory HIV-associated diarrhea. Dig Dis Sci 1991;36:476-480 [April).

This paper reports the results of a pilot dose-escalating study of Sandostatin (octreotide; Sandoz Pharmaceuticals human Corp., East Hanover, NJ] in 17 nonconsecutive immunodeficiency virus (HIV] antibody-positive patients with refractory diarrhea. The entry criteria included demonstration of HIV antibody; clinical features of the acquired immunodeficiency syndrome (AIDS) or HIV infection; diarrhea of at least 1 month’s duration unresponsive to at least 1 week of conventional antidiarrheal therapy; and previous stool testing for bacteria, parasites, Cryptosporidium, and Clostridium difficile toxin and, in culture-positive cases, persistence of the infection despite specific therapy. Diarrhea was defined as more than three unformed bowel movements per day, stool volume of at least 1 L/day, or both; patients were asked to record the number and volume of stools in a diary. Octreotide therapy was started at a dose of 59 p,g SC three times a day and increased every 48 hours to 100 kg, 200 kg, and 500 pg three times a day, successively, if the diarrhea was not controlled with the previous dose. If

the diarrhea was not controlled, after 1 week at 500 pg three times a day, octreotide therapy was discontinued. If the diarrhea was controlled, octreotide was administered for an additional 2 weeks and then discontinued, to be restarted if the diarrhea recurred. Efficacy was defined as a decrease in the number of stools to no more than three per day, a 50% decrease in daily stool volume over 2 weeks, or both. Of the 17 patients entered into this study, 1 withdrew

November

SELECTED

1991

because the diagnosis of HIV-associated disease could not be confirmed; 5 cases were not assessable because of rapid progression of AIDS with early demise in 4 and neurological deterioration in 1. Thus, only 11 participants, 2 women and 9 men with a mean age of 38 + 11 years (range, 24-65 years), completed the trial. The patients had had AIDS for a mean of 5.1 k 4.5 months (range, 1-16 months), and 6 had previously had confirmed isolation of an intestinal pathogen. At the time of the study, only 3 participants had an intestinal pathogen, in each case Cryptosporidium. At the start of the study, the mean daily number of bowel movements was 8 k 4 (range, 3-14 movements). Stool volume was only measured in 6 subjects and ranged from 1 to 4.4 L/day. Overall, 5 of 11 patients responded to therapy with octreotide; 2 responded to the 50-Fg dose, 2 to the loo-kg dose, and 1 to the 250-p,g dose. One of the 3 patients with cryptosporidiosis responded. The mean number of bowel movements per day was shown to improve in the responders, but the extent of improvement varied from an impressive decrease of 12 to 2 per day in 1 case to slight improvement of 5 to 3 per day in another case. Data regarding stool volumes were quite incomplete. In 2 responders, stool volumes were not determined before treatment, and in 4 responders, stool volumes were not determined during the maintenance phase and after discontinuation of drug administration. In fact, complete data were only available on 1 responder whose stool volume deceased from 2515 mL (11 bowel movements/day) to 700 mL (3 bowel movements/day] with treatment, only to increase lo 4650 mL/day (19 bowel movements/day) with discontinuation of octreotide. A 6th patient had a moderate reduction in stool volume from 1375 mL to 900 mL on octreotide, 250 p,g three times

a day,

and

this

response

was

said

to be

clinically

relevant.

The 5 responders were ultimately maintained on longterm octreotide therapy. Three remained stable on the same dose of octreotide either until death or to date, while two experienced a worsening of diarrhea that required further increases in the dose of octreotide, with ultimate control of the diarrhea being achieved in only 1 of these patients. Toxicity due to octreotide was mild and limited to abdominal pain in 1 patient, nausea in 2 patients, including 1 who had

pain

at the

abnormalities authors value

site of injection, of uncertain

conclude in this

group

that

and

liver

significance octreotide

may

biochemical in 3 patients. be

of

test The

therapeutic

of patients.

Comment. Diarrhea is a common and important clinical problem in patients with symptomatic HIV infection. The frequency of diarrhea in HIV infection varies with the stage of disease, with a range of 30% at the time of the diagnosis of AIDS to as high as 80% at some time during the course of the illness (Gut 1989;30:195ZOO). There are many causes of diarrhea in patients with AIDS, and, as diagnostic testing has become more refined, new infectious causes of diarrhea continue to be identified: recent studies suggest that a thorough evaluation will now fail to reveal a specific cause of diarrhea in no more than lo%-30% of cases [Aliment Pharmacol Therap 1990:4:317-324). The numerous infectious causes of AIDSassociated diarrhea may be conveniently divided into two broad groups: those causes that lead to small-volume stools and that are generally associated with colorectal disease and usually characterized by painful defecation and rectal bleeding, and those causes

that

lead

to large-volume

often

profuse

SIJMMARIES

diarrhea

and

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that

are

typically associated with small intestinal disease often with crampy midabdominal pain and weight loss [Stand J Gastroenterol 1990; 25(Suppl 175):146-1581. The list of causative agents is quite long and includes enteric bacteria such as Salmonella, Campylobacter. and Shigella, and protozoa1 infections such as amebiasis. A large proportion of cases are related to opportunistic infections with Cyptosporidium, accounting for up to 50% of cases of diarrhea in patients with AIDS (Gut 1988;29:593-597; Gut 1989;34:773-780). Other potentially important causes of diarrhea in patients with AIDS include cytomegalovirus (CMV). h&cobacterium avium intracellulare, and Isospora belli (Semin Gastrointest Dis 1991;2:3-16). Recently, an increasing number of cases of diarrhea related to Microsporidia has been described in HIV-infected patients, particularly in those with severe immune deficiency (Hum Pathol199O;Zl: 475-481: Lancet 1991;337:895-898), and there have been anecdotal reports of numerous other organisms causing diarrhea. including Aeromonas(J Clin Gastroenterol 1989:11:552-5543, adenovirus (Gastroenterology 1991:100:976-979). and Histoplosmu (Dis Colon Rectum 1991;34:185-190). Compelling evidence suggests that enterocytes or monocytes in the lamina propria, or both, can be infected with HIV with resulting minor abnormalities of absorption and villous structure (Ann Intern Med 1989:111:15-21: Semin Gastrointest Dis 1991:2:3-16: Gastroenterology 1991;100:1521-1527). Alternatively, villous atrophy and crypt hyperplasia could result from T-cell dysfunction (Ann Intern Med 1991;114:366-372). In patients with diarrhea but no detectable enteric pathogen and these architectural abnormalities, diarrhea has been attributed to HIV infection per se. but this diagnosis of exclusion has been invoked less and less as additional potential pathogens are identified [Ann Intern Med 1990;113:444449). It has been suggested that the changes of HIV enteropathy may be important in producing micronutrient malabsorption at an early stage of disease. thereby inhibiting free-radical and potentiating the progression of HIV disease trointest Dis 1991;2:3-16). In general, the standard approach diarrhea is to obtain six stool samples

scavenging (Semin Gas-

to the AIDS patient with for microbiological assess-

ment and perform sigmoidoscopy with rectal biopsy (Gut 1989;30: 195-200). One study has shown that simple clinical features are a useful predictor of the likelihood that stool samples will yield a positive diagnosis (Gut 1990;31:886-889). Macroscopic abnormalities on sigmoidoscopy or microscopic evidence of severe inflammation on rectal biopsy suggest infection with a known pathogen. usually CMV or a bacterial infection. Patients with stool volumes in excess of 500 mL/day or those who have lost more than 5 kg in weight nearly always have a pathogen, often Cryvptosporidium. Additionally, an abnormally low Schilling test result indicating terminal ileal disease is likely to be found in cryptosporidial infection (Gut 1990:31:886-889). Further testing may increase the diagnostic yield slightly. Upper endoscopy and duodenal aspiration has been shown to be of value in detecting Isosporm. Cgptosporidium. and Helminthic infections in tropical countries (Bull Sot Pathol Exot Filiales 1989:82:316-320), and electron microscopy or light microscopy of Giemsa-stained or plastic sections of jejunal specimens are useful for detecting microsporidial infection (Gastroenterology 1991;100:271-273). although routine H&E staining may suffice ( J Clin Patholl991:44:558-563). Whether it is cost-effective to perform these invasive studies in all AIDS patients with diarrhea is debatable, and one analysis has suggested that initial empirical symptomatic therapy may be preferable (Ann Intern Med 1990:112:942-948). Although some causes of AIDS-related diarrhea may be treated specifically, such as Salmonella. Camp.vlobacter. and CMV infection. for most patients with AIDS-related diarrhea, even those with an identifiable pathogen, no specific therapy exists. For example, in the casca of Crypfospoddium. initiall>r promising agents such as

1448

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SUMMARIES

spiramycin, interleukin-2, diclazuril, and others have proved disappointing (Semin Gastrointest Dis 1991:2:3-16; Am J Gastroenterol 1991;86:615-618). It is in this context that somatostatin has been eyed with anticipation and hope. The long-acting, synthetic form of somatostatin, octreotide acetate, has been approved by the Food for use in controlling the symptoms of and Drug Administration

patients with metastatic carcinoid tumors and vasoactive intestinal peptide (VIP)-secreting tumors. On the basis of its widespread inhibitory effects on numerous gastrointestinal hormones, it has been hoped that octreotide might prove useful in a broad range of diarrhea1 diseases. Somatostatin has been shown to prolong intestinal transit time and to induce net intestinal water and electrolyte reabsorption in patients with diarrhea from a variety of causes. Additional justification for the use of somatostatin in AIDS-related diarrhea has been speculation that, because HIV has amino acid sequences in its protein coat homologous with VIP, HIV may induce diarrhea in part by activating VIP receptors in the intestine and that somatostatin may thus block a direct secretory effect of HIV (Drug Intel1 Clin Pharmacol 1988;22:154-155). Since 1988, anecdotal reports have suggested that somatostatin might be beneficial in some patients with AIDS-related diarrhea (Ann Intern Med 1988;108:708-709; Klin Wochenschr 1989;67:452-455; Klin Wochenschr 1988;66(Suppl 13):240-241; Drug Intel1 Clin Pharmaco1 1988;22:134-136: Can J Physiol Pharmacol 1986;64:70: Ann Intern Med 1988;109:680-681; Am J Gastroenterol 1991;86:615618). The report by Fanning and colleagues, the largest experience fully reported to date, highlights many of the difficulties in studying the efficacy of individual drugs in AIDS-related diarrhea and emphasizes the need for rigorously conducted placebocontrolled trials. Of 17 patients entered into the study, only 11 actually participated. Based on the data provided, the 11 were somewhat heterogeneous regarding the probable cause of their diarrhea. Disappointingly, the evaluation to determine the cause of diarrhea in these cases was quite limited; techniques were not used to detect mycobacteria, CMV, or microsporidia, thereby limiting the chance of identifying a subset of patients with HIV- or AIDS-related diarrhea who might benefit from octreotide. Moreover, the data regarding stool volumes were scant, and remarkably 2 of 5 “responders” to octreotide had no data whatsoever on stool volIt would be gratifying to have a single simple treatment for AIDS-related diarrhea, regardless of the cause. This study, preliminary as it is, tells us that octreotide is not that drug. It is possible that octreotide will prove useful for an identifiable subset of patients with AIDS-related diarrhea, but to determine this will require not only a placebo-controlled trial but also a full characterization of study participants and better compliance with stool collections. This pilot study offers only modest optimism for octreotide in that long-term benefit was ultimately achieved in only 3 of the original 17 patients. Still, additional symptomatic benefit was achieved in several other patients, and dramatic anecdotal successes are well described (Am J Gastroenterol 1991;86:615618). Clearly, the results support the authors’ recommendation for further controlled studies, several of which are now in progress (Gastroenterology 1990;98:A163). Progress in treating AIDS-related diarrhea is likely to come slowly, and much remains to be learned. In addition to identifying the full spectrum of pathogenic organisms involved in AIDS-related diarrhea, the specific mechanisms of pathogenicity require elucidation, and the role of HIV itself needs to be clarified. Intuitively, it seems that therapies aimed at specific causes of diarrhea, including HIV infection itself, are more likely to hold promise than lessspecific symptomatic therapies. Indeed, a recent report describes anecdotal efficacy of metronidazole in AIDS patients with diarrhea and intestinal microsporidiosis (Lancet 1991;337:895-898); whether the metronidazole affected the microsporidial infection, which

GASTROENTEROLOGY

Vol. 101, No. 5

persisted in some responders. or an unidentified copathogen is unclear (Lancet 1991;337:1488-1489). Additional reports raise the hope that immunological reconstitution with zidovudine may be effective in the treatment of cryptosporidiosis in patients with AIDS (Gastroenterology 1989;97:1327-1330). Where octreotide will ultimately fit into the scheme of things is not at all clear. L. S. FRIEDMAN. M.D.

H, ANTAGONISTS BY CONTINUOUS INFUSION: IV OR IG? Mutihy UK, Linscheer WG (Departments

of Medicine, State University of New York Health Science Center, and the Veterans Administration Medical Center, Syracuse, New York). Modulation of gastric pH by continuous gastric and jejunal infusion of cimetidine. Dig Dis Sci 1991;36:137141. The nutritional management of patients with feeding disorders can be facilitated by the endoscopic placement of gastrostomy or jejunostomy feeding tubes. The latter, although uncommonly necessary, can be particularly helpful in patients with tracheopulmonary aspiration due to chronic gastroesophageal reflux. However, a recent report by the authors of this paper has suggested that the use of feeding jejunostomy tubes (J tubes) may precipitate upper gastrointestinal hemorrhage. Although the pathogenesis of bleeding in this clinical setting has not been elucidated, Murthy and Linscheer hypothesize that the acid-stimulatory effects of intrajejunal protein, particularly in the absence of the buffering effects of food in the stomach, may predispose these patients to gastroduodenal ulceration and subsequent hemorrhage. Their hypothesis was examined in this study, during which patients were given nutritional supplementation with continuous intragastric or intrajejunal feedings containing the H, antagonist cimetidine. The patient population consisted of 26 men with swallowing disorders secondary to neurological disease who were otherwise stable and had no significant concomitant medical problems or history of gastric or small bowel surgery. A gastrostomy feeding tube (G tube) was placed in 19 patients, 6 of whom also underwent J-tube placement; in the remaining 7 patients, only a J tube was placed. Intragastric pH was monitored continuously with a nasogastric bipolar pH probe connected to a microprocessor-controlled recorder. Intragastric pH was measured during four study periods: fasting, tube feeding alone, cimetidine (60 mgih) alone, and tube feeding with cimetidine. Blood samples were taken for the subsequent measurement of serum cimetidine and gastrin concentrations. In the G-tube study, mean fasting pH increased from 1.32 * 0.10 to 2.78 2 0.30 during the administration of the tube feeding alone. Cimetidine increased fasting pH to 5.06 ? 0.35, which increased further to 5.14 ? 0.33 when the nutritional supplement was administered simultaneously. In the J-tube study, although fasting pH was similar (1.22 2 0.13), the administration of jejunal feeding decreased the intragastric pH to 1.02 2 0.14. Cimetidine increased the mean pH to 4.81 t 0.54, which decreased to 4.15 * 0.65 when the tube feedings were added. In all but one patient, serum cimetidine levels were considered thera-