Persistent, Fulminant Watery Diarrhea Complicating Chronic Active Hepatitis

Vol. 62, No.2 Printed in U. S. A.

GASTROENTEROLOGY

Copyright @ 1972 by The Williams & Wilkins Co.

PERSISTENT, FULMINANT WATERY DIARRHEA COMPLICATING CHRONIC ACTIVE HEPATITIS GERALD T. KEUSCH, M.D., MARSHALL M. KAPLAN, M.D., DUANE SMITH, M.D., AND PETER RAVANESI, M.D.

Infectious Disease and Gastroenterology Services, Department Tufts-New England Medical Center, Boston, Massachusetts

of Medicine,

A 52-year-old nurse with well documented chronic aggressive hepatitis and postnecrotic cirrhosis developed fulminant and persistent watery diarrhea. The stool volumes and ionic composition were identical to those seen in true Vibrio cholerae syndromes. The diarrhea was associated with diffuse inflammation of the small intestine, lasted 6 weeks, and responded only to corticosteroids. It recurred when steroids were tapered. No etiology could be established for the diarrhea. Multiple stool cultures failed to demonstrate any pathogen. No tumor capable of secreting diarrheogenic substances was found at autopsy. As in true Vibrio cholerae, the intestine was able to absorb sodium and water when glucose was present in the intestinal lumen. Case Report

Many patients with chronic active hepatitis have associated extrahepatic disorders, including mild diarrhea and ulcerative colitis. 1 Fulminant persistant diarrhea due to diffuse small bowel disease has not been previously reported. We recently have seen a patient with chronic active hepatitis, without neoplasia, who developed diffuse inflammation of the small intestine with fulminant diarrhea that lasted 6 weeks and responded only to corticosteroids. The stool volume and ionic composition were identical to those found in cholera syndromes 2, 3 and in certain hormoneproducing tumors. 4

A 52-year-old nurse was first admitted to the New England Medical Center Hospitals in December, 1966, for evaluation of painless jaundice, intermittent pruritus, and a 15-lb weight loss of at least 12-month duration. The physical examination was normal except for faint scleral icterus and a soft, nontender liver that was palpable 3 em below the right costal margin. A complete blood count, urinalysis, and serum electrolytes were normal. The bilirubin was 3.8 mg per 100 ml, 1.6 mg direct; alkaline phosphatase 35.2 Bodansky units; serum glutamic oxaloacetic transaminase 20 Karmen units; serum glutamic pyruvic transaminase 90 U; prothrombin time 86%; serum albumin 3.8 g per 100 ml; globulin 3.8 g per 100 ml; IgG 12.0 mg per ml; IgA 1.6 mg per ml; and IgM 2.7 mg per ml. An upper gastrointestinal series was normal, and an oral cholecystogram showed a faintly visualized gallbladder without gallstones. A percutaneous needle biopsy of the liver demonstrated chronic aggressive hepatitis with early cirrhosis (fig. 1). Results of tests for lupus erythematosis cells, antirheumatoid factor and antimitochondrial antibody were negative, but smooth muscle antibody was present. Therapy was begun with prednisone, 30 mg per day, and the patient was discharged from the hospital. There was very little improvement in liver

Received June 25, 1971. Accepted September 1, 1971. Address requests for reprints to: Dr. Marshall Kaplan, Tufts-New England Medical Center, 171 Harrison Avenue, Boston, Massachusetts 02111. This work was supported by Research Grant AM 10571 and Training Grants AI 00276 and AM 5424 from the National Institutes of Health. Dr. Keusch was a fellow on the Infectious Disease Service and is now on the staff of The Mount Sinai Hospital, New York, New York. Dr. Kaplan is the recipient of a research career development award from the National Institutes of Health. 307

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FIG. 1. Percutaneous needle biopsy of the liver. Portal triads are enlarged and infiltrated with chronic inflammatory cells. Thin strands of connective tissue and inflammatory cells extend from the triads and break the parenchyma into nodules (Masson trichrome x 120).

function tests, and prednisone was increased to 45 mg per day 4 weeks after discharge. Three months after beginning prednisone there was still no response. The prednisone was gradually discontinued, and azathioprine (Imuran), 150 mg per day, was initiated. This was continued for 1 year, during which time the patient felt well and was able to work as a secretary. However, the bilirubin fluctuated between 1 and 4 mg per 100 ml, the alkaline phosphatase between 17 and 35 Bodansky units, and the serum glutamic oxaloacetic transaminase between 65 and 150. The liver was now palpable 4 cm below the right costal margin, and the spleen could be felt for the first time. A repeat liver biopsy showed marked progression of the hepatic lesion to postnecrotic cirrhosis (fig. 2). Because there had been no apparent response to azathioprine, it was discontinued. The patient continued asymptomatic on no medications for 1 V2 years. During the summer of 1969, clinical jaundice, fatigue, and anorexia reap-

peared. She developed severe diarrhea in early December and was admitted to the hospital in deep coma on December 27, 1969. There had been no antecedent blood loss, recent travel, exposure to infection, and no ingestion of drugs or alcohol. Australia antigen and antibody were not present in serum. On physical examination, she was afebrile, deeply jaundiced, and had poor skin turgor. Her blood pressure was 105/80 mm Hg, the pulse 80 per min and regular, and the respiratory rate 16 per min. The liver was firm, smooth, and extended 5 cm below the right costal margin. There was no ascites. A small rectal prolapse was noted. She responded to painful stimuli but did not respond to vocal command. Laboratory data are summarized in table 1. The values are consistent with a contracted extracellular fluid space secondary to dehydration from diarrhea. Metabolic acidosis with hypokalemia was present. Examination of a

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Gram stain of the stool showed three to four polymorphonuclear leukocytes per high power field and an assortment of gram-positive and gram-negative bacteria. Eleven stool cultures in the first 2 weeks of hospitalization did not contain enteric pathogens. Neither ova nor amoebae were found in multiple stool specimens, and the guaiac test was negative. Chest X-ray was normal. She was thought to be in hepatic coma induced by hypokalemia which was due to gastroenteritis of unknown etiology. Treatment

was initiated with intravenous fluid and electrolyte replacement and neomycin, 1 g every 6 hr, by nasogastric tube. During the first 24 hr, she received 4 liters of intravenous fluid, 160 mEq of KCl, and 180 mEq of NaHCO a with considerable laboratory improvement, but only modest clinical progress. She had 11 pale, nonfeculent watery bowel movements and 13 more the following day. Her weight was unchanged from that on admission. Gram stain of the stool now showed five to seven polymorphs per high power field, occasional gram-

FIG. 2. Percutaneous needle biopsy of the liver obtained 15 months after the first liver biopsy. Dense bands of connective tissue disrupt the liver architecture, a picture diagnostic of postnecrotic cirrhosis (Masson trichrome x 120). TABLE

1. Laboratory data

Test

Hematocrit (%) . ........ .. . .. . .. . .. ... .. . . . . . White blood count (x 10 3) • . . •• . . • . . . • •. • . . • • •• % Polymorphonuclear cells .. . ........ . . . ... . . . Blood urea nitrogen (mg per 100 ml) ... . ...... . . Creatinine (mg per 100 ml) ............ . .. . . . .. . Na (mEq per liter) ... . ............. . .. . ...... . K (mEq per liter) . . . . ..... . ... . ... .. . .. .... . . Cl (mEq per liter) . . ........... . ....... . .... . . CO 2 content (mEq per liter) .. . .. . .... .. .. . .. . . Arterial pH . . .............. . .... . . . . ..... . . . . pC0 2 • . . . . . . . . . . . . • • . . . . . . . . . . • . . . •. . Total protein (g per 100 ml) ......... . ...... . Serum glutamic pyruvic transaminase (Karmen units) .... . . . ........ . . . ...... .. .... . . .. . . Bilirubin (mg per 100 ml) .. . . . . . . ....... . . Alkaline phosphatase (Bodansky units) ........ . . Prothrombin time (%) . . . . . . .. . .... . . . .

Admission

Day 1

Day 7

Day 14

54.0 16.9 64.0 40.0 2. 1 132.0 2.6 103.0 14.0 7.39 17 .5 8.5

43.0 12.2 44.0 1.4 147.0 3.0 101.0 20.0

27.5 24.3 79.0 56.0 2. 1 141.0 4.7 108.0 16.0 7.38 24.5 6.8

26 .5 18.5 75.0 9.0 1.2 137 .0 4.2 107.0 13 .0

295.0

300 . 0

280.0 13.4

90.0 8.2

38.2 80.0

68.0

71.0

11.0

11.1

42.5 22 .0

17.0

4.8

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positive cocci, and a striking absence of gramnegative rods. A presumptive diagnosis of staphylococcal enteritis was made and the neomycin discontinued. Vancomycin, 0.5 g every 6 hr via nasogastric tube was begun. However, staphylococci were not grown from the stool cultured prior to vancomycin therapy or thereafter, and 5 days later it too was discontinued. In spite of attempts to control the diarrhea with opiates and anticholinergics, she continued to have six to 16 watery stools daily. Proctoscopy and barium enema were negative. Contrast studies of the small bowel demonstrated thickened mucosal folds with narrowing of the lumen from the duodenum to the terminal ileum. Selective superior mesenteric and celiac arteriography showed patent superior mesenteric, splenic, and portal veins. There was no evidence of tumor. For accurate determination of the stool volume, a rectal tube was inserted and 3.0 to 7.5 liters per day were collected. Continuous nasogastric suctioning returned only 200 to 500 ml per 24 hr. The pH was 4.5 and the calculated H + concentration was 0.014 mEq per liter. Fluid and electrolyte balance were maintained by intravenous replacement of 5 to 9 liters per day. Stool electrolytes were repeatedly measured. The sodium concentration ranged from 90 to 120 mEq per liter, the potassium from 12 to 26 mEq per liter, and the chloride from 81 to 118 mEq per liter. Stool protein concentration was less than 100 mg per 100 ml. By the end of the 2nd week she had gained 4.5 kg in weight and was mentally clear. Under normal conditions 5 as well as during active Vibrio cho/erae,6 the small bowel responds to the presence of intraluminal glucose by enhanced sodium absorption. To test glucose-facilitated sodium absorption, the perfusion solution described by Pierce et al. 6 was infused over 8-hr periods via nasogastric tube at a rate of 400 to 500 ml per hr. Three separate perfusions were done (table 2). Net stool output markedly decreased during both glucose perfusion periods and there was, in fact, net retention of 370 ml during the second period. Perfusion with the nonactively transported hexose fructose did not reduce stool ouput, a result similar to that reported in patients with Vibrio cho/erae. 7 Small bowel biopsy was performed with the Crosby-Kugler capsule. Under a dissecting microscope leaf-shaped villi were absent and only small convolutions were seen. Histological sections of two separate biopsies demonstrated marked shortening of the villi which were lined by flattened cuboidal cells. The lamina propria

was crowded with inflammatory cells which consisted of lymphocyte, plasma cells, and eosinophiles. The patient haa, at this point, been in the hospital for 3 weeks and had experienced continuous, massive, painless, watery diarrhea for at least 6 weeks. Intravenous methylprednisolone (Solumedrol), 20 mg every 6 hr was started. Stool output dramatically diminished during the second 24 hr of corticosteroid therapy. Two days later, oral prednisone, 80 mg per day, was substituted, and for the first time in 4 weeks intravenous fluid was discontinued. The patient was passing three to four semiformed stools daily. After 1 week the prednisone was reduced to 40 mg per day. A repeat jejunal biopsy appeared less abnormal under the dissecting microscope, but the poor orientation of the first specimen prevented meaningful comparison of the microscopic sections. However, the epithelial cells were now columnar (fig. 3). After 2 weeks of prednisone therapy, there was little evidence of malabsorption. Fecal fat averaged 7.1 g per day during a 3-day period on a high fat diet (normal < 5 g per day). For the next 5 weeks the patient did well. Prednisone was gradually tapered and finally discontinued. Within a day after stopping prednisone, diarrhea recurred. She lost 2 kg in weight and became disoriented, necessitating intravenous fluids once again. Prednisone, 20 mg per day, was reinstituted. Mter initial improvement, gastrointestinal bleeding occurred. Repeat X-ray studies and sigmoidoscopy failed to demonstrate the source. She did not respond to conservative management, hepatic encephalopathy recurred, and death followed in the middle of the 15th week in the hospital. At postmortem examination, severe postnecrotic cirrhosis with the sequelae of portal TABLE

2. Stool output in response to intralumirwl

perfusion with hexose and sodium

Perfusion solution°

None· " .. . . Glucose ... . . None ....... . Fructose .. . . None . , . . .. . Glucose .. ... None .. .. ...

Gastric input

Total stool output

ml

ml

1100 3000 1530 3400 1200 4000 260

2900 3287 3890 5000 2260 3630 1800

Net stool output

ml

1800 287 2360 1600 1060 -370 1540

aNa, K, Cl, hexose. • Water was allowed and measured during control periods.

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FIG. 3 . Peroral biopsy of the proximal jejunum 9 days after beginning prednisone. The epithelial cells are now columnar and the nuclei are regularly aligned at the cell base. Normal villi are still absent, and the lamina propria still infiltrated with inflammatory cells consisting of lymphocytes, plasma cells, and eosinophils (hematoxylin and eosin x 120).

hypertension were present. The liver weighed only 570 g and was stained green. The extrahepatic biliary tract and portal vein were both widely patent, and there were no gallstones. The entire bowel was edematous with evidence of diffuse small vessel oozing in the stomach and cecum. Despite a careful search of the pancreas and thyroid gland, there was no evidence of tumor. Histological examination revealed extremely advanced postnecrotic cirrhosis (fig. 4). The small intestinal histology was difficult to interpret because of postmortem autolysis. However, villi were present, mucosal cells were columnar, and there was no evidence of any tumor infiltrate. In addition, there was mild chronic thyroiditis.

Discussion The primary disease and that which ultimately caused death was chronic active hepatitis with progression to postnecrotic cirrhosis and liver failure. The remarkable feature of the terminal

hospitalization was the profound diarrhea with passage of an isotonic liquid stool and a small content of protein. When dehydration had been corrected by vigorous fluid and electrolyte replacement therapy, the patient passed the startling quantity of 5 to 7.5 liters of fluid per day. Such fulminant diarrhea may occur in certain enteric infections including cholera, 2 staphylococcal enterocolitis,8 shigellosis, 9 and salmonella enteritis. 10 These diseases, however, are self-limited by either rapid death or recovery and ordinarily yield the responsible microorganisms on culture of the stool. No recognized enteric pathogen was recovered from our patient, and in contrast to the self-limited bacterial diarrheas, her symptoms were unremitting. Another cause for such severe diarrhea is the release of certain hormones by tumors. Chronic massive diarrhea associated with gastric hypersecretion and ulcer

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FIG. 4. Postmortem section of liver. Small islands of degenerating parenchymal cells are st:rrounded by dense bands o f connective tissue (Gomori trichrome x 120).

disease (Zollinger-Ellison syndrome) has been observed in patients with gastrinsecreting pancreatic tumors. 11 Other patients with similar tumors have had severe watery diarrhea with achlorhydria or hypochlorhydria and no ulcer diathesis. In these individuals, the diarrhea was thought to be related to the release of secretin 12 or possibly to prostaglandin 1 3 and has prompted the use of the term " pancreatic cholera" to call attention to the severity of the diarrhea. 14 Other tumors secreting prostaglandins, particularly medullary carcinoma of the thryoid, 1 5 may also cause severe diarrhea. Finally, intractable watery diarrhea has been reported in association with intestinal lymphoma. 16 There was no gastric hypersecretion in our patient and no evidence of any tumor at autopsy.

Chronic active hepatitis per se has not been previously associated with such severe diarrhea. Mild diarrhea, usually of unknown cause, has been reported in 30% of such patients, and ulcerative colitis has been documented in up to 10%.17 However, fulminant diarrhea due to diffuse inflammation of the small bowel has not been previously reported. Other causes for the diarrhea, such as an untoward reaction to either the oral neomycin or vancomycin with which the patient was initially treated, are unlikely since the diarrhea began before these drugs were instituted and lasted long after they were stopped. The demonstration of normal glucosefacilitated sodium absorption suggested that the diarrhea was at least in part the result of secretion of water and electrolytes by the small bowel, similar to cholera. Non-

CASE REPORTS

Febrnary 1972

tropical sprue, which could have accounted for the abnormal small bowel histology, may result in a secretory state in the jejunum. IS However, the presence of glucose in the lumen does not affect the transport of water or electrolytes in sprue l S and in this regard differs from the disease encountered in our patient. Stool volumes greater than 3 liters per day with electrolyte composition approaching that of serum would also be very unusual for gluten-induced enteropathy l9 as would the failure to respond to a gluten-free diet. The flattened villi in the small bowel biopsy and the intense inflammatory infiltrate in the lamina propria led us to institute steroid therapy. There was a rapid and impressive reduction in stool volume. The temporal relation to steroid administration was proven when prednisone was later discontinued for several days with almost immediate increase in the stool volume to over a liter per day. Reinstitution of the drug resulted in a prompt response again. The etiology of this syndrome and its relationship to the severe underlying liver disease remain open to speculation. REFERENCES 1. Mistilis SP, Skyring AP, Blackburn CRB: Natu· ral history of active chronic hepatitis. 1. Clinical

2. 3. 4.

5.

features, course, diagnostic criteria, morbidity, mortality and survival. Australas Ann Med 17: 214-223, 1968 Watten RH, Morgan FM, Songkhla YN, et al: Water and electrolyte studies in cholera. J Clin Invest 38:1879-1889, 1959 Lindenbaum J, Greenough WB, Benenson AS, et al: Non-Vibrio cholera. Lancet 1:1081-1083, 1965 Kraft AR, Tompkins RK, Zollinger RM : Recognition and management of the diarrheal syndrome caused by non beta islet cell tumors of the pancreas. Am J Surg 119:163-170, 1970 Malawer SJ, Ewton M, Fortran JS, et al: Interrelation between jejunal absorption of sodium, glucose, and water in man (abstr). J Clin Invest 44:1072, 1965

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6. Pierce NF, Sack RB, Mitra RC : Replacement of water and electrolyte loss by an oral glucoseelectrolyte solution. Ann Intern Med 70:11731181, 1969 7. Hirschhorn N, Kinzie JL, Sachar DB, et al : Enteral glucose solutions to decrease stool output in cholera. N Engl J Med 279:176-181,1968 8. Dearing WH, Heilman FR: Micrococcic (Staphylococcic) enteritis as a complication of antibiotic therapy: its response to erythromycin. Proc Staff Meet Mayo Clinic 28: 121-134, 1953 9. Morgan HR: The Shigella and bacillary dysentery, Bacterial and Mycotic Infections of Man. Fourth edition. Edited by RJ Dubos, JG Hirsch. Philadelphia, JB Lippincott Co, 1965, p 634 10. Saphra I, Winter JW: Clinical manifestations of salmonellosis in man. An evaluation of 7779 human infections identified at the New York Salmonella Center. N Engl J Med 256:1128-1134, 1957 11. Zollinger RM, Moore FT: Zollinger-Ellison syndrome comes of age. Recognition of the complete clinical spectrum and its management. JAMA 204:361-365, 1968 12. Zollinger RM, Tompkins RK, Amerson JR, et al : Identification of the diarrheogenic hormone associated with non-beta islet cell tumors of the pancreas. Ann Surg 168:502- 521, 1968 13. Sandler M, Karim SMM, Williams ED : Prostaglandins in amine-peptide-secreting tumors. Lancet 2:1053- 1054, 1968 14. Matsumoto KK, Peter JB, Schultze RG, et al: Watery diarrhea and hypokalemia associated with pancreatic islet cell adenoma. Gastroenterology 50:231-242, 1966 15. Williams ED, Karim SMM, Sandler M: Prostaglandin secretion by medullary carcinoma of the thyroid. A possible cause of the associated diarrhea. Lancet 1:22-23, 1968 16. Seijffers MJ, Levy M, Hermann G: Intractable watery diarrhea, hypokalemia, and malabsorption in a patient with Mediterranean type of abdominal lymphoma. Gastroenterology 55: 118-124, 1968 17. Mistilis SP, Blackburn CRB: Active chronic hepatitis. Am J Med 48:484-495, 1970 18. Fordtran JS, Rector FC, Locklear TW, et al: Water and solute movement in the small intestine of patients with sprue. J Clin Invest 46:287-298, 1967 19. Cooke WT: Water and electrolyte upsets in the steatorrhea syndrome. J Mount Sinai Hosp NY 24:221-231, 1957