HEPATITIS COMPLICATING CHRONIC HÆMODIALYSIS

675

HEPATITIS COMPLICATING CHRONIC

HEPATITIS IN PATIENTS UNDERGOING CHRONIC HÆMODIALYSIS

HÆMODIALYSIS ELI A. FRIEDMAN M.D. CAREER SCIENTIST, NEW YORK CITY HEALTH RESEARCH COUNCIL; ASSISTANT PROFESSOR OF MEDICINE, STATE UNIVERSITY OF NEW YORK, DOWNSTATE MEDICAL CENTER

GERALD E. THOMSON M.D. INSTRUCTOR IN STATE UNIVERSITY OF NEW

MEDICINE, YORK, DOWNSTATE

MEDICAL CENTER

From the Department of Medicine, State University of New York, Downstate Medical Center, and the Kings County Medical Center, Brooklyn, New York

hepatitis attributable to the administration of blood, serum, or plasma was not reported until 1943 (see Palmer 1962). Since the 1939-45 war a firm association VIRAL

has been established between the infusion of blood or blood

products and the subsequent development of hepatitis. The risk of post-transfusion hepatitis has been reported to be as low as 1 case for every 1775 units (Grady et al. 1964) and as high as 13 cases per 1000 units of blood transfused (Mirick et al. 1965). Any therapeutic regimen which includes blood-transfusion introduces the serious, and at present unavoidable, hazard of hepatitis-virus infection. The urxmic patient subjected to long-continued intermittent haemodialysis requires one to four transfusions of " ’ packed erythrocytes per month to sustain a hsematocrit of 25-30% (Pendras and Erickson 1966). Additional exposure to hepatitis virus may be encountered when a blood-primed hæmodialyser is used for dialysis. We report here 2 fatal and 4 non-fatal cases of hepatitis among 19 patients who underwent a total of 1407 haemodialyses. Patient Population The dialysis unit has been in operation since March, 1964. Until October, 1964, a twin-coil haemodialyser primed with two units of fresh bank blood was utilised to effect twiceweekly haemodialysis for each patient. Thereafter, all chronic dialyses were performed with a Kiil parallel-flow haemodialyser, which does not require priming with blood. Repeated access to patient’s blood is permitted by the insertion into an extremity of indwelling arterial and venous teflon-silastic cannulas Quinton et al. 1960). Each of the 19 patients (15 men and 4 women), treated with repeated hxmodialysis, had intrinsic renal disease without systemic disease (chronic glomerulonephritis in 14 patients, chronic pyelonephritis in 4, hereditary nephritis in 1). Inadequate renal function for preservation of life was documented in each instance by endogenous-creatinine clearance values of less than 3 ml. per minute and the failure of intensive conservative

therapy. Results

patients dialysed with blood-primed twin-coil hæmodialysers,2 (cases 1 and 2) contracted hepatitis and : d. A 3rd patient in this group (case 3) had transient ..’.:mical abnormalities consistent with the diagnosis of anicteric hepatitis (see accompanying table). Of 14 patients dialysed with Kiil haemodialysers, which :, not require blood-priming, 3 (cases 4-6) contracted -fatal hepatitis and recovered fully. Of 5

CASE-REPORTS

Case1

A 20-year-old college student had had progressive renal due

chronic glomerulonephritis for two years before hospital because of fatigue, nausea, and headache. On admission, the blood-urea-nitrogen was 180 mg. per 100 ml., to

admission to

Units of whole blood or packed erythrocytes administered up before onset of hepatitis.

to ten

days

serum-creatinine 18 mg. per 100 ml., heamatocrit 21%, endogenous-creatinine clearance 1-2 ml. per minute, serumbilirubin 0.3 mg. per 100 ml., serum-glutamic-oxaloaceticacid-transaminase (S.G.O.T.) 28 units, serum-alkaline-phosphatase 10-4 King-Armstrong units, and total serum-cholesterol 200 mg. per 100 ml. Progressive peripheral sensory and motor neuropathy, metastatic calcification, and arthritis of the shoulders and wrists complicated the patient’s early care. Intermittent haemodialysis was performed twice weekly with a twin-coil haemodialyser primed with two units of fresh bank blood for four months, with no improvement in either peripheral neuropathy or metastatic calcification. For the next four months the frequency of dialysis was increased to three to four times weekly without detectable clinical improvement. During the ninth month of hsemodialysis therapy the patient developed icterus, an exacerbation of nausea and vomiting, and a confused sensorium. The serum-bilirubin was 4-5 mg. per 100 ml., serum-alkaline-phosphatase 24-5 King-Armstrong units, S.G.O.T. 136 units, and cephalin flocculation 4+. Despite hxmodialysis every other day the patient’s condition deteriorated over the next two weeks, and he lapsed into hepatic coma. Terminally the blood-ammonia level was 445 µg. per 100 ml. During the nine months of hæmodialysis therapy the patient had been exposed to 208 units of blood by transfusion or admixture with dialyser prime. At necropsy mononuclear-cell infiltration and hepatic parenchymal necrosis consistent with viral hepatitis were found. Case 2 A 43-year-old married businessman was admitted to hospital because of azotxmia and hypertension due to chronic glomerulonephritis. Proteinuria had been noted during an examination for life assurance nine years previously. The patient had been well until a year before admission when hypertension, proteinuria, and anaemia were detected. Progressive fatigue, nausea, and leg oedema developed in the next twelve months. On admission physical examination disclosed pallor, deep urochrome pigmentation of the skin, and 3+ leg oedema. The hamiatocrit was 23%, blood-urea-nitrogen 125 mg. per 100 ml., serum-creatinine 13 mg. per 100 ml., serum-bilirubin 0-1 mg. per 100 ml., and S.G.O.T. 14 units. To prevent chronic urasmia, the patient required dialysis, which was performed for five months as intermittent peritoneal dialysis and then as intermittent hsemodialysis with a bloodprimed twin-coil hsemodialyser. During the fifth month of twice-weekly intermittent hsemodialysis the patient complained of nausea, insomnia, and fatigue. Two days after the onset of these symptoms, icterus and asterixis were noted. The serumbilirubin was 8-3 mg. per 100 ml., serum-alkaline-phosphatase 19-4 King-Armstrong units, and S.G.O.T. 1150 units. Despite attempts to sterilise the bowel with neomycin, repeated enemas, and gastric lavage, and continuous hxmodialysis resulting in the reduction of the blood-urea-nitrogen level to 26 mg. per 100 ml. and serum-creatinine to 1-2 mg. per 100 ml.,

676

dialysis, utilising a. Kiil dialyser, the patient complained of fatigue and nausea.

Liver-function tests, pre-

viously normal, were now as follows: serum-alkaline-phosphatase 358 King-Armstrong units, S.G.O.T. 92 units, serum-bilirubin 0-6 mg.

per

100 ml. During the next three weeks, the patient experienced easy fatigability and anorexia associated with sustained elevation of the alkaline-

phosphatase and transaminase values. Neither hepatomegaly nor icterus was detected during the four-week illness. Disappearance of the fatigue and malaise coincided with return to normal of the serum-alkaline-phosphatase and S.G.O.T. levels. The patient had received a total of 19 units of packed erythrocytes before the chemical evidence of anicteric hepatitis was first noted. Case 5 An 18-year-old college freshman with a lifelong history of proteinuria Fig. 1-Case 2: section of liver. (Heematoxylin and eosin. Reduced to two-thirds from x 135.) The architecture of the liver is intact. There is massive diffuse hepatocellular necrosis. Tht and hasmaturia developed renal failure. hepatocytes are in various stages of necrosis, are enlarged, and contain abundant cytoplasrr Two maternal uncles and a maternal and nuclear debris. cousin had died of kidney disease, Renal biopsy three years before admission had shown focal glomerulonephritis, foam cells in the patient developed hepatic coma and died on the fifth day the convoluted tubules, and nephrocalcinosis consistent with after onset of symptoms of hepatitis. Necropsy confirmed the the diagnosis of hereditary nephritis. On admission, the clinical diagnosis of fulminant hepatitis. The liver was entirely necrotic (fig. 1). A total of 39 units of whole blood and packed blood-urea-nitrogen was 149 mg. per 100 ml., serum-creatinine erythrocytes had been transfused or used as dialyser prime 26 mg. per 100 ml., hasmatocrit 14%, serum-bilirubin 02 mg, before the onset of hepatitis. per 100 ml., serum-alkaline-phosphatase 2-6 King-Armstrong units, and S.G.O.T. 12 units. Case 3 Twice-weekly hasmodialysis with a two-layer Kiil dialyser A 22-year-old college student developed renal failure due to was performed for eight months while the patient returned to chronic glomerulonephritis. He had been treated in hospital college as a full-time student. During the ninth month of eight years earlier for acute glomerulonephritis, which had haemodialysis therapy, following the cumulative transfusion of cleared rapidly. Thereafter there had been no further 58 units of packed erythrocytes, the patient complained of symptoms or signs of renal disease until fourteen months somnolence and anorexia. Although neither tenderness nor before his present admission when hypertension and proteinuria enlargement of the liver was noted, the S.G.o.T. was 76 units were detected. and the serum-alkaline-phosphatase was 5-9 units. Ten days Because of deterioration of renal function, twice-weekly after the onset of fatigue and anorexia, slight scleral icterus was intermittent haemodialysis with a blood-primed twin-coil detected. The serum-bilirubin was 2-5 mg. per 100 ml. Fig, 2 was At that time estimations of serumshows the S.G.O.T. and serum-alkaline-phosphatase levels during dialyser begun. bilirubin, S.G.O.T., serum-alkaline-phosphatase, and thymol the course of hepatitis. The patient resumed full-time studies turbidity yielded normal values. After the fourteenth hxmo- four weeks after the onset of hepatitis. Liver function, as dialysis, during the eighth week of dialysis therapy, the S.G.O.T. assessed by alkaline-phosphatase and bilirubin determinations, rose to 115 units and the serum-alkaline-phosphatase to has remained within normal limits. 24-5 units. Neither hepatomegaly nor other clinical manifestaA percutaneous liver-biopsy specimen obtained six weeks tions of hepatitis developed at any time during the next six weeks, although both the transaminase and the alkaline-phosphatase remained raised. The bilirubin was consistently normal. No additional evidence of hepatic dysfunction has been detected in the ten months of twice-weekly dialysis therapy since this episode of anicteric hepatitis. The patient had been exposed to a total of 310 units of whole blood or packed erythrocytes when the signs of hepatitis appeared. Case 4 A 56-year-old paint salesman developed renal failure due to chronic pyelonephritis. Thirty years earlier transient jaundice had followed a blood-transfusion for a bleeding ulcer ". At the time of initial hxmodialysis the serum-alkaline-phosphatase, serum-bilirubin, and S.G.O.T. were all normal. "

Fig. 2 Case therapy. -

After his

twenty-eighth semi-weekly haemo-

5::

course

of

hepatitis complicating protracted heemodialy’ - -1

677

viruses is still in the experimental stage, the diagnosis of the two diseases rests on the results of epidemiological investigation of each case or cluster of The difficulty of establishing a cases. specific cause-infective or serum-in hepatitis arising in patients receiving haemodialysis is evident from previous communications on this subject. Scribner et al. (1965) cite 2 deaths due to hepatitis in 125 patients receiving longcontinued haemodialysis therapy in the United States, though the reporting centres did not specify the type of hepatitis. The Lancet (1965) described 8 cases of hepatitis in patients and staff of a hasmodialysis unit: a staff nurse died of what was thought to be infective hepatitis contracted from a patient. Ringertz and Melen (1965) mentioned 28 cases of two

F)S 3-Case 6:

course

of

hepatitis complicating protracted hoernodialysis therapy.

hfDHtitis in

jtter all chemical evidence of hepatitis had no evidence of continuing hepatitis.

disappeared showed.

Case6 A 24-year-old systems engineer was admitted to hospital because of progressive renal failure due to glomerulonephritis

of eight years’ duration. The blood-urea-nitrogen was 130 mg. per 100 ml., serum-creatinine 20 mg. per 100 ml., and endogenous-creatinine clearance 1 ml. per minute, S.G.O.T. 18 units, serum-alkaline-phosphatase 7-2 King-Armstrong its, and total serum-proteins 7-3 g. (albumin 5-2 g., globulin 21g.) per 100 ml. Because of nausea, pruritis, and lethargy, twice-weekly overnight hasmodialyses utilising a Kiil dialyser were begun, with amelioration of all symptoms during the first month of hxmodialysis therapy. The patient returned tofull-time employment but suffered at least three septic pulmonary emboli, presumably arising from a contaminated prosthetic arteriovenous shunt, during the fourth month of continued hxmodialysis therapy. Additional septic pulmonary emboli during the sixth and seventh months of therapy necessitated transfer of the arteriovenous shunt to another site. After ninety-four hxmodialyses and forty blood-transfusions, dunng the eleventh month of continued dialysis the s.G.o.T. level was raised to 75 units. The patient admitted to mild " anorexia and a sour taste in my stomach ". The S.G.o.T. level remained high for the next two weeks, during which the patient had mild symptoms but was able to continue full-time work. Owing to intensification of anorexia and the onset of nausea during the third week of illness, the patient was conned to bed at home (fig. 3). Pruritis, vomiting, and icterus Tour weeks after onset of illness necessitated admission to hospital, where the patient’s subjective and biochemical .ondmon improved rapidly. He returned to full activities a ’eck after discharge from his ten-day stay in hospital, and his Sequent course has been uncomplicated.

Discussion The diagnosis of serum hepatitis, in the absence of clear ’frrential evidence, such as multiple cases traceable to a ,cclfic batch of antiserum or plasma, is generally made by .x:iuston of toxic and infectious causes. None of the :!=nts referred to here was receiving any drugs with ’",’.<.n hepatotoxicity. No patient reported exposure to .:Yl1cals or insecticides known to cause toxic hepatitis. Htobgica! examination of liver sections from case 2 was intent with either infective or serum viral hepatitis. Infective hepatitis may be differentiated from serum ’.’-’;; anus by its shorter incubation period, milder course, =’. .ower mortality. Since laboratory identification of the -

staff

members. including 9

hxmodialysis nurses, of a Stockholm hospital. It was concluded, from the incubation period, the absence of secondary cases in the family environment of affected personnel, and the insidious onset, that the cases were probably due to serum hepatitis contracted from a patient. Pendras and Erickson (1966) ascribed 8 cases of hepatitis occurring during the course of hmmodialysis therapy at the Seattle artificial-kidney centre to infective hepatitis. The simultaneous onset of 2 cases on three occasions, and the affliction of 3 staff members, were thought consistent with infective hepatitis. Reports from other haemodialysis units do not mention hepatitis among the complications (Smith et al. 1964, Schreiner and Maher 1965, Shupak and Merrill 1965, Shimizu et al. 1966). A similar variation in the incidence of hepatitis following extracorporeal circulation during cardiovascular surgery has been reported. Thus Rosenblum and Heidenberg (1966) found that post-transfusion hepatitis following open-heart surgery occurred in 10’300 of patients aged 16-25 years, 16-2% of patients aged 26-39 years, and 14 3% of patients aged 40-59 years. In contrast, Adashek and Adashek (1963) detected only 12 cases of hepatitis in 644 patients undergoing openheart surgery who received a total of 11,597 units of blood —a case incidence of only 1 86%. Any analysis of the comparative risks of hepatitis in different groups of patients in separate institutions, or as complication of blood-transfusion,

a

a

therapeutic regimen incorporating

will be strongly influenced by the method chosen for data collection. Retrospective casefinding grossly underestimates the number of cases of hepatitis because their detection depends on signs of serious illness. Asymptomatic nonicteric cases may remain undetected unless the physician is attuned to the possibility of hepatitis. The deficiencies of the retrospective method of case-finding are apparent in the report by Grady et al. (1964) which records that only 1 case of hepatitis was identified for every 1775 units of blood transfused. Similarly, only 3% (77 out of 2547) of the blood recipients studied by Allen and Sayman (1962) at the University of Chicago clinics were known to have developed hepatitis, though the " average patient received 34 units of blood. "

Prospective epidemiological techniques present an picture of the risks attending blood-transfusion.

obverse

678

al. (1964), for example, studied patients who had been transfused while on an obstetrics and gynaecology service in Philadelphia. They found that every recipient of 6 or more units of blood developed either icteric or anicteric hepatitis. A similar prospective study of transfused patients in Japan suggested that 113 out of i75 (64-5%) blood recipients in five hospitals developed sustained elevations of S.G.O.T. activity consistent with the diagnosis of viral hepatitis (Shimizu and Kitamoto 1963). Liver biopsy in selected patients supported the diagnosis of hepatitis in both these prospective studies. Unexplained elevations of S.G.O.T. activity have not been observed by us. Increased serum-alkaline-phosphatase values have, in every instance, been ascribable either to secondary hyperparathyroidism or to hepatitis. We believe that the rise in both serum-alkaline-phosphatase and S.G.O.T. activities indicates hepatic parenchymal

Hampers

et

disease. The epidemiological pattern of the 6 cases reported here is consistent with the diagnosis of serum hepatitis. Not more than one case was seen at any one time. No secondary cases occurred in staff members or the families of patients or staff. The case-fatality rate-33% (2 out of 6)-was high. Repeated blood-transfusion was part of the treatment of each patient. A total of 395 units of whole blood or packed cells had been administered to the 6 patients who contracted hepatitis. If it is assumed that each case resulted from a single exposure to blood contaminated with hepatitis virus, and that each exposure resulted in a detectable infection, then the infectivity-rate for blood at this institution is 1-5%. The inclusion of the total number of transfusions administered to all 19 patients in the dialysis unit-1119would yield an infectivity-rate of only 0-5%, which is considerably lower than that found by the prospective studies cited above. There are two possible explanations for the relatively low incidence of hepatitis in multiple transfused patients undergoing haemodialysis: (1) transfusions administered before the patients’ transfer to the dialysis unit may have caused subclinical hepatitis with subsequent immunity; and (2) y-globulin, as a component of the multiple transfusions, may have conferred passive

immunity to hepatitis on some patients.

Requests for reprints should be addressed to E. A. F., Depanc::; Medicine, State University of New York, Downstate V4ed.c: Center, 450 Clarkson Avenue, Brooklyn, N.Y. 11203, U.S.A.

of

REFERENCES

Adashek, E. P., Adashek, W. H. (1963) Archs Surg., Chicago, 87, 104 Allen, J. G., Sayman, W. A. (1962) J. Am. med. Ass. 180, 1079. Grady, G. F., Chalmers, T. C., and the Boston Inter-Hospital Group (1964) New Engl. J. Med. 271, 337. Hampers, C. L., Prager, D., Senior, J. R. (1964) ibid. p. 747. Lancet (1965) ii, 1000. Mirick, G. S., Ward, R., McCollum, R. W. (1965) New Engl. J Med. 273, 60. Palmer, W. L. (1962) J. Am. med. Ass. 180, 1123. Pendras, J. P., Erickson, R. (1966) Ann. intern. Med. 64, 293. Quinton, W., Dillard, D., Scribner, B. H. (1960) Trans. Am. Soc. and internal Organs, 6, 104. Ringertz, D., Melen, B. (1965) Lancet, i, 151. Rosenblum, R., Heidenberg, W. J. (1966) Clin. Res. 14, 260. Schreiner, G. E., Maher, J. F. (1965) Ann. intern. Med. 62, 551. Scribner, B. H., Fergus, E. B., Boen, S. T., Thomas, E. D. (1965) A. Rev Med. 16, 285. Shimizu, A. G., Kaye, M., Innes, B. J. (1966) Can. med. Ass. J. 94, 311. Kitamoto, O. (1963) Gastroenterology, 44, 740. Shupak, E., Merrill, J. P. (1965) Ann. intern. Med. 62, 509. Smith, R. D., Simon, N. M., del Greco, F. (1964) Archs intern Med 114, 610. —

EXPERIMENTAL USE OF CETRIMIDE IN THE PREVENTION OF WOUND

IMPLANTATION WITH CANCER CELLS M.B.

GEOFFREY R. GIBSON Sydney, F.R.C.S., F.R.A.C.S.

HONORARY ASSISTANT

UROLOGIST, SYDNEY HOSPITAL

FREDERICK O. STEPHENS Sydney, F.R.C.S.E., F.A.C.S.

M.B.

ASSOCIATE PROFESSOR OF SURGERY, THE UNIVERSITY OF SYDNEY. AND HONORARY SURGEON, SYDNEY HOSPITAL

LOCAL

recurrence

in

cancer

operation

wounds is

a

Halsted was well aware of the problem when he introduced his radical procedure for breast cancer, in which he removed a large area of the skin. Even so there was local recurrence in 320G of his series of cases (Lewis and Reinhoff1932). In some types of head and neck cancer, the local recurrencerate approaches 50% (Moore 1956, Arons and Smith constant concern to surgeons.

1961). There is evidence that some local wound recurrences due to seeding of cells at the time of operation (Smith 1964), and many physical and chemical agents have been used, both experimentally and clinically, to reduce the frequency of recurrence in wounds. Amongst the most effective agents are nitrogen mustard 1 or2mg. per 100 ml. (McDonald et al. 1960); proflavine hemisulphate (Kash et al. 1962); a fresh preparation of the unstable sodium hypochlorite (McDonald et al. 1960); and the "stable" hypochloriteMilton ’(Vincent et al. 1964; Oates et al, 1965). Probably the most universally accepted and therefore the most widely used of these agents is nitrogen mustard 1 mg. per 100 ml., which McDonald et al. (1960) found effective in reducing tumour growth from an incidence of 100% to 4% in experimental wounds seeded with Walker 256 cancer cells. We have recently reported results of our experiment use of cetrimide (Stephens and Gibson 1966), When wounds seeded with cancer cells were irrigated withr 10% cetrimide solution followed by distilled water; th,-, was a greatly reduced incidence of tumour takes, ar,-4 irrigation was considerably more effective than irrigate with a 1 mg. per 100 ml. solution of nitrogen musi are

Summary 2 fatal and 4 non-fatal cases of serum hepatitis were observed among 19 patients subjected to repeated haemodialyses undertaken on account of terminal renal failure. The absence of synchronous secondary staff cases is consistent with the epidemiological pattern of serum rather than infective hepatitis.

This prospective study, in comparison with other prospective studies of blood recipients, yielded a low infectivity-rate of 0-5% per unit of blood transfused. Previous subclinical infection and transient passive immunity conferred by the I-globulin present in the multiple transfusions may explain the relatively low attack-rate. Dr. R. Keith Waterhouse and Dr. Harold P. McDonald, Jr. share in the responsibility of directing the dialysis unit. Dr. Norma J. Goodwin, Dr. Stephen M. Seltzer, Dr. Edmund S. Butts, and Dr. Ljubomir Hadzi-Pesic assisted in the haemodialyses on the patients reported. Dr. Stanley Minkowitz interpreted the pathology of the liver sections described. This work was supported in part by a grant (CH34-44) from the United States Public Health Service.

"