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Fulminant hepatitis
CLINICOPATHOLOGIC
CONFERENCE
Fulminant Hepatitis
Stenographic reports edited by Philip E. Cryer, M.D. and John Kissane, M.D. of weekly clinicopathologic conferences held In the Barnes and Wohl Hospitals, are published in each Issue of the Journal. These conferences are participated In jointly by members of the Departments of Internal Medicine and Pathology of the Washington University School of Medicine. A 76 year old woman was transferred to Barnes Hospital on November 6, 1974, because of progressive jaundice. She died 3 weeks later. The patient was in apparent good health until June 10, 1974, when she had severe abdominal pain and fever with temperatures as high as 102’F. The serum amylase was found to be 900 U. After 3 days in a local hospital a laparotomy was performed under halothane anesthesia. A diffusely edematous pancreas and small stones in the cystic duct were found; the common bile duct was not explored. A cholecystectomy was performed. No transfusions were given during surgery. Postoperatively, she did poorly. A “pancreatic abscess” drained through the incision site. In July the serum total bilirubin was 0.8 mg/lOO ml and the serum glutamic oxaloacetic transaminase (SGOT) was 10 mlU/ml. She was discharged 8 weeks after surgery but continued to feel weak and anorectic. She experienced periods of nausea and vomiting, and lost 25 pounds in weight. Because of rectal bleeding, the patient was again hospitalized on October 15, 1974. The hemoglobin concentration was 8.4 g/l00 ml. The serum total bilirubin was 2.2 mg/lOO ml, the SGOT 205 mlU/ml, the prothrombin time 100 per cent and the amylase 80 U. A left pleural effusion was noted on roentgenograms of the chest. Sigmoidoscopy and a barium enema were negative. Thereafter the total bilirubin level rose progressively to 9.6 mg/lOO ml, and the patient was transferred to Barnes Hospital on November 6, 1974. At that time, the patient denied light colored stools, ethanol or drug abuse, and exposure to well water or jaundiced persons. Her medications had included digoxin, spironolactone and meclizine. On examination she was an obese, lethargic elderly woman in no acute distress. The blood pressure was 140/70 mm Hg, the pulse rate 120/min, the respiratory rate 24/min, the temperature 36.2OC and the weight 156 pounds. The skin was icteric and dry with multiple ecchymoses. There were dullness to percussion and decreased breath sounds at the base of the left lung. The cardiac examination was within normal limits except for a grade 2/6 systolic murmur at the left sternal border. The abdomen was not tender, and no palpable abdominal masses were detected. The percussion span of the liver was 8 cm; the spleen was not palpable. There August
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was a midline incisional hernia. Ascites was not evident. Aside from hemorrhoids, the rectal examination was within normal limits. Aside from asterixis, the neurologic examination was within normal limits. There was 4-F edema of the lower extremities. Initial laboratory data included a hemoglobin value of 9.4 g/100 ml, a white blood cell count of 8,900/ mm3 and a platelet count of 88,000/mm3. The urine contained bilirubin and urobilinogen; 3-I bacteriuria, and 20 white blood cells per high power field were also noted. More than 100,000 colonies/ml of Escherichia coli were subsequently cultured from the urine. The serum sodium concentration was 125 meq/liter, the serum potassium 5.3 meq/liter, the serum chloride 100 meq/liter, the serum bicarbonate 19 meq/ liter, the serum urea nitrogen 21 mg/lOO ml and the serum creatinine 1.1 mg/lOO ml. The total bilirubin was 10.0 mg/lOO ml, the albumin 0.8 g/100 ml, the SGOT 725 mlU/ml, the lactic dehydrogenase (LDH) 253 mlU/ml, the alkaline phosphatase 158 mlU/ml, the cholesterol 135 mg/lOO ml and the prothrombin time 25 per cent. The blood ammonia level was 182 pg/ 100 ml (normal less than 48 pg/lOO ml) and the amylase was 161 U. The serum calcium concentration was 6.9 mg/lOO ml and the serum phosphorous 4.2 mg/lOO ml. Chest films demonstrated a left pleural effusion: an electrocardiogram was within normal limits. The serum was positive for hepatitis B surface antigen (HB,Ag). The x-ray series of the upper gastrointestinal tract demonstrated an esophageal hiatus hernia with reflux, prominent distal esophageal mucosal folds, a mass involving the body of the pancreas and a large gastric antral polyp. The patient was initially treated with salt and water restriction, a low protein diet, oral neomycin and multivitamins. Urine volumes ranged from 300 to 800 ml/day initially and a urine sodium was 3 meq/liter. On the 5th hospital day, therapy was initiated for her urinary tract infection with a trimethoprim-sulfamethoxazole preparation. By November 11, 1974, she was more alert. However, on November 17, the patient became increasingly lethargic, and vomiting and abdominal distention developed. Nasogastric suction was instituted. On November 19, the 24 hour urine volume was 200 ml, the urine sodium was 3 meq/ liter and the urine:plasma creatinine ratio was 46. The serum urea nitrogen level had risen to 53 mg/ 100 ml and the serum creatinine level to 3.3 mg/lOO ml. The total bilirubin was 6.2 mg/lOO ml and the SGOT 86 mlU/ml. Despite parenteral vitamin K, the prothrombin time ranged from 16 to 23 per cent. The fibrinogen level was 14 mg/ 100 ml (normal 200 to 400 mg/iOO ml), and the blood ammonia was 151 wg/lOO ml. The platelet count was 185,000/mm3. Despite the intravenous administration of fluids and
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albumin, azotemia progressed. The blood pressure fell to 85140 mm Hg. Dopamine and then norepinephrine were administered, but the urine output remained below 400 ml/day despite central venous pressures of 10 to 12 cm of saline solution. Over the subsequent week the patient became progressively obtunded, the serum creatinine level rose to 6.0 mg/lOO ml, and she died on November 26, 1974.
CLINICAL
BISCUSSION
Dr. Richard Aach: It seems to me that this patient presented two major medical problems which must be considered in some detail and which may be interconnected. The first was the problem, presumably acute pancreatitis, which led to her initial hospitalization and prompted her surgery elsewhere, and the second was hepatic failure, which complicated her subsequent course, prompted her admission to this hospital and was responsible ultimately for her death. Dr. Stanley will review the patient’s roentgenographic studies.
Dr. Robert Stanley:
Serial chest roentgenograms were obtained during the patient’s hospitalization. A chest film, taken shortly after admission, demonstrated a left pleural effusion and a retrocardiac density which suggested the presence of an infiltrate in the lower lobe of the left lung. The heart size and pulmonary vasculature were unremarkable. Several days later a repeat chest film again showed essentially unchanged left pleural effusion and retrocardiac infiltrate. No evidence of pulmonary vascular congestion was present. Six days before death, a chest roentgenogram demonstrated increased density of the infiltrate in the lower lobe of the left lung, suggesting consolidation of the infiltrative process. An x-ray series of the upper gastrointestinal tract, performed on November 13, demonstrated a hiatus hernia and a widening of the duodenal loop. A small diverticulum arose from the medial aspect of the duodenal loop and there was some distortion of this diverticulum, presumably related to changes which occurred in the head of the pancreas. This finding of distortion of a medially placed duodenal diverticulum has been seen with both pancreatitis and tumor in the head of the pancreas. A somewhat stretched appearance to the mucosa of the third and fourth duodenum, suggested generalized involvement of the pancreas and a peripancreatic area with a process such as chronic pancreatitis. The lack of mucosal edema makes a diagnosis of acute pancreatitis less tenable. An incidental finding was a 1 cm gastric antral polyp. Dr. Aach: Thank you. Dr. Alpers, you managed the patient while she was at Barnes Hospital. She came here with the diagnosis of pancreatitis, secondary to
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cholecystitis, which was complicated postoperatively by a pancreatic abscess. Do you believe these diagnoses explain her clinical course? Dr. David Alpers: We did not have much information about her pancreatic surgery. We did not think that she had a pancreatic abscess, because her course had been a little benign for that. She was actually transferred to us because she had begun to become obtunded, even at the time of her admission to this hospital. We believed that she had had some pancreatic inflammatory process, probably uncomplicated by true abscess and related to her stones. On admission it seemed clear that parenchymal liver disease was the more important problem because of the combination of obtundation, low albumin and prolonged prothrombin time. Even if we had wanted to investigate the biliary tract and pancreatic duct further, it was not possible. With her prolonged prothrombin time, angiography was not reasonable and with her positive hepatitis B antigen, retrograde duct cannulation was not possible: so we were left with our clinical judgment at the time. Dr. Aach: Dr. Alpers, what features would you have expected to see in a patient with a pancreatic abscess? Dr. Alpers: The most characteristic findings are (1) recurrent spiking fevers and (2) a tender area, sometimes with a palpable mass. Tenderness is quite common, even if it is not specifically localized. She had a nontender abdomen at the time of admission. Although she was intermittently febrile, the fever was not of the spiking variety. Microabscesses of the pancreas do not present in this fashion, but an abscess that needs to be surgically drained usually is associated with recurrent spiking fevers and with localized tenderness. Dr. Aach: An abdominal mass is felt in approximately 50 per cent of the people and leukocytosis, often quite high, is characteristic. Dr. Alpers: The mass might be felt in even greater than 50 per cent of the people if the diagnosis was seriously considered in more patients, and if a mass was carefully sought. Dr. Aach: Even with surgical drainage, a pancreatic abscess carries a very high fatality rate, on the order of 60 per cent even if it is promptly recognized. Dr Alpers, what about the normal level of the serum amylase? Would this finding be evidence against this diagnosis? Dr. Alpers: No, not really. The serum amylase level is only important in making the diagnosis of pancreatitis. It does not help, thereafter, except when a pseudocyst is present. Once the serum amylase level has been elevated, it can return to normal even in the face of severe persistent pancreatitis or with the development of a superimposed abscess.
August
HEPATITIS
Dr. Aach:
The absence of fever and leukocytosis and the patient’s prolonged course without sepsis are evidence against a diagnosis of pancreatic abscess. A pseudocyst or an inflammatory mass, or matted bowel and omentum as late residue of severe hemorrhagic pancreatitis, are more tenable explanations for the abdominal mass. Dr. Alpers has already described the restrictions which led to the decision not to pursue the problems with further endoscopic studies, such as retrograde pancreatic duodenography. Dr. Stanley, what noninvasive technics might have been used in the work-up of a patient with a possible pancreatic mass lesion? Dr. Stanley: I would like to discuss briefly the use of abdominal ultrasound in the evaluation of pancreatic disease. Although our experience here is limited, we have derived significant diagnostic information in patients with suspected pancreatic pseudocyst and pancreatitis. In a recent study on the efficacy of Bscan ultrasound in the evaluation of pancreatic disease [l] it was found that the diagnostic accuracy of sonography compared very favorably with barium studies, radioisotope scanning and pancreatic arteriography. The investigators suggested that sonography be used as the initial diagnostic tool in the evaluation of pancreatic disease prior to barium studies or other methods. Although ultrasound has not been the initial diagnostic study on all the patients we have evaluated here, we would nevertheless support the concept of turning to ultrasound before the other types of examinations. When a palpable mid-epigastric mass is totally sonolucent with essentially no attenuation of the ethos transmitted through the mass, the likelihood that it is a fluid filled cystic structure such as a pseudocyst is very great. However, some pseudocysts of the pancreas have produced a mixed solid-cystic echo pattern related to inhomogeneity of the material within the cyst as well as to septations within the cystic structure. By current technics, the normal pancreas is virtually invisible by sonography. In acute pancreatitis an echo pattern is produced in the bed of the pancreas consistent with enlargement of the organ, frequently over its entire length. More commonly, carcinoma of the pancreas will be localized to one segment of the pancreas. Ultrasound was not employed in the evaluation of the patient being discussed. It may have been of some help in explaining some of the changes which were seen during the examination of the upper gastrointestinal tract. Dr. Alpers: Dr. Stanley, how helpful is this test in the postoperative period after pancreatic surgery? Dr. Stanley: Abdominal ultrasound is ideally suited to serial evaluation of a patient because of its nonin-
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vasive nature and the ease with which it can be performed. Preoperative and postoperative evaluation of pancreatic pseudocysts have been made here. We have been able to document postoperative persistence of a pseudocyst, redevelopment of a pseudocyst, as well as the gradual return to normal in various patients who were surgically proved to have originally had a pancreatic pseudocyst. Walls and coworkers [I] found an over-all diagnostic accuracy of 84 per cent with pancreatic sonography. As a relatively simple screening test, this percentage of accuracy is quite acceptable. For this reason, we are convinced that abdominal ultrasound is currently the best initial diagnostic procedure for suspected pancreatic disease as well as the best method for serially evaluating a patient’s progress. Dr. Aa& The potential value of this noninvasive technic is important to remember. We often see patients with pancreatitis who continue to have roentgenographic evidence of pancreatic enlargement. In that setting, ultrasound would be valuable because, as Dr. Stanley indicated, ultrasound may distinguish between slowly resolving inflammation and edema, which requires only continued conservative therapy, and a pseudocyst, which is likely to require surgical drainage. It should be pointed out that in the presence of ascites correct interpretation of sonography may be impossible. It is not possible to be sure whether this patient had a pseudocyst or residual inflammatory changes when she was transferred here, although I favor the latter possibility. However, virtually everyone who saw this woman in the hospital believed that her major problem was parenchymal liver cell failure. The primary question is, what was the etiology of the hepatic disease? There are several possibilities that could be considered, most of which can be dismissed very rapidly. It is possible that this patient had chronic liver disease and that her surgery and postoperative complications led to worsening of this condition. However, there is very little to support this. Although a liver biopsy specimen was not obtained at surgery, the liver was not observed to be abnormal. Also, in July, her liver function tests were entirely normal. Further, at no time did she give a history, or have physical findings suggestive of chronic liver disease, such as cirrhosis or chronic active hepatitis. One must also consider a complication directly resulting from her initial problems, cholecystitis, pancreatitis and biliary tract surgery, One possible complication is portal vein thrombosis which can complicate acute pancreatitis. When this occurs acutely, it will often give rise to findings of an acute abdomen with abdominal pain, an ileus and evidence of peritonitis resulting from mesenteric venous thrombosis
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and intestinal infarction, eventuating in melena. sepsis and shock. This patient had none of these manifestations. Occasionally, portal vein thrombosis may present in a more insidious fashion as unexplained portal hypertension or splenomegaly, but in neither instance would portal vein thrombosis give rise to any of the profound hepatic derangements that were so striking in this patient. Hepatic abscess, either a large single lesion or multiple abscesses, could give rise to hepatocellular dysfunction but rarely, if ever, to such an extreme. There was really nothing to support this diagnosis; her liver was not tender or enlarged, and there was no evidence, even later in her course, of a serious pyogenic process involving the liver. Tumor metastatic to the liver, such as extension of an unsuspected pancreatic neoplasm, should also be considered but only briefly. Her liver appeared normal at surgery, was never enlarged later in her course and was never tender. Furthermore, her liver function derangements, a substantially elevated serum transaminase and only marginally elevated alkaline phosphatase levels, were opposite to what would be expected from metastatic disease to the liver. Rather, they are indicative of some form of acute, severe hepatocellular injury. This patient’s clinical picture would fit with what has been called fulminant hepatitis or fulminant hepatic failure in that coma developed apparently within approximately 4 weeks of the onset of what appeared to be acute liver disease. The two possible explanations for this are halothane or viral hepatitis type 0. There are certain features of halothane hepatitis which, I believe, allow us to convincingly rule out this possibility in this patient. This form of fulminant hepatitis is really a rather rare condition [2-41. From retrospective studies, fulminant hepatitis, secondary to halothane, occurs in no more than 1 of 10,000 anesthetic exposures. When it does occur, at least two thirds of the patients have had prior halothane exposure. The time course is rather characteristic and depends in large part upon whether there has been one exposure or multiple exposures. When fulminant hepatitis evolves in a patient who has had a single exposure to halothane, hepatitis is usually characterized by unexplained fever within a period of about 8 to 14 days after halothane inhalation. Jaundice and other evidence of liver disease occurs approximately 10 to 28 days after exposure to halothane. In patients with multiple exposures to halothane, both the fever and the onset of clinically evident liver disease occur within a shorter interval, but the illness is usually evident within 2 weeks and always evident within 1 month of the time of exposure. This patient had been given halothane only once as far as we can tell. Pan-
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creatitis
postoperatively
would have obscured
HEPATITIS
hepatitis B, in which the finding of HBs Ag in serum was a prerequisite, indicate a fatality rate of 1 per cent [5]. Even so, type B hepatitis is certainly one important factor associated with a more severe course. Epidemiologic studies suggest that different strains of hepatitis B likely exist which also differ in
a fever
arising from halothane-associated disease. However, the first evidence of hepatic decompensation occurred 120 days after exposure to halothane which makes halothane hepatitis untenable as the explanation for the fatal hepatic decompensation in this patient. This leaves viral hepatitis B, a disease we know she had because her serum contained hepatitis B surface antigen (HB,Ag), formerly called the Australia antigen. Obviously, the question is how did she contract this disease? The history obtained on admission here indicated that she was not given blood transfusions prior to or during surgery for she was not anemic and did not sustain a substantial blood loss. Further, there was no earlier history of hepatitis or liver disease to suggest earlier exposure to hepatitis B. Although there is no way to rule in or rule out clinically inapparent chronic hepatitis B, severely exacerbated by the events which occurred in June, this theory seems unlikely to me, particularly because of the long interval between her initial insults and the development of hepatic failure. This long interval would nicely be explained by exposure to type B hepatitis during her initial hospitalization. The negative history of apparent exposure so troubled me that I called the hospital where she was first admitted and reviewed her records page by page. It is true that the estimated blood loss was only 150 ml, and she did not receive blood transfusions at surgery. However, because of her protracted and prolonged postoperative course, she became increasingly anemic and on July 8 and 10 she was given blood transfusions. Obviously there is no way to prove that this was how she contracted viral hepatitis B, but it is a very attractive explanation: the interval between the blood transfusions and the time she was first found to have abnormal liver tests in mid-October was about 100 days, the average incubation period of viral hepatitis B. Regardless of how she contracted hepatitis B, I believe this was the cause of what proved to be fatal hepatic parenchymal cell failure. An intriguing question is why was her disease so severe? Why did she have such a rapid and progressively downhill course? There is no simple answer to this for many factors appear to determine the severity of hepatitis in a given person. The first factor is that she had type B hepatitis. Type B hepatitis, in the main what was formerly called “serum hepatitis,” is associated with a higher fatality rate’than type A disease. In older studies, the fatality rate of “serum hepatitis” ranged from 1 to 40 per cent with a mean of about 10 per cent, whereas deaths resulting from infectious or type A hepatitis were rare, averaging well under 1 per cent. Of note, very recent analyses of
the severity of disease they produce. Another factor correlated with severity
is chronic
underlying disease or debility which may lower host resistance. This is often alluded to and talked about, but is actually not well documented. One of the few studies in which this factor was examined, by Chalmers and his associates [6], showed that 29 per cent of patients with malignancy who manifested post-transfusion hepatitis died from the combination, whereas only 7 per cent of their “control” population of patients without malignancy who manifested posttransfusion serum hepatitis had a fatal outcome. Although I do not suspect that this woman had an underlying malignancy, she was very debilitated, and this could have contributed to the severity of her disease. Another, and very important, determinant in the severity of viral hepatitis is the age of the patient. In virtually every study in which this relationship has been examined, elderly persons had a more severe course and were more likely to die from their illness than were younger persons. In fact, a noticeable difference in the fatality rates can be seen between those contracting hepatitis before age of 60 and in some instances,
and those after the age 40. This is viv-
idly demonstrated by the series of the liver unit at John Wesley Hospital, University of Southern California [5] where approximately 4,000 patients with viral hepatitis have been observed over the last 4 years. Of these, fulminant hepatitis developed in 81 patients, defined by the onset of hepatic failure (e.g., hepatic encephalopathy) within 4 weeks of onset. Although the over-all survival rate was 25.9 per cent, not one person with fulminant hepatitis past the age of 40 survived. Obviously, one has to be cautious in interpreting these data because adults, especially after age 40, are more likely to have hepatitis resulting from blood transfusions given for an underlying illness, as was true of our patient, although age in itself does appear to be related to the severity of hepatic infection. An intriguing hypothesis advanced by Redeker [5] is that the liver of an elderly person has an impaired regenerative capacity and that the patient is more likely, therefore, to ultimately die from less extensive (submassive) necrosis. This is consistent with the very gradual downhill course of many elderly patients with severe hepatitis in whom death eventually resulted, not within several days to a week or 2, but in
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1 to 2 months after its appearance. Further, despite the long duration of the process, only a limited degree of hepatic regeneration may be present in the older person at autopsy. I would not be surprised if this was true of this patient. One of the problems dominating the later phase of this patient’s course was renal failure. Dr. Harter, would you discuss this patient’s renal complications? Did she have the hepatorenal syndrome and, if so, what is it and what can be done about it? Dr. Herschel Harter: Before discussing the hepatorenal syndrome, Dr. Aach, I would like to make a comment regarding the use of thrimethoprim and sulfamethoxazole in this patient.‘These are an extremely useful adjunct to our armamentarium of antibiotics. However, sulfamethoxazole is primarily excreted by the kidneys and should be used cautiously in patients with glomerular filtration rates below 20 ml/min. Likewise, its use is contraindicated in patients with hepatic disease. Because of the intense sodium retention associated with extremely low urine flow rates, the use of this drug in this patient could have been potentially disastrous. I would not be at all surprised to see precipitation of sulfa crystals within both the renal tubular lumen and the renal interstitium on the postmortem examination. I believe that this patient probably had the hepatorenal syndrome. The term “hepatorenal syndrome” really is a misnomer, since it implies both hepatic and renal disease. In fact, the kidneys may be completely normal as shown by the results obtained in transplanted kidneys from hepatorenal syndrome victims, although significant hypertension secondary to elevated renin levels may develop in the recipient. The hepatorenal syndrome occurs most often in patients with decompensated hepatic cirrhosis, although it may occur in patients with fulminant hepatitis. In this respect then, our patient is a bit atypical. The disease is typified by a progressive decrease in urine output progressing to oliguric levels over various lengths of time depending upon the course of the hepatic failure. It may be precipitated by vigorous diuretic therapy, paracentesis or gastrointestinal hemorrhage. The reduction in urine output is similar to that in other conditions inducing prerenal azotemia, such as severe congestive heart failure, or intravascular volume depletion induced by dehydration, hypoalbuminemia or the like. The kidneys respond appropriately to the decrease in renal blood flow by increasing salt and water reabsorption leading to a high urine:plasma creatinine ratio, a very low urine sodium value (often less than 1 meq/liter) and a urine:plasma osmolar ratio greater than 1.2. This is markedly different from the values obtained in acute tubular necrosis which leads to a urine:plasma creatinine ratio of less than 20, a urine sodium often great-
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er than 50 meq/liter ratio less than 1.2.
and a urine:plasma
osmolar
The patient with the hepatorenal syndrome typically excretes 500 to 1,000 ml of urine/day regardless of intake, with a glomerular filtration rate greater than 20 ml/min. The reduction in glomerular filtration rate reflects a reduced renal blood flow. Normally the renal cortex receives 70 to 80 per cent of the total blood supply and the medulla receives the rest. The cortical nephrons are salt-wasting nephrons with short loops of Henle, whereas the juxtamedullary nephrons possess longer proximal segments and longer loops of Henle and are associated with both salt and water conservation. Patients with the hepatorenal syndrome have a redistribution of their blood supply towards the juxtamedullary nephrons and away from the cortical nephrons which leads to a reduction in glomerular filtration rate and renal blood flow as well as extreme salt and water retention [ 71. Not only is there a reduction and redistribution in renal blood flow but there is also an increase in renal vascular resistance [ 71. The exact mechanisms which induce these changes are unknown. A reduction in effective plasma volume has been shown to occur in some of these patients despite normal or elevated central venous pressures [8]. Expansion of the extracellular volume may lead to increased urine output, but everyone would not agree that such patients, in fact, have the hepatorenal syndrome. The association of intense renal vasoconstriction with redistribution of blood supply has made some investigators believe that toxic metabolites, humoral substances or inadequately metabolized substances led to this abnormality; some evidence exists to support this hypothesis [9,10]. It is well known that patients with cirrhosis or other forms of early hepatic failure have an increased cardiac output associated with shunting of the blood away from the kidneys and to the splanchnit vascular bed, muscles and skin. As the hepatic failure becomes worse, the shunting becomes more intense and ultimately the hepatorenal syndrome emerges. It is likely that this sequence of events is a manifestation of abnormal hepatic metabolism. Dr. Aach: This patient received dopamine and then norepinephrine infusions. Dr. Harter, would you comment on the role of adrenergic agents in an attempt to treat the hepatorenal syndrome? Dr. Harter: The possibility has been raised that false neurotransmitters may play a significant role in the genesis of the hepatorenal syndrome, Dopamine is a major central nervous system neurotransmitter whereas norepinephrine is the major peripheral adrenergic neurotransmitter. Various beta hydroxylated phenylethylamines may function as false neurotransmitters if concentrations are high enough, since
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fulminant hepatitis is to survive until regeneration
these compounds are assimilated, stored and released by nerve endings. Under normal circumstances, aromatic amines are catabolized, at least in part, by monoamine oxidase which is present in the liver. With liver failure, there is shunting of these compounds away from the liver and they can be beta hydroxylated locally in the synaptic nerve endings. The compounds most often marked as the false neurotransmitters are octapamine and beta-hydroxy phenyethylamine [lo]. In limited studies, the use of L-dopa in large doses has been shown to improve central nervous system function in patients with hepatic coma [ 111. The benefit of the drug could possibly relate to displacement of the false neurotransmitter. The changes in renal function seen in patients with severe hepatic failure may also be due to accumulation of a false neurotransmitter, resulting in redistribution of the cardiac output to splanchnic areas, skin and muscle and away from the kidneys. Many drugs have been used in the treatment of the hepatorenal syndrome and have met with various degrees of success. Metaraminol has been shown, on occasion, to increase vascular tone, decrease splanchnic pool size, and increase glomerular filtration rate and fractional renal sodium excretion in patients with the hepatorenal syndrome [lo]. On the other hand, dopamine will increase renal blood flow with little or no change in glomerular filtration rate or renal sodium excretion in severe cases of the hepatorenal syndrome [ 121. Prostaglandin A has been found to increase renal blood flow and glomerular filtration rate except in severe cases of hepatic failure [ 131. Many other compounds, including phentolamine, aminophylline, mannitol, angiotensin and isoproterenol, have produced little or no benefit in these patients
[gl. Octapressin (phenylalanine*-lysine vasopressin), a synthetic lysine vasopressin analogue, has been shown to have the vascular effect of vasopressin with minimum antidiuretic effect and has been shown by Cohn and co-workers [ 141 to be beneficial in patients with the hepatorenal syndrome, The investigators demonstrated a reduction in renal vascular resistance, an increase in renal blood flow, especially in the cortical region, and an increase in glomerular filtration rate and salt and water excretion. Although the improvement was only transient, the results looked encouraging. Another compound which has potential is glucagon. It can be injected in microgram quantities into the renal artery producing intense renal vasodilatation lasting up to 2 hours with little or no peripheral effect. As far as I know, glucagon has not been used in the hepatorenal syndrome. Very few survivals have been reported [ 91, but if the patient with hepatorenal syndrome secondary to
of
the liver occurs, the foregoing forms of therapy with intermittent hemodialysis seem the most tenable. Dr. Ash: Thank you. An important point to remember is that although patients with the hepatorenal syndrome have abundant chemical evidence of renal failure. only rarely do they die from complications of uremia, per se; they usually die from complications of hepatocellular failure. This emphasizes that the basic derangement is hepatic dysfunction. The clue to successful management of fulminant hepatic failure is to maintain life support systems until the liver is able to sufficiently regenerate in order to sustain life. Our current methods of assistance are not very adequate, and aggressive modes of therapy such as exchange transfusion or total body washout have not proved efficacious [ 151. Better methods are very much needed. Finally, the process of regeneration must be better understood so that in the future it might be possible to initiate or to accelerate hepatic regeneration after acute extensive liver cell damage. This may well be mandatory for the ultimate survival of the elderly patient with fulminant or subacute hepatitis. Very recent observations by Karvountzis and his associates [ 161 of patients who survived fulminant hepatitis indicate that normal liver structure and function can be expected, with but few exceptions. This certainly should provide incentive for intense efforts in developing much more effective methods of managing fulminant hepatic failure. In summary, I believe this patient had acute pancreatitis as a consequence of cholelithiasis and cholecystitis, perhaps with the passage of a common duct stone. Postoperatively, she most likely had a pancreatic abscess or, more likely, an intense flareup of her pancreatitis. She then acquired hepatitis B, probably via blood transfusion, and died as a result of fulminant hepatic failure. Does anyone on the panel wish to make a comment or propose alternative diagnoses? Dr. Harter: In a patierlt with fulminant hepatic failure and the hepatorenal syndrome, intermittent hemodialysis can be very difficult. Because of their extremely labile circulatory system, a venous to venous dialysis is better tolerated than a routine arterial venous dialysis.
PATHOLOGIC
DISCUSSION
Dr. Dan McKeel: At autopsy, the liver was shrunken, weighing only 580 g, and had a focally nodular, yellow-white surface partly covered with exudate and fibrosis. The gallbladder was absent, and the common bile duct was patent. The cut surfaces of the liver were yellow mixed with small islands of red tis-
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Figure 1. Liver specimen. Photomicrograph shows confluent interlobular necrosis and broad collagenized septurns. A&son stain; original magnification X 40, reduced by 34 per cent.
sue representing residual hepatocytes. The histologic sections revealed a spectrum of changes associated with clinical fulminant viral hepatitis [ 171. Submassive, interlobular, confluent necrosis with only slight regenerative activity (Figure l), increased fibroblastic activity with collagen deposition and formation of active septums (Figure 2). marked bile duct proliferation (Figure 3), and cholestasis represent inconstant morphologic features of acute viral hepatitis indicative of severe pathologic alteration [ 181. The more constant changes seen in cases of acute viral hepatitis were present, including Kuppfer cell hyperplasia, accumulation of ceroid in lobular and portal macrophages
(Figure 4) reticulin condensation and septal inflammatory cell infiltrates. The majority of these cells were lymphocytes and mononuclear cells; however, large numbers of neutrophils were also seen. Although it is clear that these morphologic changes may all be seen in fatal, severe cases of Australia antigen-positive hepatitis, the exact nosologic classification of this case is somewhat difficult. Some clinical features of the present case (marked bile duct proliferation and the neutrophilic inflammatory component seen histologically) are suggestive of cholestatic hepatitis [ 181. Finally, it may be argued that this case demonstrates the evolution of acute viral hepa-
Figure 2. Liver specimen. Photomicrograph illustrates septums infiltrated with mononuclear cells. MaSSOn stain; original magnification X 100, reduced by 34 per cent.
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HFPATITIS
Liver specimen. Photomireveals striking proliferation of
Figure 3. crograph
bile duct&s within fibrous tissue, admixed with lymphocytes and neutrophi/s. Hematoxylin and eosin stain; original magnification X 100, reduced by 34 per cent.
the remaining parenchyma Microscopic examination
titis to cirrhosis, a phenomenon which has been shown to occur through serial biopsy studies [ 191. The abdomen contained 3,000 ml of ascitic fluid, part of which was loculated at the head of the pancreas. I believe this finding accounted for the duodenal mass effect demonstrated roentgenographically. Numerous adhesions of the small bowel, transverse colon and splenic flexure of the colon were present. The pancreas showed no evidence of any neoplasm, pseudocyst, healed or active abscess, or duct obstruction. Focal fat necrosis and fibrosis were present involving the head of the pancreas. Microscopic, focal acute and chronic inflammation occurred in the head of the pancreas but spared
which appeared normal. revealed maturing, nonin-
fected granulation tissue with no evidence of organisms. Postmortem examination further demonstrated organizing Staphylococcus aureus pneumonia involving mainly the lower lobe of the left lung at the site of roentgenographic opaclfication. Both kidneys were of normal size. Microscopic examination revealed dilatation and necrosis of scattered renal tubules, tubular casts, interstitial and tubular concentrically lamellated crystals and mild inflammation at the corticomedullary junction. Striking glomerular changes were not present: however, the
Figure 4. Liver specimen. Photomicrograph demonstrates accumulation of ceroid macrophages and Kuppfer cells. Hema toxylin and eosin stain; original magnification X 100, reduced by 34 per cent.
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mesangial hilus was focally prominent and the afferent arterioles were thickened. In the absence of more specific changes, such as tubular mitoses, a firm diagnosis of acute tubular necrosis could not be made. These nonspecific pathologic alterations probably indicate relative ischemia. Immune complex glomerular disease, previously described in patients with viral hepatitis [20], was not specifically sought in this patient. In summary, viral hepatitis B probably developed in this patient 3 months after she received blood transfusions. Because of her age, Australia antigenemia and other unknown factors, her liver disease was severe, eventually leading to coma, renal disease and death.
Dr. Aach: I would like to point out that hepatitis B was also the diagnosis of the staff who had taken care of this patient while she was alive. Even armed with this knowledge and with the delivery of high
powered therapy, this patient, as most patients with this disorder, did not survive. Until better methods of therapy are developed, fulminant hepatitis will continue to be associated with a high mortality rate.
Final Anatomic Diagnoses. Primary: Acute fulminant viral hepatitis with cirrhosis; ascites (3,000 cc, serosanguinous) with multiloculated fluid in subdiaphragmatic and peripancreatic areas; pancreatitis, focal (head); marked retroperitoneal fibrosis in area of pancreas: multiple large and small bowel adhesions; bilateral pleural effusions, small (200 cc, serosanguinous); bronchopneumonia, lower lobe of the left lung (Staph. aureus); and focal tubular necrosis, mild (history of terminal oliguric renal failure). Accessory: Absent gallbladder; mucosal erosions of upper gastrointestinal tract, multifocal, superficial: healed right abdominal scar with abdominal hernia; laryngeal erosions: and moderate arterionephrosclerosis.
REFERENCES
2. 3.
4. 5.
6. 7.
8.
9. IO.
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Walls WJ, Gonzalez G, Martin NL, Templeton AW: B-scan ultrasound evaluation of the pancreas. Radiology 114: 127, 1975. National Halothane Study. Summary of the National Halothane Study. JAMA 197: 775, 1966. Trey C, Lipworth L, Chalmers TC, Davidson C, Gotlieb L, Popper H, Saunders S: Fulminant hepatic failure: presumable contribution of halothane. N Engl J Med 279: 798, 1968. Klion F, Schaffner F, Popper H: Hepatitis after exposure to halothane. Ann Intern Med 71: 467, 1969. Redeker A: Fulminant hepatitis, The Liver and Its Diseases’ (Schaffner F, Sherlock S, Leevy C, eds). New York, Intercontinental Medical Book Corp., 1974, p 149. Chalmers TC, Koff RS, Grady GF: A note on fatality in serum hepatitis. Gastroenterology 49: 22, 1965. Epstein M, Berk DP, Hollenberg NK, Adams DF. Chalmers TC, Abrams HL, Merrill JP: Renal failure in the patient with cirrhosis. Am J Med 49: 175, 1970. Tristani FE, Cohn JN: Systemic and renal hemodynamics in oliguric hepatic failure. Effect of volume expansion. J Clin Invest 46: 1894, 1967. Conn HO: A rational approach to the hepatorenal syndrome. Gastroenterology 65: 321, 1973. Fischer JE, Baldessarini RJ: False neurotransmitters and
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11. 12.
13. 14.
15. 16.
17. 18. 19. 20.
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hepatic failure. Lancet 2: 75, 1975. Porkes JD, Sharpstone P, Williams R: L-Dopa in hepatic coma. Lancet 2: 1341, 1970. Barnard0 DF, Baldus WP, Maher FT: Effects of dopamine on renal function in patients with cirrhosis. Gastroenterology 58: 524, 1970. Arieff Al, Chidsey CA: Renal function in cirrhosis and the effects of prostaglandin. Am J Med 56: 695, 1974. Cohn JN, Tristani FE, Khati IM: Renal vasodilator therapy in the hepatorenal syndrome. Med Ann DC 39: 1, 1970. Redeker A, Yamahiro H: Controlled trial of exchange-transfusion therapy in fulminant hepatitis. Lancet 1: 3, 1973. Karvountzis G, Redeker A, Peters R: Long-term follow-up studies of patients surviving fulminant viral hepatitis. Gastroenterology 67: 870, 1974. Williams R: Fulminant viral hepatitis. Clin Gastroenter 3: 419, 1974. Desmet VJ, DeGroote J: Histological diagnosis of viral hepatitis. Clin Gastroenter 3: 337, 1974. Bjornboe M: Viral hepatitis and cirrhosis. Clin Gastroenter 3: 409, 1974. Kneiser MR. Jenis EH, Lowenthal, DT, Bancroft WH, Burns W, Shaloub R: Pathogenesis of renal disease associated with viral hepatitis. Arch Pathol 97: 193, 1974.
CONFERENCE
Fulminant Hepatitis
Stenographic reports edited by Philip E. Cryer, M.D. and John Kissane, M.D. of weekly clinicopathologic conferences held In the Barnes and Wohl Hospitals, are published in each Issue of the Journal. These conferences are participated In jointly by members of the Departments of Internal Medicine and Pathology of the Washington University School of Medicine. A 76 year old woman was transferred to Barnes Hospital on November 6, 1974, because of progressive jaundice. She died 3 weeks later. The patient was in apparent good health until June 10, 1974, when she had severe abdominal pain and fever with temperatures as high as 102’F. The serum amylase was found to be 900 U. After 3 days in a local hospital a laparotomy was performed under halothane anesthesia. A diffusely edematous pancreas and small stones in the cystic duct were found; the common bile duct was not explored. A cholecystectomy was performed. No transfusions were given during surgery. Postoperatively, she did poorly. A “pancreatic abscess” drained through the incision site. In July the serum total bilirubin was 0.8 mg/lOO ml and the serum glutamic oxaloacetic transaminase (SGOT) was 10 mlU/ml. She was discharged 8 weeks after surgery but continued to feel weak and anorectic. She experienced periods of nausea and vomiting, and lost 25 pounds in weight. Because of rectal bleeding, the patient was again hospitalized on October 15, 1974. The hemoglobin concentration was 8.4 g/l00 ml. The serum total bilirubin was 2.2 mg/lOO ml, the SGOT 205 mlU/ml, the prothrombin time 100 per cent and the amylase 80 U. A left pleural effusion was noted on roentgenograms of the chest. Sigmoidoscopy and a barium enema were negative. Thereafter the total bilirubin level rose progressively to 9.6 mg/lOO ml, and the patient was transferred to Barnes Hospital on November 6, 1974. At that time, the patient denied light colored stools, ethanol or drug abuse, and exposure to well water or jaundiced persons. Her medications had included digoxin, spironolactone and meclizine. On examination she was an obese, lethargic elderly woman in no acute distress. The blood pressure was 140/70 mm Hg, the pulse rate 120/min, the respiratory rate 24/min, the temperature 36.2OC and the weight 156 pounds. The skin was icteric and dry with multiple ecchymoses. There were dullness to percussion and decreased breath sounds at the base of the left lung. The cardiac examination was within normal limits except for a grade 2/6 systolic murmur at the left sternal border. The abdomen was not tender, and no palpable abdominal masses were detected. The percussion span of the liver was 8 cm; the spleen was not palpable. There August
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was a midline incisional hernia. Ascites was not evident. Aside from hemorrhoids, the rectal examination was within normal limits. Aside from asterixis, the neurologic examination was within normal limits. There was 4-F edema of the lower extremities. Initial laboratory data included a hemoglobin value of 9.4 g/100 ml, a white blood cell count of 8,900/ mm3 and a platelet count of 88,000/mm3. The urine contained bilirubin and urobilinogen; 3-I bacteriuria, and 20 white blood cells per high power field were also noted. More than 100,000 colonies/ml of Escherichia coli were subsequently cultured from the urine. The serum sodium concentration was 125 meq/liter, the serum potassium 5.3 meq/liter, the serum chloride 100 meq/liter, the serum bicarbonate 19 meq/ liter, the serum urea nitrogen 21 mg/lOO ml and the serum creatinine 1.1 mg/lOO ml. The total bilirubin was 10.0 mg/lOO ml, the albumin 0.8 g/100 ml, the SGOT 725 mlU/ml, the lactic dehydrogenase (LDH) 253 mlU/ml, the alkaline phosphatase 158 mlU/ml, the cholesterol 135 mg/lOO ml and the prothrombin time 25 per cent. The blood ammonia level was 182 pg/ 100 ml (normal less than 48 pg/lOO ml) and the amylase was 161 U. The serum calcium concentration was 6.9 mg/lOO ml and the serum phosphorous 4.2 mg/lOO ml. Chest films demonstrated a left pleural effusion: an electrocardiogram was within normal limits. The serum was positive for hepatitis B surface antigen (HB,Ag). The x-ray series of the upper gastrointestinal tract demonstrated an esophageal hiatus hernia with reflux, prominent distal esophageal mucosal folds, a mass involving the body of the pancreas and a large gastric antral polyp. The patient was initially treated with salt and water restriction, a low protein diet, oral neomycin and multivitamins. Urine volumes ranged from 300 to 800 ml/day initially and a urine sodium was 3 meq/liter. On the 5th hospital day, therapy was initiated for her urinary tract infection with a trimethoprim-sulfamethoxazole preparation. By November 11, 1974, she was more alert. However, on November 17, the patient became increasingly lethargic, and vomiting and abdominal distention developed. Nasogastric suction was instituted. On November 19, the 24 hour urine volume was 200 ml, the urine sodium was 3 meq/ liter and the urine:plasma creatinine ratio was 46. The serum urea nitrogen level had risen to 53 mg/ 100 ml and the serum creatinine level to 3.3 mg/lOO ml. The total bilirubin was 6.2 mg/lOO ml and the SGOT 86 mlU/ml. Despite parenteral vitamin K, the prothrombin time ranged from 16 to 23 per cent. The fibrinogen level was 14 mg/ 100 ml (normal 200 to 400 mg/iOO ml), and the blood ammonia was 151 wg/lOO ml. The platelet count was 185,000/mm3. Despite the intravenous administration of fluids and
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albumin, azotemia progressed. The blood pressure fell to 85140 mm Hg. Dopamine and then norepinephrine were administered, but the urine output remained below 400 ml/day despite central venous pressures of 10 to 12 cm of saline solution. Over the subsequent week the patient became progressively obtunded, the serum creatinine level rose to 6.0 mg/lOO ml, and she died on November 26, 1974.
CLINICAL
BISCUSSION
Dr. Richard Aach: It seems to me that this patient presented two major medical problems which must be considered in some detail and which may be interconnected. The first was the problem, presumably acute pancreatitis, which led to her initial hospitalization and prompted her surgery elsewhere, and the second was hepatic failure, which complicated her subsequent course, prompted her admission to this hospital and was responsible ultimately for her death. Dr. Stanley will review the patient’s roentgenographic studies.
Dr. Robert Stanley:
Serial chest roentgenograms were obtained during the patient’s hospitalization. A chest film, taken shortly after admission, demonstrated a left pleural effusion and a retrocardiac density which suggested the presence of an infiltrate in the lower lobe of the left lung. The heart size and pulmonary vasculature were unremarkable. Several days later a repeat chest film again showed essentially unchanged left pleural effusion and retrocardiac infiltrate. No evidence of pulmonary vascular congestion was present. Six days before death, a chest roentgenogram demonstrated increased density of the infiltrate in the lower lobe of the left lung, suggesting consolidation of the infiltrative process. An x-ray series of the upper gastrointestinal tract, performed on November 13, demonstrated a hiatus hernia and a widening of the duodenal loop. A small diverticulum arose from the medial aspect of the duodenal loop and there was some distortion of this diverticulum, presumably related to changes which occurred in the head of the pancreas. This finding of distortion of a medially placed duodenal diverticulum has been seen with both pancreatitis and tumor in the head of the pancreas. A somewhat stretched appearance to the mucosa of the third and fourth duodenum, suggested generalized involvement of the pancreas and a peripancreatic area with a process such as chronic pancreatitis. The lack of mucosal edema makes a diagnosis of acute pancreatitis less tenable. An incidental finding was a 1 cm gastric antral polyp. Dr. Aach: Thank you. Dr. Alpers, you managed the patient while she was at Barnes Hospital. She came here with the diagnosis of pancreatitis, secondary to
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cholecystitis, which was complicated postoperatively by a pancreatic abscess. Do you believe these diagnoses explain her clinical course? Dr. David Alpers: We did not have much information about her pancreatic surgery. We did not think that she had a pancreatic abscess, because her course had been a little benign for that. She was actually transferred to us because she had begun to become obtunded, even at the time of her admission to this hospital. We believed that she had had some pancreatic inflammatory process, probably uncomplicated by true abscess and related to her stones. On admission it seemed clear that parenchymal liver disease was the more important problem because of the combination of obtundation, low albumin and prolonged prothrombin time. Even if we had wanted to investigate the biliary tract and pancreatic duct further, it was not possible. With her prolonged prothrombin time, angiography was not reasonable and with her positive hepatitis B antigen, retrograde duct cannulation was not possible: so we were left with our clinical judgment at the time. Dr. Aach: Dr. Alpers, what features would you have expected to see in a patient with a pancreatic abscess? Dr. Alpers: The most characteristic findings are (1) recurrent spiking fevers and (2) a tender area, sometimes with a palpable mass. Tenderness is quite common, even if it is not specifically localized. She had a nontender abdomen at the time of admission. Although she was intermittently febrile, the fever was not of the spiking variety. Microabscesses of the pancreas do not present in this fashion, but an abscess that needs to be surgically drained usually is associated with recurrent spiking fevers and with localized tenderness. Dr. Aach: An abdominal mass is felt in approximately 50 per cent of the people and leukocytosis, often quite high, is characteristic. Dr. Alpers: The mass might be felt in even greater than 50 per cent of the people if the diagnosis was seriously considered in more patients, and if a mass was carefully sought. Dr. Aach: Even with surgical drainage, a pancreatic abscess carries a very high fatality rate, on the order of 60 per cent even if it is promptly recognized. Dr Alpers, what about the normal level of the serum amylase? Would this finding be evidence against this diagnosis? Dr. Alpers: No, not really. The serum amylase level is only important in making the diagnosis of pancreatitis. It does not help, thereafter, except when a pseudocyst is present. Once the serum amylase level has been elevated, it can return to normal even in the face of severe persistent pancreatitis or with the development of a superimposed abscess.
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Dr. Aach:
The absence of fever and leukocytosis and the patient’s prolonged course without sepsis are evidence against a diagnosis of pancreatic abscess. A pseudocyst or an inflammatory mass, or matted bowel and omentum as late residue of severe hemorrhagic pancreatitis, are more tenable explanations for the abdominal mass. Dr. Alpers has already described the restrictions which led to the decision not to pursue the problems with further endoscopic studies, such as retrograde pancreatic duodenography. Dr. Stanley, what noninvasive technics might have been used in the work-up of a patient with a possible pancreatic mass lesion? Dr. Stanley: I would like to discuss briefly the use of abdominal ultrasound in the evaluation of pancreatic disease. Although our experience here is limited, we have derived significant diagnostic information in patients with suspected pancreatic pseudocyst and pancreatitis. In a recent study on the efficacy of Bscan ultrasound in the evaluation of pancreatic disease [l] it was found that the diagnostic accuracy of sonography compared very favorably with barium studies, radioisotope scanning and pancreatic arteriography. The investigators suggested that sonography be used as the initial diagnostic tool in the evaluation of pancreatic disease prior to barium studies or other methods. Although ultrasound has not been the initial diagnostic study on all the patients we have evaluated here, we would nevertheless support the concept of turning to ultrasound before the other types of examinations. When a palpable mid-epigastric mass is totally sonolucent with essentially no attenuation of the ethos transmitted through the mass, the likelihood that it is a fluid filled cystic structure such as a pseudocyst is very great. However, some pseudocysts of the pancreas have produced a mixed solid-cystic echo pattern related to inhomogeneity of the material within the cyst as well as to septations within the cystic structure. By current technics, the normal pancreas is virtually invisible by sonography. In acute pancreatitis an echo pattern is produced in the bed of the pancreas consistent with enlargement of the organ, frequently over its entire length. More commonly, carcinoma of the pancreas will be localized to one segment of the pancreas. Ultrasound was not employed in the evaluation of the patient being discussed. It may have been of some help in explaining some of the changes which were seen during the examination of the upper gastrointestinal tract. Dr. Alpers: Dr. Stanley, how helpful is this test in the postoperative period after pancreatic surgery? Dr. Stanley: Abdominal ultrasound is ideally suited to serial evaluation of a patient because of its nonin-
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vasive nature and the ease with which it can be performed. Preoperative and postoperative evaluation of pancreatic pseudocysts have been made here. We have been able to document postoperative persistence of a pseudocyst, redevelopment of a pseudocyst, as well as the gradual return to normal in various patients who were surgically proved to have originally had a pancreatic pseudocyst. Walls and coworkers [I] found an over-all diagnostic accuracy of 84 per cent with pancreatic sonography. As a relatively simple screening test, this percentage of accuracy is quite acceptable. For this reason, we are convinced that abdominal ultrasound is currently the best initial diagnostic procedure for suspected pancreatic disease as well as the best method for serially evaluating a patient’s progress. Dr. Aa& The potential value of this noninvasive technic is important to remember. We often see patients with pancreatitis who continue to have roentgenographic evidence of pancreatic enlargement. In that setting, ultrasound would be valuable because, as Dr. Stanley indicated, ultrasound may distinguish between slowly resolving inflammation and edema, which requires only continued conservative therapy, and a pseudocyst, which is likely to require surgical drainage. It should be pointed out that in the presence of ascites correct interpretation of sonography may be impossible. It is not possible to be sure whether this patient had a pseudocyst or residual inflammatory changes when she was transferred here, although I favor the latter possibility. However, virtually everyone who saw this woman in the hospital believed that her major problem was parenchymal liver cell failure. The primary question is, what was the etiology of the hepatic disease? There are several possibilities that could be considered, most of which can be dismissed very rapidly. It is possible that this patient had chronic liver disease and that her surgery and postoperative complications led to worsening of this condition. However, there is very little to support this. Although a liver biopsy specimen was not obtained at surgery, the liver was not observed to be abnormal. Also, in July, her liver function tests were entirely normal. Further, at no time did she give a history, or have physical findings suggestive of chronic liver disease, such as cirrhosis or chronic active hepatitis. One must also consider a complication directly resulting from her initial problems, cholecystitis, pancreatitis and biliary tract surgery, One possible complication is portal vein thrombosis which can complicate acute pancreatitis. When this occurs acutely, it will often give rise to findings of an acute abdomen with abdominal pain, an ileus and evidence of peritonitis resulting from mesenteric venous thrombosis
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and intestinal infarction, eventuating in melena. sepsis and shock. This patient had none of these manifestations. Occasionally, portal vein thrombosis may present in a more insidious fashion as unexplained portal hypertension or splenomegaly, but in neither instance would portal vein thrombosis give rise to any of the profound hepatic derangements that were so striking in this patient. Hepatic abscess, either a large single lesion or multiple abscesses, could give rise to hepatocellular dysfunction but rarely, if ever, to such an extreme. There was really nothing to support this diagnosis; her liver was not tender or enlarged, and there was no evidence, even later in her course, of a serious pyogenic process involving the liver. Tumor metastatic to the liver, such as extension of an unsuspected pancreatic neoplasm, should also be considered but only briefly. Her liver appeared normal at surgery, was never enlarged later in her course and was never tender. Furthermore, her liver function derangements, a substantially elevated serum transaminase and only marginally elevated alkaline phosphatase levels, were opposite to what would be expected from metastatic disease to the liver. Rather, they are indicative of some form of acute, severe hepatocellular injury. This patient’s clinical picture would fit with what has been called fulminant hepatitis or fulminant hepatic failure in that coma developed apparently within approximately 4 weeks of the onset of what appeared to be acute liver disease. The two possible explanations for this are halothane or viral hepatitis type 0. There are certain features of halothane hepatitis which, I believe, allow us to convincingly rule out this possibility in this patient. This form of fulminant hepatitis is really a rather rare condition [2-41. From retrospective studies, fulminant hepatitis, secondary to halothane, occurs in no more than 1 of 10,000 anesthetic exposures. When it does occur, at least two thirds of the patients have had prior halothane exposure. The time course is rather characteristic and depends in large part upon whether there has been one exposure or multiple exposures. When fulminant hepatitis evolves in a patient who has had a single exposure to halothane, hepatitis is usually characterized by unexplained fever within a period of about 8 to 14 days after halothane inhalation. Jaundice and other evidence of liver disease occurs approximately 10 to 28 days after exposure to halothane. In patients with multiple exposures to halothane, both the fever and the onset of clinically evident liver disease occur within a shorter interval, but the illness is usually evident within 2 weeks and always evident within 1 month of the time of exposure. This patient had been given halothane only once as far as we can tell. Pan-
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would have obscured
HEPATITIS
hepatitis B, in which the finding of HBs Ag in serum was a prerequisite, indicate a fatality rate of 1 per cent [5]. Even so, type B hepatitis is certainly one important factor associated with a more severe course. Epidemiologic studies suggest that different strains of hepatitis B likely exist which also differ in
a fever
arising from halothane-associated disease. However, the first evidence of hepatic decompensation occurred 120 days after exposure to halothane which makes halothane hepatitis untenable as the explanation for the fatal hepatic decompensation in this patient. This leaves viral hepatitis B, a disease we know she had because her serum contained hepatitis B surface antigen (HB,Ag), formerly called the Australia antigen. Obviously, the question is how did she contract this disease? The history obtained on admission here indicated that she was not given blood transfusions prior to or during surgery for she was not anemic and did not sustain a substantial blood loss. Further, there was no earlier history of hepatitis or liver disease to suggest earlier exposure to hepatitis B. Although there is no way to rule in or rule out clinically inapparent chronic hepatitis B, severely exacerbated by the events which occurred in June, this theory seems unlikely to me, particularly because of the long interval between her initial insults and the development of hepatic failure. This long interval would nicely be explained by exposure to type B hepatitis during her initial hospitalization. The negative history of apparent exposure so troubled me that I called the hospital where she was first admitted and reviewed her records page by page. It is true that the estimated blood loss was only 150 ml, and she did not receive blood transfusions at surgery. However, because of her protracted and prolonged postoperative course, she became increasingly anemic and on July 8 and 10 she was given blood transfusions. Obviously there is no way to prove that this was how she contracted viral hepatitis B, but it is a very attractive explanation: the interval between the blood transfusions and the time she was first found to have abnormal liver tests in mid-October was about 100 days, the average incubation period of viral hepatitis B. Regardless of how she contracted hepatitis B, I believe this was the cause of what proved to be fatal hepatic parenchymal cell failure. An intriguing question is why was her disease so severe? Why did she have such a rapid and progressively downhill course? There is no simple answer to this for many factors appear to determine the severity of hepatitis in a given person. The first factor is that she had type B hepatitis. Type B hepatitis, in the main what was formerly called “serum hepatitis,” is associated with a higher fatality rate’than type A disease. In older studies, the fatality rate of “serum hepatitis” ranged from 1 to 40 per cent with a mean of about 10 per cent, whereas deaths resulting from infectious or type A hepatitis were rare, averaging well under 1 per cent. Of note, very recent analyses of
the severity of disease they produce. Another factor correlated with severity
is chronic
underlying disease or debility which may lower host resistance. This is often alluded to and talked about, but is actually not well documented. One of the few studies in which this factor was examined, by Chalmers and his associates [6], showed that 29 per cent of patients with malignancy who manifested post-transfusion hepatitis died from the combination, whereas only 7 per cent of their “control” population of patients without malignancy who manifested posttransfusion serum hepatitis had a fatal outcome. Although I do not suspect that this woman had an underlying malignancy, she was very debilitated, and this could have contributed to the severity of her disease. Another, and very important, determinant in the severity of viral hepatitis is the age of the patient. In virtually every study in which this relationship has been examined, elderly persons had a more severe course and were more likely to die from their illness than were younger persons. In fact, a noticeable difference in the fatality rates can be seen between those contracting hepatitis before age of 60 and in some instances,
and those after the age 40. This is viv-
idly demonstrated by the series of the liver unit at John Wesley Hospital, University of Southern California [5] where approximately 4,000 patients with viral hepatitis have been observed over the last 4 years. Of these, fulminant hepatitis developed in 81 patients, defined by the onset of hepatic failure (e.g., hepatic encephalopathy) within 4 weeks of onset. Although the over-all survival rate was 25.9 per cent, not one person with fulminant hepatitis past the age of 40 survived. Obviously, one has to be cautious in interpreting these data because adults, especially after age 40, are more likely to have hepatitis resulting from blood transfusions given for an underlying illness, as was true of our patient, although age in itself does appear to be related to the severity of hepatic infection. An intriguing hypothesis advanced by Redeker [5] is that the liver of an elderly person has an impaired regenerative capacity and that the patient is more likely, therefore, to ultimately die from less extensive (submassive) necrosis. This is consistent with the very gradual downhill course of many elderly patients with severe hepatitis in whom death eventually resulted, not within several days to a week or 2, but in
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1 to 2 months after its appearance. Further, despite the long duration of the process, only a limited degree of hepatic regeneration may be present in the older person at autopsy. I would not be surprised if this was true of this patient. One of the problems dominating the later phase of this patient’s course was renal failure. Dr. Harter, would you discuss this patient’s renal complications? Did she have the hepatorenal syndrome and, if so, what is it and what can be done about it? Dr. Herschel Harter: Before discussing the hepatorenal syndrome, Dr. Aach, I would like to make a comment regarding the use of thrimethoprim and sulfamethoxazole in this patient.‘These are an extremely useful adjunct to our armamentarium of antibiotics. However, sulfamethoxazole is primarily excreted by the kidneys and should be used cautiously in patients with glomerular filtration rates below 20 ml/min. Likewise, its use is contraindicated in patients with hepatic disease. Because of the intense sodium retention associated with extremely low urine flow rates, the use of this drug in this patient could have been potentially disastrous. I would not be at all surprised to see precipitation of sulfa crystals within both the renal tubular lumen and the renal interstitium on the postmortem examination. I believe that this patient probably had the hepatorenal syndrome. The term “hepatorenal syndrome” really is a misnomer, since it implies both hepatic and renal disease. In fact, the kidneys may be completely normal as shown by the results obtained in transplanted kidneys from hepatorenal syndrome victims, although significant hypertension secondary to elevated renin levels may develop in the recipient. The hepatorenal syndrome occurs most often in patients with decompensated hepatic cirrhosis, although it may occur in patients with fulminant hepatitis. In this respect then, our patient is a bit atypical. The disease is typified by a progressive decrease in urine output progressing to oliguric levels over various lengths of time depending upon the course of the hepatic failure. It may be precipitated by vigorous diuretic therapy, paracentesis or gastrointestinal hemorrhage. The reduction in urine output is similar to that in other conditions inducing prerenal azotemia, such as severe congestive heart failure, or intravascular volume depletion induced by dehydration, hypoalbuminemia or the like. The kidneys respond appropriately to the decrease in renal blood flow by increasing salt and water reabsorption leading to a high urine:plasma creatinine ratio, a very low urine sodium value (often less than 1 meq/liter) and a urine:plasma osmolar ratio greater than 1.2. This is markedly different from the values obtained in acute tubular necrosis which leads to a urine:plasma creatinine ratio of less than 20, a urine sodium often great-
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er than 50 meq/liter ratio less than 1.2.
and a urine:plasma
osmolar
The patient with the hepatorenal syndrome typically excretes 500 to 1,000 ml of urine/day regardless of intake, with a glomerular filtration rate greater than 20 ml/min. The reduction in glomerular filtration rate reflects a reduced renal blood flow. Normally the renal cortex receives 70 to 80 per cent of the total blood supply and the medulla receives the rest. The cortical nephrons are salt-wasting nephrons with short loops of Henle, whereas the juxtamedullary nephrons possess longer proximal segments and longer loops of Henle and are associated with both salt and water conservation. Patients with the hepatorenal syndrome have a redistribution of their blood supply towards the juxtamedullary nephrons and away from the cortical nephrons which leads to a reduction in glomerular filtration rate and renal blood flow as well as extreme salt and water retention [ 71. Not only is there a reduction and redistribution in renal blood flow but there is also an increase in renal vascular resistance [ 71. The exact mechanisms which induce these changes are unknown. A reduction in effective plasma volume has been shown to occur in some of these patients despite normal or elevated central venous pressures [8]. Expansion of the extracellular volume may lead to increased urine output, but everyone would not agree that such patients, in fact, have the hepatorenal syndrome. The association of intense renal vasoconstriction with redistribution of blood supply has made some investigators believe that toxic metabolites, humoral substances or inadequately metabolized substances led to this abnormality; some evidence exists to support this hypothesis [9,10]. It is well known that patients with cirrhosis or other forms of early hepatic failure have an increased cardiac output associated with shunting of the blood away from the kidneys and to the splanchnit vascular bed, muscles and skin. As the hepatic failure becomes worse, the shunting becomes more intense and ultimately the hepatorenal syndrome emerges. It is likely that this sequence of events is a manifestation of abnormal hepatic metabolism. Dr. Aach: This patient received dopamine and then norepinephrine infusions. Dr. Harter, would you comment on the role of adrenergic agents in an attempt to treat the hepatorenal syndrome? Dr. Harter: The possibility has been raised that false neurotransmitters may play a significant role in the genesis of the hepatorenal syndrome, Dopamine is a major central nervous system neurotransmitter whereas norepinephrine is the major peripheral adrenergic neurotransmitter. Various beta hydroxylated phenylethylamines may function as false neurotransmitters if concentrations are high enough, since
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FULMINANT HEPATITIS
fulminant hepatitis is to survive until regeneration
these compounds are assimilated, stored and released by nerve endings. Under normal circumstances, aromatic amines are catabolized, at least in part, by monoamine oxidase which is present in the liver. With liver failure, there is shunting of these compounds away from the liver and they can be beta hydroxylated locally in the synaptic nerve endings. The compounds most often marked as the false neurotransmitters are octapamine and beta-hydroxy phenyethylamine [lo]. In limited studies, the use of L-dopa in large doses has been shown to improve central nervous system function in patients with hepatic coma [ 111. The benefit of the drug could possibly relate to displacement of the false neurotransmitter. The changes in renal function seen in patients with severe hepatic failure may also be due to accumulation of a false neurotransmitter, resulting in redistribution of the cardiac output to splanchnic areas, skin and muscle and away from the kidneys. Many drugs have been used in the treatment of the hepatorenal syndrome and have met with various degrees of success. Metaraminol has been shown, on occasion, to increase vascular tone, decrease splanchnic pool size, and increase glomerular filtration rate and fractional renal sodium excretion in patients with the hepatorenal syndrome [lo]. On the other hand, dopamine will increase renal blood flow with little or no change in glomerular filtration rate or renal sodium excretion in severe cases of the hepatorenal syndrome [ 121. Prostaglandin A has been found to increase renal blood flow and glomerular filtration rate except in severe cases of hepatic failure [ 131. Many other compounds, including phentolamine, aminophylline, mannitol, angiotensin and isoproterenol, have produced little or no benefit in these patients
[gl. Octapressin (phenylalanine*-lysine vasopressin), a synthetic lysine vasopressin analogue, has been shown to have the vascular effect of vasopressin with minimum antidiuretic effect and has been shown by Cohn and co-workers [ 141 to be beneficial in patients with the hepatorenal syndrome, The investigators demonstrated a reduction in renal vascular resistance, an increase in renal blood flow, especially in the cortical region, and an increase in glomerular filtration rate and salt and water excretion. Although the improvement was only transient, the results looked encouraging. Another compound which has potential is glucagon. It can be injected in microgram quantities into the renal artery producing intense renal vasodilatation lasting up to 2 hours with little or no peripheral effect. As far as I know, glucagon has not been used in the hepatorenal syndrome. Very few survivals have been reported [ 91, but if the patient with hepatorenal syndrome secondary to
of
the liver occurs, the foregoing forms of therapy with intermittent hemodialysis seem the most tenable. Dr. Ash: Thank you. An important point to remember is that although patients with the hepatorenal syndrome have abundant chemical evidence of renal failure. only rarely do they die from complications of uremia, per se; they usually die from complications of hepatocellular failure. This emphasizes that the basic derangement is hepatic dysfunction. The clue to successful management of fulminant hepatic failure is to maintain life support systems until the liver is able to sufficiently regenerate in order to sustain life. Our current methods of assistance are not very adequate, and aggressive modes of therapy such as exchange transfusion or total body washout have not proved efficacious [ 151. Better methods are very much needed. Finally, the process of regeneration must be better understood so that in the future it might be possible to initiate or to accelerate hepatic regeneration after acute extensive liver cell damage. This may well be mandatory for the ultimate survival of the elderly patient with fulminant or subacute hepatitis. Very recent observations by Karvountzis and his associates [ 161 of patients who survived fulminant hepatitis indicate that normal liver structure and function can be expected, with but few exceptions. This certainly should provide incentive for intense efforts in developing much more effective methods of managing fulminant hepatic failure. In summary, I believe this patient had acute pancreatitis as a consequence of cholelithiasis and cholecystitis, perhaps with the passage of a common duct stone. Postoperatively, she most likely had a pancreatic abscess or, more likely, an intense flareup of her pancreatitis. She then acquired hepatitis B, probably via blood transfusion, and died as a result of fulminant hepatic failure. Does anyone on the panel wish to make a comment or propose alternative diagnoses? Dr. Harter: In a patierlt with fulminant hepatic failure and the hepatorenal syndrome, intermittent hemodialysis can be very difficult. Because of their extremely labile circulatory system, a venous to venous dialysis is better tolerated than a routine arterial venous dialysis.
PATHOLOGIC
DISCUSSION
Dr. Dan McKeel: At autopsy, the liver was shrunken, weighing only 580 g, and had a focally nodular, yellow-white surface partly covered with exudate and fibrosis. The gallbladder was absent, and the common bile duct was patent. The cut surfaces of the liver were yellow mixed with small islands of red tis-
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Figure 1. Liver specimen. Photomicrograph shows confluent interlobular necrosis and broad collagenized septurns. A&son stain; original magnification X 40, reduced by 34 per cent.
sue representing residual hepatocytes. The histologic sections revealed a spectrum of changes associated with clinical fulminant viral hepatitis [ 171. Submassive, interlobular, confluent necrosis with only slight regenerative activity (Figure l), increased fibroblastic activity with collagen deposition and formation of active septums (Figure 2). marked bile duct proliferation (Figure 3), and cholestasis represent inconstant morphologic features of acute viral hepatitis indicative of severe pathologic alteration [ 181. The more constant changes seen in cases of acute viral hepatitis were present, including Kuppfer cell hyperplasia, accumulation of ceroid in lobular and portal macrophages
(Figure 4) reticulin condensation and septal inflammatory cell infiltrates. The majority of these cells were lymphocytes and mononuclear cells; however, large numbers of neutrophils were also seen. Although it is clear that these morphologic changes may all be seen in fatal, severe cases of Australia antigen-positive hepatitis, the exact nosologic classification of this case is somewhat difficult. Some clinical features of the present case (marked bile duct proliferation and the neutrophilic inflammatory component seen histologically) are suggestive of cholestatic hepatitis [ 181. Finally, it may be argued that this case demonstrates the evolution of acute viral hepa-
Figure 2. Liver specimen. Photomicrograph illustrates septums infiltrated with mononuclear cells. MaSSOn stain; original magnification X 100, reduced by 34 per cent.
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f’UMINAN’:
HFPATITIS
Liver specimen. Photomireveals striking proliferation of
Figure 3. crograph
bile duct&s within fibrous tissue, admixed with lymphocytes and neutrophi/s. Hematoxylin and eosin stain; original magnification X 100, reduced by 34 per cent.
the remaining parenchyma Microscopic examination
titis to cirrhosis, a phenomenon which has been shown to occur through serial biopsy studies [ 191. The abdomen contained 3,000 ml of ascitic fluid, part of which was loculated at the head of the pancreas. I believe this finding accounted for the duodenal mass effect demonstrated roentgenographically. Numerous adhesions of the small bowel, transverse colon and splenic flexure of the colon were present. The pancreas showed no evidence of any neoplasm, pseudocyst, healed or active abscess, or duct obstruction. Focal fat necrosis and fibrosis were present involving the head of the pancreas. Microscopic, focal acute and chronic inflammation occurred in the head of the pancreas but spared
which appeared normal. revealed maturing, nonin-
fected granulation tissue with no evidence of organisms. Postmortem examination further demonstrated organizing Staphylococcus aureus pneumonia involving mainly the lower lobe of the left lung at the site of roentgenographic opaclfication. Both kidneys were of normal size. Microscopic examination revealed dilatation and necrosis of scattered renal tubules, tubular casts, interstitial and tubular concentrically lamellated crystals and mild inflammation at the corticomedullary junction. Striking glomerular changes were not present: however, the
Figure 4. Liver specimen. Photomicrograph demonstrates accumulation of ceroid macrophages and Kuppfer cells. Hema toxylin and eosin stain; original magnification X 100, reduced by 34 per cent.
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mesangial hilus was focally prominent and the afferent arterioles were thickened. In the absence of more specific changes, such as tubular mitoses, a firm diagnosis of acute tubular necrosis could not be made. These nonspecific pathologic alterations probably indicate relative ischemia. Immune complex glomerular disease, previously described in patients with viral hepatitis [20], was not specifically sought in this patient. In summary, viral hepatitis B probably developed in this patient 3 months after she received blood transfusions. Because of her age, Australia antigenemia and other unknown factors, her liver disease was severe, eventually leading to coma, renal disease and death.
Dr. Aach: I would like to point out that hepatitis B was also the diagnosis of the staff who had taken care of this patient while she was alive. Even armed with this knowledge and with the delivery of high
powered therapy, this patient, as most patients with this disorder, did not survive. Until better methods of therapy are developed, fulminant hepatitis will continue to be associated with a high mortality rate.
Final Anatomic Diagnoses. Primary: Acute fulminant viral hepatitis with cirrhosis; ascites (3,000 cc, serosanguinous) with multiloculated fluid in subdiaphragmatic and peripancreatic areas; pancreatitis, focal (head); marked retroperitoneal fibrosis in area of pancreas: multiple large and small bowel adhesions; bilateral pleural effusions, small (200 cc, serosanguinous); bronchopneumonia, lower lobe of the left lung (Staph. aureus); and focal tubular necrosis, mild (history of terminal oliguric renal failure). Accessory: Absent gallbladder; mucosal erosions of upper gastrointestinal tract, multifocal, superficial: healed right abdominal scar with abdominal hernia; laryngeal erosions: and moderate arterionephrosclerosis.
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