The distal splenorenal shunt

Our initial use of the distal splenorenal shunt (DSRS) in 1973 was fostered by disappointment with the results of so-called total shunts. This selective shunt was, when anatomically feasible, our preferred therapy until 1980, when surgical referral was affected by enthusiasm for sclerotherapy. Our study of 71 DSRSs is uncontrolled because we could not recruit patients for a prospective randomized trial that involved either no treatment of operations that had proven faults. Our experience shows that operative risk (4%) and incidence of postshunt encephalopathy (6%) are low, that the rate of shunt occlusion is acceptable (10%), and that bleeding is as well controlled as with other shunts. Survival rates correlate with the cause of portal hypertension and with hepatic functional reserve. Analysis of the causes of death shows that the natural history of cirrhosis and coexistent disease are major determinants of prognosis.     

Noncirrhotic portal vein thrombosis. Physiology before and after shunts.

Controversy exists concerning the proper therapy for bleeding gastroesophageal varices secondary to noncirrhotic portal vein thrombosis. Disparity of opinion exists regarding the significance of hepatic portal blood flow and the consequences of total portal-systemic shunts in this condition. One patient is presented who developed severe, crippling encephalopathy 20 years after a central splenorenal shunt. This was associated with loss of portal flow to the liver and marked nitrogen intolerance. Closure of the shunt resulted in restoration of hepatic portal flow via collateral veins (HPI 0.36), clearance of encephalopathy and return to near normal protein tolerance. An additional patient was studied with hyperammonemia and early suggestive signs of encephalopathy eight years following a mesocaval shunt. Four patients were evaluated before and after selective distal splenorenal shunts. All had "cavernous transformation" of the portal vein with angiographic evidence of portal flow to the liver. Postoperative angiograms revealed continued hepatic portal perfusion and a patent shunt in each patient. Radionuclide imaging postoperatively gave an estimated portal fraction of total hepatic blood flow (HPI) of .39 and .60 in two of the four patients. We conclude that 1) there is significant hepatic portal perfusion in noncirrhotic portal vein thrombosis (cavernous transformation), 2) loss of this hepatic portal flow following total shunts can lead to severe encephalopathy, 3) the selective distal splenorenal shunt maintains hepatic portal perfusion and is the procedure of choice when there is a patent splenic vein and surgical intervention is indicated.     

Selective distal splenorenal shunt versus side-to-side portacaval shunt. Clinical results of a prospective, controlled study

A prospective, controlled study comparing the clinical results of the selective distal splenorenal shunt procedure and the side-to-side portacaval shunt procedure was undertaken in 1980. Ninety-three cirrhotic patients with previous episodes of bleeding from esophageal varices underwent a distal splenorenal shunt procedure (47 patients). The operative mortality rate was 2 percent in both groups. The intraoperative decrease of portal hypertension after the portacaval shunt procedure was higher than after the distal splenorenal shunt procedure (p less than 0.05), and in those with patent shunts, there was a 0 percent incidence of early variceal rebleeding after the portacaval shunt procedure compared with a 9 percent incidence after the distal splenorenal shunt procedure (p less than 0.05). Both shunts, however, had similarly satisfactory results in preventing long-term variceal rebleeding (portacaval shunt 2 percent and distal splenorenal shunt 0 percent). Postoperative ascites was more common after the distal splenorenal shunt procedure (58 percent versus 24 percent; p less than 0.01). Analysis of actuarial survival curves showed no difference between the two procedures. The incidences of long-term episodes of chronic encephalopathy were not statistically different after both procedures. The only three instances of severe encephalopathy occurred in patients with the portacaval shunt (p less than 0.05). The distal splenorenal shunt also seemed to have a less negative effect on postoperative liver function than the portacaval shunt. These data suggest that the selective shunt should be viewed as a first choice strategy in the treatment of portal hypertension.     

Comparison of Distal and Proximal Splenorenal Shunts: A Randomized Prospective Trial

Controversy still surrounds the place of portalsystemic shunting in the therapy of bleeding esophageal varices. Recently, a selective shunt, the distal splenorenal shunt, has achieved some degree of popularity and, apparently, is associated with less chronic encephalopathy. Because of this, a trial was initiated at the Massachusetts General Hospital and continued at the University of Cincinnati Medical Center, prospectively randomizing central and distal splenorenal shunts in consecutive elective cases of patients with established variceal bleeding. Preoperative evaluation included endoscopic examination at the time of hemorrhage, angiography and upper gastrointestinal series, emphasis on mental function including EEG, amino acids, neurologic examination, as well as standard liver chemistries. Nineteen patients underwent central splenorenal shunts and 23 distal splenorenal shunt. There was one operative death from hemorrhagic pancreatitis in a Child's Class A patient with distal splenorenal shunt. Four late deaths, from gunshot wound, auto accident, overwhelming pneumonitis similar to postsplenectomy syndrome, and metastatic carcinoma (2.5 years after operation), have been recorded in the distal splenorenal shunt group, and none in the central splenorenal shunt group. On follow-up angiographic examination, six shunts have clotted, with three patients requiring reoperation, generally mesocaval shunt. There has been no chronic encephalopathy, three individual episodes of encephalopathy, two in the central splenorenal shunt group and one in the distal splenorenal shunt group, two associated with gastrointestinal bleeding and one with intercurrent infection and overdiuresis. Follow-up liver chemistries and amino acids which may be useful as an indicator of hepatic function suggest that although the distal shunt group had a better amino acid pattern before operation, branched-chain amino acids tend to become lower in the distal group while remaining the same in the central group. Aromatic amino acids increase post shunt, equally in the two groups. The results do not support the contention that distal splenorenal shunt is associated either with greater survival or freedom from encephalopathy than central splenorenal shunt, a small side-to-side shunt. Ascites seems better controlled by the central splenorenal shunt.     

Encephalopathy in patients with extrahepatic obstruction after lienorenal shunts.

Thirty patients with portal hypertension resulting from extrahepatic portal vein obstruction were studied. Evidence of postshunt encephalopathy was sought using neurological and psychometric tests and visual evoked potentials. Eleven patients were studied before and after lienorenal shunt operations and 19 at varying intervals, from 6 to 123 (median 26) months, after the same procedure. All the shunts were patent and none of the patients developed clinical or subclinical encephalopathy. In patients with extrahepatic portal vein obstruction, a lienorenal shunt does not appear to be associated with postshunt encephalopathy.     

Personal reflections on the surgical treatment of portal hypertension

Reports, early in this century, on the treatment of portal hypertension by surgical diversion of the portal blood flow about the liver were largely ignored because of the anticipated high mortality. Whipple, Blakemore and Lord in the early 1940's described a technique of performing a splenorenal or portacaval shunt with an epithelial lined vitallium tube. Blalock, whom I assisted, was one of the first outside of the Whipple Group to successfully perform such an operation. Although he used the vitallium tube technique in his first cases he soon became convinced that the results were better with a direct suture anastomosis. Venous shunts, which seemed such a logical way to treat portal hypertension, were widely and quickly adopted. Little attention was paid to the problem of portal encephalopathy which had been described in experimental animals years before by Pavlov. As some of the follow up studies on these shunted patients began to appear it was evident that this was a common and at times a severe problem. Some of the earliest doubts about the shunt operation were expressed by surgeons in Japan. The most successful methods developed to date for the treatment of portal hypertension provided a shunt for blood from the esophageal variceal region while at the same time preserving portal blood flow through the liver. Two of these methods have been (1) the distal or selective splenorenal shunt proposed by Warren & Zeppa and (2) the coronary caval shunt first described by Inokuchi. These methods, although somewhat more difficult technically than end to side portacaval shunts, reduce portal hypertension and preserve blood flow through the liver thereby lowering significantly the incidence of encephalopathy. The vascular stapling instrument developed by Professor Inokuchi in the 1950's has allowed him to perform this and other types of difficult vascular surgery with excellent results.     

Reversal of hepatic encephalopathy after occlusion of total portasystemic shunts

In conclusion, therefore, we recommend selective distal splenorenal shunt for patients with hepatopetal flow and nonselective total portasystemic shunt for most patients with hepatofugal flow in order to minimize the incidence of postshunt encephalopathy. Patients with hepatopetal flow who are treated by a nonselective shunt and develop chronic, refractory encephalopathy are candidates for shunt ligation if they have good liver function.     

Hepatic encephalopathy due to congenital splenorenal shunts: Report of a case

A 76-year-old Japanese woman with hepatic encephalopathy was successfully treated for congenital splenorenal shunts by surgical intervention. The flow volume of the splenorenal shunts was 800 ml/min with a shunt pressure of 9.8 mmHg. The portal pressures before and after the shunt resection were 9 mmHg and 12 mmHg, respectively. The portal flows before and after the shunt resection were 230 ml/min and 470 ml/min, respectively. Therefore, both the hepatic sinusoid and the portal vein might provide good compliance for an increased portal flow volume load after shunt resection.     

Results and hemodynamic changes after interposition mesocaval shunt

Forty-seven patients have been treated by interposition mesocaval shunting for portal hypertension and variceal bleeding between December 1973 and March 1980. The average age was 55 years. The underlying diseases were alcoholic cirrhosis in 26 patients (56%), macronodular cirrhosis in 11 patients (23%), and other causes in 10 patients (21%). Thirty-five operations (75%) were performed on an emergency basis for patients who continued to bleed after failure of conservative management. In these patients, the early mortality rate was 43%. Overall survival, rebleeding, and postshunt encephalopathy rates are correlated with the preoperative Child's classification. These figures are similar to those reported for end-to-side portocaval shunts. The improvement in postshunt encephalopathy rates as reported by Drapanas is not borne out by our results. Postshunt angiography was performed in 31 patients and shunt patency was confirmed in 28 (90%). In 26 patients, selective studies to determine portal flow patterns were carried out, and in only three patients was there any evidence of hepatopedal flow. In each of these patients, some kinking of the shunt was noted. Mesocaval shunting is a reasonable alternative to end-to-side portocaval shunts and is associated with similar rates of patency, rebleeding, mortality, and late postoperative encephalopathy. A well-constructed, patent mesocaval shunt totally diverts portal flow.     

Does portal pressure influence direction of portal flow and encephalopathy rates after 10-mm portacaval shunts in man?

Direction of portal flow after small diameter portacaval H graft has been found to significantly correlate with postshunt portasystemic encephalopathy rates. While some patients maintaining prograde portal flow were found to have a lower incidence of portasystemic encephalopathy, it has been suggested that high portal pressures are responsible for minimizing this complication. If both statements are true, then postshunt pressures should be higher in patients with prograde flow and in encephalopathy. Portal pressure and portal flow patterns were determined by shunt cannulation and fluoroscopy in 16 patients fully recovered from operation. Patients were screened for portasystemic encephalopathy over a 6- to 24-month period (average 12 months) at which time shunt patency was documented. Portal pressures were similar in patients with and without portasystemic encephalopathy and in patients with and without prograde flow. These results do not support the concept that portal pressure is an important determinant of portasystemic encephalopathy rates or flow patterns after 10-mm portacaval H graft.     

Comparative evaluation of selective and nonselective peripheral portosystemic shunts for treatment of variceal hemorrhage

There is currently available a variety of operative techniques that, by shunting of portal blood into the systemic circulation, decompress esophagogastric varices. Continued evaluation of when to employ a specific type of portosystemic shunt is indicated. This report compares experience with nonselective peripheral portosystemic shunts with selective distal splenorenal shunts. Twenty-nine patients were divided into two operative groups. All patients were operated on for variceal hemorrhage. The two patient groups were similar preoperatively in all parameters evaluated except that the patients having nonselective peripheral shunts had more ascites and four were operated on for acutely bleeding varices, whereas the selective shunt patients had minimal ascites and none were operated on for acute bleeding. Rebleeding rates, incidence of encephalopathy, and long-term survival were not significantly different between the two groups. Eight of 14 (57 percent) patients discharged from the hospital with selective distal splenorenal shunts were alive with a mean follow-up interval of 19 months. Eight of 11 (72 percent) patients discharged with nonselective peripheral shunts were alive with a mean follow-up interval of 34 months. These results suggest that if technical or clinical conditions preclude the performance of a selective distal splenorenal shunt, a nonselective peripheral shunt will produce comparable results and can be used with confidence.     

Personal reflections on the surgical treatment of portal hypertension

Reports, early in this century, on the treatment of portal hypertension by surgical diversion of the portal blood flow about the liver were largely ignored because of the anticipated high mortality. Whipple, Blakemore and Lord in the early 1940's described a technique of performing a splenorenal or portacaval shunt with an epithelial lined vitallium tube. Blalock, whom I assisted, was one of the first outside of the Whipple Group to successfully perform such an operation. Although he used the vitallium tube technique in his first cases he soon became convinced that the results were better with a direct suture anastomosis. Venous shunts, which seemed such a logical way to treat portal hypertension, were widely and quickly adopted. Little attention was paid to the problem of portal encephalopathy which had been described in experimental animals years before by Pavlov. As some of the follow up studies on these shunted patients began to appear it was evident that this was a common and at times a severe problem. Some of the earliest doubts about the shunt operation were expressed by surgeons in Japan. The most successful methods developed to date for the treatment of portal hypertension provided a shunt for blood from the esophageal variceal region while at the same time preserving portal blood flow through the liver. Two of these methods have been the distal or selective splenorenal shunt proposed by Warren & Zeppa and the coronary caval shunt first described by Inokuchi. These methods, although somewhat more difficult technically than end to side portacaval shunts, reduce portal hypertension and preserve blood flow through the liver thereby lowering significantly the incidence of encephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

A Randomized, Controlled Trial of the Distal Splenorenal Shunt

In 1971 a prospective, randomized trial was initiated to determine efficacy of the distal splenorenal shunt in the management of cirrhotic patients who had previously bled from esophageal varices. When entry into the trial was terminated in 1976, 26 patients had received the distal splenorenal shunt (selective) and 29 had undergone a nonselective shunting procedure (18 interposition mesorenal, six interposition mesocaval, and five other nonselective shunts). Three operative deaths occurred in each group. Early postoperative angiography revealed preservation of hepatic portal perfusion in 14 of 16 selective patients (88%), but in only one of 20 nonselective patients (5%; p < .001). Quantitative measures of hepatic function (maximal rate of urea synthesis or MRUS and Child's score) were similar to preoperative values in the selective group but were significantly decreased in nonselective patients on the first postoperative evaluation (p < .001 for MRUS; p < .05 for Child's score). Eighty-seven per cent of selective and 81% of nonselective patients have now been followed for three to six years since surgery. Late postoperative evaluation of 29 survivors (12 selective, 17 nonselective) still shows an advantage to the selective group with respect to MRUS, Child's score, and incidence of hepatopetal portal blood flow, but differences are no longer statistically significant. However, if the seven patients with portal flow (five selective; two nonselective) are compared to the 20 with absent portal flow (seven selective; 13 nonselective), the former group has significantly higher values for MRUS (p < .05) and Child's score (p < .025). No patient with continuing portal perfusion has developed encephalopathy as compared to a 45% incidence of this complication in individuals without portal flow (p < .05). No significant differences between selective and nonselective groups have appeared with respect to total cumulative mortality (ten selective; 38%; eight nonselective, 28%), shunt occlusion (two selective, 10%; five nonselective, 18%), or recurrent variceal hemorrhage (one selective, 4%; two nonselective, 8%). Overall, significantly fewer selective patients have developed postoperative encephalopathy (three selective, 12%; 15 nonselective, 52%; p < .001). Therefore, we conclude that the distal splenorenal shunt, especially when its objective of maintaining hepatic portal perfusion is achieved, results in significantly less morbidity than nonselective shunting procedures.     

Graft interposition splenocaval shunt for total or selective decompression of portal hypertension

A new operation for selective or total decompression of the portal venous system in cases of intrahepatic portal hypertension is described. It involves interposition of a large-caliber Dacron graft between the splenic vein and the inferior vena cava. The graft-interposition splenocaval shunt is performed readily and quickly, satisfying the variable hemodynamic needs of patients with portal hypertension. It can be either selective (S-SCS) or total (T-SCS) from the beginning, or a T-SCS may be converted subsequently to a S-SCS should surgically induced hepatic decompensation supervene. It is less demanding technically than distal splenorenal shunt (D-SRS). The S-SCS conserves portal venous perfusion of the liver, preserves hepatocellular function and architecture at the preoperative levels, avoids precipitation of postshunt portal-systemic encephalopathy, and decompresses gastric-esophageal varices with prevention of further variceal bleeding even better than D-SRS. One hundred percent graft patency has been obtained, and the surgical results have been superior to those following portacaval shunt in patients with large liver blood flow and relative benignity of the liver disease, be it cirrhosis or noncirrhotic portal fibrosis. In patients with advanced cirrhosis, variceal bleeding, and small liver blood flows, T-SCS would be indicated. Patients of this category obtained inferior surgical results and had operative deaths (16.7%) following S-SCS. The concept of the operation has merits and deserves further evaluation.     

Portal hypertension in infants and children with histiocytosis X.

Histiocytosis X describes a disease characterized by histiocytic infiltration of the reticuloendothelial system, skin, bones, and pituitary gland. The disseminated form frequently occurs in infants and children. Chemotherapy has significantly improved the prognosis in this disorder. Sixty-three per cent of survivors, however, have some residual disability related to fibrosis of tissues previously infiltrated by histiocytes. In instances of liver involvement, healing by fibrosis may result in cirrhosis with portal hypertension and bleeding esophageal varices. Clinical findings include hepatosplenomegaly, jaundice, ascites, hypoalbuminemia, prolonged prothrombin time, and Bromsulphalein retention. Histologic examination of the liver shows a characteristic dense "macronodular" periportal cirrhotic pattern. Three children with portal hypertension and bleeding varices due to healed histiocytosis X were sucessfully managed by portosystemic shunt procedures. Portacaval, mesocaval, and central splenorenal shunts were equally effective in relieving poral hypertension. These children had neither recurrence of bleeding nor evidence of encephalopathy. Two children remain well whereas in one patient a primary hepatoma developed fourteen years posthung and he died of pulmonary metastases. Portosystemic shunt procedures effectively relieve the threat of potentially fatal variceal hemorrhage and improve the opportunity for long-term survival in children with cirrhosis and portal hypertension due to healed histiocytosis X.     

The Emory prospective randomized trial: selective versus nonselective shunt to control variceal bleeding. Ten year follow-up.

From 1971 to 1975, 55 patients with variceal bleeding secondary to cirrhosis were entered into a prospective randomized trial comparing distal splenorenal (selective) and H-graft interposition (nonselective) shunt. This 10-year follow-up documents that selective shunt is better (p less than 0.05) in four of the five variables monitored. Control of bleeding: selective shunt prevented variceal bleeding better than interposition shunt due to the higher (0.05 less than p less than 0.1) occlusion rate (30%) of interposition shunt. Selective shunt maintained postoperative portal perfusion better (p less than 0.01) than patent interposition shunt. Seventy-five per cent of selective shunt survivors have portal perfusion at 10 years: no patient with a patent nonselective shunt perfuses the liver. Quantitative liver function was better preserved (p less than 0.01) 10 years after selective shunt than nonselective shunt. Postoperative encephalopathy occurred in fewer (p less than 0.01) selective (27%) than nonselective (75%) shunt patients over the 10 years. Survival: in the randomized population, the improved survival in the selective shunt subgroup did not reach statistical significance. However, improved survival was confirmed in nonalcoholics. Five of eight nonalcoholics operated with selective shunt are alive at 10 years with patent shunts. No nonalcoholic, of seven total, operated with nonselective shunt survived 10 years with a patent shunt. These data show that selective shunt was superior to nonselective shunt. There was less rebleeding and encephalopathy after distal splenorenal shunt; postoperative portal perfusion and hepatic function were maintained.     

Ten Years Portal Hypertensive Surgery at Emory: Results and New Perspectives

Five hundred four Shunt procedures have been done at Emory University Hospitals between 1971 and 1981 to decompress bleeding esophageal varices. This paper reviews how far the experiences of a prospective randomized study (55 patients) of distal splenorenal shunts against total shunts is supported by the nonrandomized experience (449 patients), and outlines our current methods of management dictated by this experience. The overall operative mortality for 348 selective shunts is 4.1% and for 156 nonselective shunts, 14.1%. The five-year survival following Selective shunt is 59%, and following nonselective shunt is 49%: more than half the selective shunt patients are alive, in contrast to the median survival of 44.5 months for patients having nonselective shunts. Following Selective shunt, the survival in nonalcoholic patients is significantly better than the median survival of alcoholic patients of 57 months. Encephalopathy, reported at three years after surgery in the randomized patients was significantly (p < 0.001) lower after selective shunt (12%) compared to nonselective shunt (52%): in the same population at seven years, all patients with patent nonselective shunts have clinical or subclinical encephalopathy, but only 30% of the selective shunt patients have subclinical encephalopathy. Shunt patency, immediately after surgery, is 93% following selective shunt, with only two documented late thromboses: nine of nine patients, at a mean of seven years, retain patency in the randomized study. Shunt occlusion increases with time after interposition nonselective shunts: seven of 13 are occluded at a mean follow-up of seven years in the randomized study. Portal venous perfusion is retained in 93% of patients seven to ten days after selective shunt, but in no patient with a patent nonselective shunt. Late portal perfusion is maintained in nine of the eleven patients in the randomized group studied at a mean of seven years after selective shunt. Restoration of portal perfusion has led to clearing of encephalopathy and improvement in hepatic function in six patients. The following conclusions are made: (1) selective shunts can be done with low operative mortality, and long-term patency with excellent control of bleeding; (2) hepatic portal venous perfusion has been maintained after selective shunt for ten years, and this is vital for preventing encephalopathy and maintaining hepatic function; (3) long-term survival after selective shunt is better than any reported series for nonselective shunt; and (4) selective shunts are the operative procedure of choice for variceal decompression and nonselective shunts should rarely be performed for elective decompression.     

The significance of portal vein thrombosis after distal splenorenal shunt

The aims of this study were to determine the incidence of portal vein thrombosis after the distal splenorenal shunt, to identify any predictive factors, and to assess the clinical significance of this complication. Preoperative and postoperative angiograms and clinical evaluation were reviewed in 124 patients who underwent distal splenorenal shunts. Total and partial portal vein thrombosis were seen on 13 (10.5%) and 22 (17.7%) postoperative angiograms, respectively. The only preoperative variable correlating with development of portal vein thrombosis was portal venous perfusion, which was significantly lower in patients with than in those without portal vein thrombosis. In six of 10 patients with postoperative pancreatitis, portal vein thrombosis developed. The frequency of early postoperative complications was significantly greater in patients with total portal vein thrombosis than in those with partial or no thrombosis. Long-term follow-up has shown no significant effects of portal vein thrombosis on late ascites, encephalopathy, or survival.     

Selectivity of the distal splenorenal shunt.

The distal splenorenal shunt is less likely to provoke encephalopathy than conventional shunting procedures, and it may offer a survival advantage for certain cirrhotic individuals, presumably because of its selective nature. This study suggests that the distal splenorenal shunt, even with exceptional efforts to achieve portomesenteric-gastrosplenic (PM-GS) disconnection, is not nearly as selective as it originally was assumed to be. In 11 patients intraoperative pressure determinations showed a significant decrease in portal pressure after end-to-side distal splenorenal anastomosis and no restoration of portal pressure after PM-GS disconnection. Measurements of flow through the shunt were comparable to those reported for portacaval shunts, and shunt flow was not decreased significantly by PM-GS disconnection. Postoperative angiography showed some PM-GS collateral in 17 of 18 patients, and later angiographic studies showed a tendency for progressive collateral development and consequent loss of hepatopetal portal perfusion. The advantages of the distal splenorenal shunt must accrue from gradual, as opposed to abrupt, portal deprivation, rather than from lasting selectivity.     

Portal diversion for portal hypertension in children. The first ninety patients.

Ninety children with portal hypertension were treated by portal diversion. Fifty-two had cavernous transformation of the portal vein and 38 had an intrahepatic block from various causes. There were 59 central splenorenal shunts, 19 mesocaval, 11 portacaval and one distal splenorenal. In 61 peripheral shunts the veins used for the anastomosis were less than 10 mm in diameter. There was no operative mortality in children with extrahepatic block. One child with cystic fibrosis died postoperatively. Thrombosis of the shunt occurred in five children (5.6 per cent) and was responsible for recurrent bleeding in two. Four children with a thrombosed shunt underwent succesful reoperation and one is awaiting another anastomosis. No late complications occurred in the 52 children with extrahepatic block, while encephalopathy developed in four children with intrahepatic block. These figures confirm our earlier results in the management of portal hypertension in childhood and suggest that portal diversion is the treatment of choice. Several precautions have permitted lowering of the rate of thrombosis whichever shunt is performed. Portal diversion should be indicated following the first episode of hemorrhage in children with extrahepatic block. In patients with intrahepatic block, congenital hepatic fibrosis and cystic fibrosis are good indications as are in general the hepatic diseases with no or mild activity.