Tumour markers in internal medicine: a low-cost test or an unnecessary expense? A retrospective study based on appropriateness.

OBJECTIVE AND BACKGROUND: In the last 35 years tumour markers (TM) have gained currency in clinical practice. However, in the light of indications by international guidelines, their use is often unjustified. Our aim was to quantify the use of some of the most common TM, assessing their appropriateness and their efficacy in an Internal Medicine Unit. METHODS: In the three Internal Medicine Units of the Department of Internal Medicine of Policlinico of Modena we have carried out a retrospective analysis of the assessment of the main TM (CEA, CA19.9, CA 125, CA 15.3, NSE). The analysis was divided into two distinct phases: (I) quantitative phase, in order to assess the scale of the problem in economical terms; (II) qualitative phase, in order to assess the efficacy of the tests and the appropriateness of their use. RESULTS: (I) At last one of the considered TM was requested in 5102 out of the 8253 admitted patients (62%) (period 2001-2003). The trend was similar in all three units examined. (II) The qualitative analyses revealed: (1) the most common motivation for their use (79%) was diagnostic, mostly prior to any other test; (2) a mere 5% of the requests were appropriate according to the international literature; and (3) TM showed a low positive predictive value when used for diagnosis in an unselected population such as that of an Internal Medicine unit. CONCLUSIONS: The results of our study showed that TM determination represents an overall cost for Internal Medicine units and that there is a high inappropriateness in their use compared to what it is suggested by international guidelines. Though the TM is a low-cost test when used correctly, it seems an unnecessary expense if not adequately incorporated into the decision making process.

Prevention of a first episode of variceal bleeding: role of duplex Doppler sonographic measurement of the acute response to beta-blockers.

The aim of our study was to assess whether acute variations in portal vein Doppler sonographic parameters induced by administration of a single beta-blocker agent are predictive of the long-term effects of these drugs in the prevention of a first episode of variceal bleeding. In 30 patients with liver cirrhosis at high risk for variceal bleeding, duplex Doppler sonographic parameters (maximal portal flow velocity, portal blood flow, and congestion index) were measured before and 4 h after the administration of 40 mg of propranolol. Twenty-three of these patients started chronic therapy with propanolol and were evaluated periodically (seven patients were excluded because they did not continue the therapy). The percentage of patients free from bleeding was 86.9% at the first year and 77.8% at the second year. Among a series of clinical, laboratory, and instrument-based parameters, the only one related to first bleeding, selected by the Cox regression model, was the percentage decrease in maximal portal flow velocity observed after initial administration of propranolol (P < 0.01). The best cutoff value for the percentage decrease in portal flow velocity (portal flow velocity test) was 12%. The prevalence of bleeding had been 25% (3 of 12) in patients with positive portal flow velocity test results (12% decrease or more), versus 64% (7 of 11) in patients with negative portal flow velocity test results. The actuarial probability of remaining free from bleeding (Kaplan-Meier analysis) was different in these two groups (log rank P < 0.01). The portal flow velocity test represents a safe and feasible method to predict the efficacy of beta-blockers in the prevention of a first bleeding episode in patients with cirrhosis. In patients with negative results on the portal flow velocity test, an alternative therapeutic approach should be considered.

Mesenteric vein thrombosis: a rare cause of abdominal pain in cirrhotic patients--two case reports.

Mesenteric vein thrombosis is a rare disorder which can develop rapidly with intestinal infarction or subacutely with abdominal pain due to intestinal ischemia. Despite the availability of modern diagnostic tools, which allow an early diagnosis in most cases, the mortality from this disease has not significantly diminished over the years. The problem is that the syndrome is rare and unusual and the clinical presentation is usually vague or confusing. Particularly in cirrhotic patients, this diagnosis requires the exclusion of several other complications of liver disease, like spontaneous bacterial peritonitis, tense ascites or portal thrombosis. Here, we report the occurrence of acute mesenteric vein thrombosis in two patients with liver cirrhosis. Severe subcontinuous abdominal pain out of proportion to the physical findings and abdominal distension were the major symptoms in both patients. Magnetic resonance imaging in one case and ultrasound scan with color Doppler followed by computed tomography in the other patient confirmed the diagnosis and enabled an appropriate early therapy to be undertaken.

Value of the measurement of portal flow velocity in the differential diagnosis of asymptomatic splenomegaly.

AIM AND METHODS: This prospective study was carried on 20 patients (10 with liver cirrhosis and 10 with myelo-lymphoproliferative disorders), consecutively admitted to our ward for splenomegaly and thrombocytopenia, with the aim of evaluating the ability of Duplex-Doppler ultrasonography (DDUS) to discriminate between congestive splenomegaly and enlarged spleen caused by haematological disorders. RESULTS: Comparing the clinical/laboratory and DDUS findings for the two groups, it emerged that maximum-portal flow velocity (PFV) values revealed the most statistically significant differences: 17.31 SD 2.48 vs. 28.27 SD 3.53 (cm/s, P < 0.001). Discriminant analysis showed that max-PFV is the variable which by itself maximizes the separation between the two groups (F = 71.56; P < 0.0001). The patients with congestive splenomegaly exhibited lower max-PFV than the controls (17.31 SD 2.48 vs. 26.29 SD 2.38 cm/s, P < 0.001), unlike those with haematological diseases, whose max-PFV values were greater, albeit not significantly so (28.27 SD 3.53 vs. 26.29 SD 2.38 cm/s, P = 0.161). CONCLUSIONS: DDUS assessment of portal haemodynamics thus proved useful in the differential diagnosis of splenomegaly in asymptomatic patients since it distinguishes rapidly and non-invasively between congestive and haemotological splenomegaly. A lower-than-normal max-PFV value indicates congestive splenomegaly; a highish value, on the other hand, suggests a splenomegaly of haematological origin.

[The use of echo-guided fine-needle biopsy in the diagnosis of nodular hepatic lesions]. / Utilità della biopsia ecoguidata con ago sottile nella diagnosi delle lesioni nodulari epatiche.

211 patients were submitted to percutaneous ultrasound-guided liver biopsy: 184 patients (87.2%) had only one focal lesion, the other 27 had two or more lesions. In 9 patients (4.27%) the material drawn out from the liver was not adequate for microscopic examination (Retrieval Rate 95.7%). Histological evaluation revealed: absence of neoplasm in 67 patients (31.75%), benign lesion in 29 patients (13.74%), primitive malignant lesion in 70 patients (33.18%) and metastatic malignant lesion in 36 patients (17.06%). Combining the histological data with disease manifestation, biopsy showed a sensitivity of 95.1%, specificity of 100%, positive predictive value of 100%, negative predictive value of 89.4% and a diagnostic accuracy of 92.4%. None of the most important complications described in literature was observed. Our study confirms that ultrasound guided biopsy is a procedure of high diagnostic value in patients with nodular liver lesions, advantageous for its simplicity, low cost and safety.

A difficult early diagnosis of pancreatic body neoplasia.

The Authors report the case of a 60-year-old man, V.A., a smoker with type II diabetes and cholelithiasis. One month after the onset of symptoms in March 1995, his clinical picture led us to suspect a pancreatic adenocarcinoma. Only 110 days after the initial discovery of a high CA 19-9, following the failure of numerous techniques and the solution of various problems of differential diagnosis, the first unclear X-ray image of a suspected pancreatic neoplasia was obtained. A new computed tomography scan and a further increase in CA 19-9 later confirmed the diagnosis. Duodenopancreatectomy with splenectomy for adenocarcinoma was performed. The thread connecting 150 days of clinical history is CA 19-9, which acted as an ideal marker. It enabled a clinical "rarity" (pancreatic neoplasia in its initial stages) to be diagnosed and it increased as the neoplasia developed. After surgical removal of the tumor, the marker is now returning to normal levels and will be used to monitor the post-operative phase, when any increase in level could mean a recrudescence of the disease.

Does the measurement of portal flow velocity have any value in the identification of patients with cirrhosis at risk of digestive bleeding?

Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. In most cases haemorrhage originates from oesophageal varices or from congestive gastropathy, and the evaluation of the bleeding risk is based on oesophagogastroduodenoscopic data. The aim of this prospective study was to determine whether the measurement of portal flow velocity by Duplex-Doppler, compared with endoscopic data, can help in detecting patients with cirrhosis at risk of bleeding. One hundred and seventy-three patients underwent endoscopy to ascertain the size of the varices and the severity of congestive gastropathy. For each patient maximal portal flow velocity measurements were obtained. No difference in portal flow velocity was observed between patients with or without oesophageal varices or congestive gastropathy. During a 2-year observation period, 27 patients (15.6%) had at least one episode of acute digestive bleeding. Stepwise multiple logistic regression analysis demonstrated a correlation between oesophageal varices and congestive gastropathy endoscopic grading and the incidence of bleeding; only the former was entered into the final regression equation (p < 0.001). No relationship between the max portal flow velocity value and incidence of bleeding was found. This study shows that portal flow velocity is unrelated to the degree of the endoscopic abnormalities in patients with liver cirrhosis and that it has no value in the identification of patients with cirrhosis at risk of upper gastrointestinal bleeding.

[Spontaneous bacterial peritonitis in liver cirrhosis. What tests to perform on the ascitic fluid?]. / La peritonite batterica spontanea nella cirrosi epatica. Quali esami sull'ascite?

Spontaneous bacterial perionitis (SBP) is a relatively frequent complication of liver cirrhosis and is associated with a high mortality if not early recognized and immediately treated. The text-books of Medicine available in Italy suggest the use of traditional laboratory tests (gravity, total protein concentration, Rivalta's test) to whom add white blood cell count for the assessment of the nature transudative (not infected) or exudative (infected) of ascitic fluid; nevertheless, in every day clinical practice, the association between total protein concentration and type of ascitic fluid may be misleading with respect to the diagnosis of SPB. The aim of this retrospective study, undertaken on 86 patients with liver cirrhosis consecutively admitted and separated in two groups, one without and the other with PSB (white blood cell count > 500/mm3), was to identify criteria for diagnosis of PSB. The traditional laboratory tests were significantly different in the two groups but Rivalta's test. Yet, none of them showed a diagnostic measurement sufficient for the use in the diagnosis of PSB (positive predittive value: gravity 41%, Rivalta's test 36%, total protein concentration 40%). The results of this work show the traditional laboratory tests unable to define the nature of the ascitic fluid. For the diagnosis of PSB the only reliable parameter is the white blood cell count.

Effects of propranolol compared with clonidine on portal haemodynamics: a double-blind cross-over study using duplex-Doppler ultrasonography.

BACKGROUND: Patients with liver cirrhosis and large oesophageal varices run a high risk of digestive haemorrhage due to the rupture of oesophageal varices, an event associated with a high mortality. At present, the only treatment for the prevention of first bleeding from oesophageal varices on which there is general agreement is drug-based. In order to tailor drug treatment to the requirements of individual patients more precisely, an ever-increasing number of drugs is being investigated. DESIGN: Double-blind cross-over study. METHODS: Sixteen cirrhotic patients with large oesophageal varices were studied by means of duplex-Doppler ultrasonography to determine variations in portal haemodynamics after oral administration of 0.150 mg clonidine and to compare these with the variations observed after oral administration of 40 mg propranolol. RESULTS: Propranolol caused a significant reduction in maximum portal flow velocity (P < 0.001), whereas clonidine failed to cause any such variation (P = 0.194). Considering as responders those patients who exhibited at least a 10% decrease in maximum portal flow velocity, 11 patients responded to propranolol; of these, three also responded to clonidine. No patient responded only to clonidine. CONCLUSION: The absence of any effects on the parameters of portal haemodynamics would appear to deny clonidine any significant role in preventing first bleeding resulting from the rupture of oesophageal varices.

[Roxatidine in the treatment of gastroduodenal mucosal lesions in hepatic cirrhosis]. / La roxatidina nel trattamento del danno mucoso gastroduodenale in corso di cirrosi epatica.

In about 50% of patients with liver cirrhosis, upper digestive bleeding is not due to oesaphageal varices rupture, but to a group of peculiar mucosal lesions usually referred as "congestive gastropathy" and "hepatogenic ulcer". The pathogenesis of such mucosal damage is still unclear: an important causative role is commonly thought to be played by portal hypertension, but the role of peptical pathway and of the mucosal barrier impairment must not be underscored as well. Aim of this study was to evaluate the effect of roxatidine in the long-term treatment of mucosal damage in 19 patients with liver cirrhosis. Patients showed a good tolerance and no side effects. The improvement of endoscopic pattern after a three months period of roxatidine therapy was statistically significant; moreover there was no occurrence of digestive bleeding. In conclusion, H2 antagonist may be considered as the drug of choice for the treatment of mucosal damage in patients with liver cirrhosis, for both its safety and effectiveness.

A case of hepatocellular carcinoma that resisted identification.

The case of a 70-year-old man with clinically-compensated alcoholic liver cirrhosis is illustrated. His serum alpha-fetoprotein level was on the increase but Ultrasonography and Magnetic Resonance detected no focal lesion of the liver. Five months after Ultrasonography, Computed Tomography and Magnetic Resonance were performed because the patient's alpha-fetoprotein level indicated hepatocellular carcinoma, but none of these tests succeeded in locating the neoplasm. Digital subtraction angiography was performed and only then was a small hepatocellular carcinoma revealed under the diaphragm. The patient underwent transcatheter arterial chemo-embolization with the result that the alpha-fetoprotein level dropped immediately and is still normal after 15 months. The case described is a model of what the ideal function of a marker of neoplasia should be, namely early detection, and subsequent precise confirmation of the continuing efficacy of the treatment adopted.

Increase in serum alpha-fetoprotein without recurrent disease after hepatectomy for hepatocellular carcinoma.

The case of a 58-year-old man with clinically-stable and compensated HBsAg-positive liver cirrhosis is reported. In April 1991, the patient underwent partial hepatectomy to treat a solitary 3.5 cm hepatocellular carcinoma (HCC), (Edmonson scale I), in the 5th liver segment. His serum alpha-fetoprotein (AFP) level was 24 ng/ml. After hepatectomy, the AFP level dropped to 8 ng/ml, but between the 4th and 12th month it rose gradually from 72 ng/ml to 4,520 ng/ml. Hepatic recurrence of HCC was excluded, but a 6 cm solitary metastasis (Edmonson scale III-IV) was detected on the right adrenal. Adrenalectomy was performed and two months later the patient is doing well and his AFP level is 51 ng/ml. The methodological approach to diagnosis, treatment and follow-up of HCC, and the relationship between AFP and liver and metastatic HCC, are discussed.

High D-dimer levels: a possible index of risk of overt disseminated intravascular coagulation and/or digestive bleeding in advanced liver cirrhosis?

The coagulation parameters of fourteen patients with advanced liver cirrhosis (3 in Child class B and 11 in class C) were prospectively determined quarterly for one year in order to evaluate the possible relationship between high D-dimer levels and incidence of disseminated intravascular coagulation (DIC) and of gastrointestinal bleeding. The values of D-dimer, fibrin(ogen) degradation products, platelets, fibrinogen, prothrombin activity and antithrombin III were fairly stable in almost all patients and no patient developed an overt DIC; one patient had a significant increase in D-dimer three months after the first control. During the one year follow-up, four patients died, one by the occurrence of hepatocellular carcinoma and three by digestive bleeding. Overall, four patients had upper digestive tract bleeding, three from esophageal varices and one from hemorrhagic gastritis. Hemorrhage was more frequent in patients with high D-dimer levels (3/7, 43%) than in patients with normal D-dimer levels (1/7, 14%). In conclusion, the detection of high D-dimer levels in patients with advanced cirrhosis is not predictive for the occurrence of a overt DIC but seems to be related with an increased risk of gastrointestinal bleeding.

[Hemoperitoneum supporting difficult diagnosis of diffuse hepatocarcinoma in liver cirrhosis]. / L'emoperitoneo quale supporto di una diagnosi non agevole di epatocarcinoma diffuso su cirrosi epatica.

The cases of two patients with liver cirrhosis HCV-related, admitted in our Department in consequence of the development of ascites, anemia and clinical deterioration, are reported. Both patients had all major risk factors for hepatocellular carcinoma and anamnestic and physical findings suggesting this diagnosis; nevertheless, the alpha-1-fetoprotein serum levels and the ultrasonographic findings were not diagnostic for primary hepatic neoplasm. Explorative paracentesis was diagnostic, demonstrating the presence of hemoperitoneum (the hematocrit ratio in the ascitic fluid was 12 and 10, respectively). Magnetic resonance revealed extensive diffuse hepatocellular carcinoma on both cases. Hemoperitoneum, in patients with liver cirrhosis, in face of non diagnostic levels of alpha-1-fetoprotein and ultrasonographic findings, can be indicative of the spontaneous rupture of a diffuse type of hepatocellular carcinoma.

MRI of hepatocellular carcinoma before and after transcatheter chemoembolization.

OBJECTIVE: Magnetic resonance imaging of hepatocellular carcinomas (HCCs) was performed before and after transcatheter arterial chemoembolization (TACE). The changes of tumor signal intensity were compared to residual tumor or tumor recurrence in the follow-up period. MATERIALS AND METHODS: Fifteen cirrhotic patients with HCC were studied. All patients were examined with MRI both before and 3 months after TACE. Requirement for the study was that all lesions were detectable by MR before TACE. RESULTS: Magnetic resonance imaging detected 31 tumors. The changes of tumor signal intensity were compared to residual tumor or tumor recurrence in the follow-up period. On T1-weighted (T1W) images before TACE, 16 tumors were hyperintense, 11 were isointense, and 4 were hypointense; on T2W images, 26 tumors were hyperintense, 5 were isointense, and none were hypointense. On T1W images 3 months after TACE, 8 tumors were hyperintense, 18 were isointense, and 9 were hypointense; on T2W images, 11 were hyperintense, 11 were isointense, and 9 were hypointense. All the tumors that became hypointense on T2W images after TACE did not recur on follow-up. All lesions that were still hyperintense on T2W images after TACE showed residual tumor during the follow-up. Among 11 tumors that were isointense on T2W images after TACE, 7 were hyperintense on T2W images before TACE; 6 of these did not recur. Four tumors were isointense on T2W images before and after TACE; 2 of these showed residual tumor in the follow-up. On T2W images after TACE, 15 of 16 HCCs that decreased in signal intensity did not recur on follow-up. On T1W images no correlation was seen between the changes of the signal intensity of the lesion and tumor recurrence in the follow-up; however, 9 of 17 HCCs that did not recur after TACE showed decreased signal intensity. All the tumors (10 of 10) with decreased signal intensity on both T1W and T2W images after TACE did not show tumor recurrence on follow-up. CONCLUSION: The results suggest that MRI is useful in the assessment of the therapeutic effect of TACE in HCC.

[The activity of misoprostol on the gastric and duodenal mucosal damage in patients with liver cirrhosis]. / Attività del misoprostol sul danno mucoso gastrico e duodenale in pazienti con cirrosi epatica.

Twenty-five liver cirrhosis patients with endoscopically demonstrated gastro-duodenal mucosal damage (microhemorrhages, erosions, ulcers) were treated with misoprostol (prostaglandin E1) 400 mg/die. Eleven patients (44%) had abdominal pain and diarrhea and stopped treatment. Three months later, a new endoscopy was performed in the 11 patients that completed the study (3 patients were lost at follow up). Mucosal damage was stable in 5 patients (45%) and improved in 6 patients (55%), with complete absence of mucosal lesions in 2 patients (P = 0.027, Wilcoxon Ranks test). No case of worsening was observed and no patient had digestive bleeding during treatment. Digestive bleeding is a common complication of liver cirrhosis, originating in about 50% of cases from gastro-duodenal mucosal damage. Misoprostol suggests itself as a possible alternative therapy to the drugs usually utilized in these lesions (beta-blockers, H2-inhibitors), but individual intolerance is frequent and must be preliminary excluded.

Duplex-Doppler ultrasonography in the assessment of portal hypertension. Utility of the measurement of maximum portal flow velocity.

To assess the utility of Duplex-Doppler ultrasonography (DDUS) in the evaluation of portal haemodynamics we studied 52 patients with compensated liver cirrhosis (mean age 53.9 +/- 9.2 years, males 32, females 20) diagnosed by laparoscopy and biopsy. All patients underwent laparoscopy and oesophageal-gastro-duodenoscopy (OGDS): we postulated that haemodynamically significant portal hypertension (PH) was present if varices were detected at OGDS and/or if collateral veins were revealed at laparoscopy. DDUS was performed with a strictly standardized method and maximum portal flow velocity (PFV) was measured in all patients. Max-PFV ranged between 3.5 and 33.4 cm/s. Overall, 36 patients (69%) had a max-PFV lower than 20.3 cm/s (normal max-PFV range in our laboratory is 20.3-33.3 cm/s), while 16 patients (31%) had normal max-PFV values. Five patients (9.6%) had no signs of PH at laparoscopy and/or OGDS and all five had normal max-PFV values. The other 47 patients (90.4%) had collateral circuli at laparoscopy and 29/47 (61.7%) exhibited also varices at OGDS: max-PFV was lower than 20.3 cm/s in 36/47 patients (76.6%). The measurement of max-PFV demonstrated a 76.6% sensitivity and a 100% specificity in detecting PH, with 100% positive predictive value and 31% negative predictive value. Three patients with PH and apparently normal max-PFV values exhibited a recanalization of the umbilical vein.(ABSTRACT TRUNCATED AT 250 WORDS)

Duplex Doppler ultrasonographic comparison of the effects of propranolol and isosorbide-5-mononitrate on portal hemodynamics.

Eighteen cirrhotic patients with esophageal varices at risk for bleeding took part in a double-blind study. The variations in PFV induced by either 40 mg of propranolol or 60 mg of sustained-release isosorbide-5-mononitrate on two consecutive days were evaluated with a duplex Doppler device. Both drugs caused a significant decrease in maximum (propranolol, P = 0.002; isosorbide-5-mononitrate, P = 0.021). Four patients responded to propranolol, three to isosorbide-5-mononitrate, and eight to both drugs; three did not show any change. Duplex Doppler sonography may be of use in the selection of the right pharmacologic treatment for the individual patient for the prevention of a bleeding esophageal varix.