Hyperdynamic circulation in portal hypertension: a comparative model of arterio-venous fistula.

Complications of portal hypertension remain perplexing physiologic phenomena in the understanding of shunt hemodynamics with multiple theories. Hyperdynamic circulation was also found in sepsis, chronic anemia and arterio-venous (A-V) fistula which relate to an increase in nitric oxide. We hypothesize that portosystemic collaterals may mimic an A-V fistula in which the high-pressure portal blood connects with the lower pressure systemic venous circulation. Although these collaterals decompress the portal circulation, a number of secondary hemodynamic phenomena occur which increase portal blood flow and tend to counteract the portal hypotensive effect of the portosystemic shunt. The consequent increases in cardiac output and portal blood flow perfuse the compromised liver. As portal blood flow increases, collateral flow increases and is nearly totally shunted in the systemic circulation. This shunt may eventually introduce a vicious cycle of hyperdynamic circulation into a compromised host. Ultimately, high-output cardiac failure occurs, leading to cirrhotic cardiomyopathy.

Hepatitis C-related hepatocellular carcinoma. Prevalence and significance.

BACKGROUND: In reports from worldwide sources, antibodies to hepatitis C virus (HCV) have been observed in patients with primary hepatocellular carcinoma (HCC). The current survey is designed to analyze the prevalence and significance of the relationship of HCV infection to HCC. METHODS: A MEDLINE search terminating on October 1, 1991, produced 15 reports from eight nations in which the frequency of antibodies to HCV by an enzyme-linked immunosorbent assay test in HCC and control groups was obtained. Patient gender, occurrence of cirrhosis, role of alcoholism and transfusion history, and seropositivity for HCV and hepatitis B viral (HBV) markers were recorded. RESULTS: Among 1930 patients with HCC, antibodies to HCV were found in 47% (95% confidence interval [CI], 37% to 57%), while HBV markers occurred in 59% (95% CI, 27% to 91%) of subjects studied; hepatitis B surface antigen (HBsAg) positivity was noted in 37% (95% CI, 18% to 56%). The odds ratio (OR) for HBV markers relative to HCV antibodies was 1.73 (95% CI, 1.52 to 1.96) and for HCV antibodies relative to HBsAg, 1.40 (95% CI, 1.23 to 1.59). Among HBsAg-positive subjects, 25% had seropositivity for HCV, but for HBsAg-negative patients, 59% were HCV antibody positive (P < .001). Male gender and cirrhosis were prominent factors (92% +/- 7% and 88 +/- 6%, respectively). The OR for HCC in patients with antibody to HCV compared with controls was 25 (95% CI, 18 to 33). The OR comparing HCC with chronic liver disease with respect to HCV antibodies was 0.81 (95% CI, 0.65 to 1.01). We applied chi 2 tests to each report to detect, if present, a pattern of dominance favoring HCV, HBV markers, or HBsAg; none was observed. CONCLUSIONS: The prevalence of HCV seropositivity in HCC is substantial and virtually comparable with HBV. Hepatocellular carcinoma is usually associated with chronic liver disease, which may be required for tumor transformation. Both HCV and HBV may function independently in the pathogenesis of HCC.

Intestinal permeability in gastrointestinal disorders. Use of oral [99mTc]DTPA.

This study examined intestinal permeability in gastrointestinal disorders by measuring urinary recovery following oral administration of [99mTc]DTPA in 117 subjects. The mean percent of the ingested dose excreted in a 24-hr urine sample was 2.8 +/- 1.6% in 11 healthy controls, 10.8 +/- 10.2% (P less than 0.001) in 21 ulcerative colitis patients, 8.0 +/- 4.7% (P less than 0.001) in 35 Crohn's disease patients, 5.1 +/- 2.9% (P less than 0.01) in 17 patients with heterogeneous digestive disease diagnoses, and 3.2 +/- 4.7% (P greater than 0.05) in 33 patients with hepatobiliary diagnoses. Among ambulatory patients, Crohn's disease subjects, but not ulcerative colitis patients, had greater urinary recovery than the controls (P less than 0.05). The Crohn's disease activity index correlated positively with the radionuclide recovery in Crohn's subjects (r = 0.455, P less than 0.02). In a heterogeneous sample of subjects simultaneous ingestion of [99mTc]DTPA and [51Cr]EDTA produced urinary levels that were correlated positively (r = 0.556, P less than 0.001). Increased absorption of [99mTc]DTPA relative to [51Cr]EDTA, however, was noted in ulcerative colitis patients (P less than 0.05). In conclusion, increased intestinal permeability has been demonstrated by utilizing [99mTc]DTPA in Crohn's disease and ulcerative colitis patients. Although this observation appears to be a nonspecific indicator of injury, the test provides a simple objective means of establishing disease activity, which possibly may be utilized for therapeutic and investigative studies.

Distal splenorenal vs. portal-systemic shunts after hemorrhage from varices: a randomized controlled trial.

Between 1975 and 1983, 303 cirrhotic patients with endoscopically proven major variceal hemorrhage were admitted to the participating hospitals of the Boston-New Haven Collaborative Liver Group. Of these, 274 were evaluated for admission to a prospective, randomized controlled trial comparing portal-systemic shunts with distal splenorenal shunts. The criteria for inclusion were as follows: (i) a portohepatic pressure gradient greater than or equal to 12 mmHg; (ii) angiographic evidence of antegrade portal venous flow; (iii) angiographic demonstration that the inferior vena cava and portal, splenic and left renal veins were anatomically suitable for either a portal-systemic or distal splenorenal shunt, and (iv) the patient was a reasonable operative risk. Eighty-one patients from the six participating hospitals fulfilled the criteria and consented to participate. Thirty-eight patients were randomly assigned to have portal-systemic shunt and 43 to have distal splenorenal shunt. After a follow-up period of 11 years (mean = 3.5 years for all patients), survival was found to be similar in the two groups of patients. The 30-day operative mortality was 13% for the portal-systemic shunt group and 9% for the distal splenorenal shunt patients. Late mortality was 55% for the portal-systemic shunt and 37% for the distal splenorenal shunt group. Total mortality was 68% for the portal-systemic shunt and 46% for the distal splenorenal shunt group. None of these differences is statistically significant. In those patients who survived greater than 30 days after surgery, recurrent variceal hemorrhage occurred in four (12%) in the portal-systemic shunt group compared to seven in the distal splenorenal shunt group (18%) (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Severe alcoholic hepatitis in a hypothyroid patient.

A treated hypothyroid patient with chronic alcoholism stopped replacement therapy with the onset of heavy drinking. The resulting hypothyroid state did not protect against an eventually fatal termination of acute alcoholic liver disease. Unlike the controlled trials of anti-thyroid therapy for alcoholic hepatitis, this experience simulates the animal experiments suggesting a hypermetabolic mechanism in alcohol hepatotoxicity. The outcome in this instance, however, is not supportive of this hypothesis.

Primary hepatocellular carcinoma following non-A, non-B posttransfusion hepatitis.

In 1964 a 42-year-old woman was hospitalized with clinical and laboratory signs of posttransfusion hepatitis five weeks after administration of six whole blood transfusions. During the following 17 years anicteric chronic liver disease was repeatedly documented by elevations of serum aspartate aminotransferase (SGOT) and alkaline phosphatase enzymes. In 1981 hepatomegaly, progressive jaundice, and a serum alphafetoprotein level of 516,000 ng/ml were observed. Percutaneous liver biopsy showed a primary hepatocellular carcinoma (PHC). Serologic examinations failed to reveal markers for hepatitis B virus including HBsAg, anti-HBs, and anti-HBc by radioimmunoassay; antibody to hepatitis A virus was also absent. This sequence of events demonstrates a presumptive association of PHC and the agent(s) of non-A, non-B viral hepatitis.

Ethanol, thyroid hormones and acute liver injury: is there a relationship?

Alcoholic liver disease continues to be an important cause of morbidity and mortality, and the hypermetabolic hypothesis continues to be an attractive area for research. However, the current state of knowledge does not allow unequivocal acceptance or rejection of the role of thyroid hormone and antithyroid medication in alcoholic hepatitis. Clinical trials will help to establish or disprove the veracity of this hypothesis. What has been established is that chronic ethanol ingestion enhances EMR (19-22) which probably reflects the degree of hepatocellular necrosis, at least when relatively mild (25). The influence of thyroid hormone or a hyperthyroid-like state on EMR would be established if it could be shown that different antithyroid medications inhibit the enhanced EMR in chronic alcoholics. This effect has been shown in rats (125), but not in man. It is not apparent that events in the rat model can be readily applied to man. Furthermore, proof that antithyroid medications can inhibit enhanced EMR in chronic ethanol-consuming patients may allow this feature to be used to select patients who may best benefit from such treatment. A controlled randomized clinical trial using different anti-thyroid medications in alcoholic hepatitis may shed light on this important question. At the very least, demonstration of inhibition of enhanced EMR by antithyroid medications may provide the rationale for research concerning the role of thyroid hormone (or a similar hypermetabolic factor) in alcohol-mediated hepatocellular injury.

A prospective trial of D-penicillamine in primary biliary cirrhosis.

We evaluated D-penicillamine in the treatment of primary biliary cirrhosis. In a prospective double-blind trial, 26 patients received D-penicillamine (250 mg four times a day), and 26 received an identical placebo. Although the desired urinary excretion of copper was achieved in patients taking D-penicillamine, there was no improvement in survival or symptoms after 28 months. Serum bilirubin and alkaline phosphatase increased equally in both groups. Alanine and aspartate aminotransferases were lower in the D-penicillamine group, but serum albumin was also lower in this group. Liver histology worsened equally in both groups. Major side effects, some appearing more than 24 months after the start of treatment, occurred in 31 per cent of the patients receiving D-penicillamine. Less serious side effects occurred in an additional 46 per cent. We conclude that D-penicillamine at the dosage we used is not effective in the treatment of primary biliary cirrhosis and is associated with a high incidence of serious side effects.

Distal splenorenal shunt vs. portal-systemic shunt: current status of a controlled trial.

A prospective controlled comparison of portal-systemic (PSS) and distal splenorenal shunts (DSRS) in cirrhotic patients who had survived hemorrhage from esophagogastric varices was undertaken 5 yr ago at five hospitals by the Boston-New Haven Collaborative Liver Group. The clinical and endoscopic criteria for massive hemorrhage were satisfied in 155 patients. Thirty-four patients were excluded, primarily because of uncontrolled hemorrhage. Thirty-four were rejected because the were poor operative risks and 21 because they did not satisfy criteria. Thirteen patients refused to participate; the remaining 53 were randomized; 29 to receive PSS and 24, DSRS. The two groups were similar in clinical, laboratory, and manometric characteristics. The DSRS group was older and tended to have had more previous hemorrhages. Followup ranged from 1 to 56 months (mean 21). After PSS, which was performed by 10 different surgeons, 6 patients died during the hospital admission (21%) compared to 2 after DSRS (12%). There were 6 late deaths in the PSS group and 4 in the DSRS group. Portal-systemic encephalopathy occurred in 5 of the 23 survivors of PSS (23%), and in 6 of the 19 who survived DSRS (32%. Two patients in the PSS group bled (9%), 1 after thrombosis and 1 after stenosis of the shunt. Three patients in the DSRS group bled (16%) and all had thrombosis of the shunt. PSS was associated with an unexplained but inordinately high operative mortality. Although the DSRS was accomplished with an acceptably low operative mortality, it was associated with frequent portal-systemic encephalopathy, shunt occlusion, and recurrent hemorrhage. Similar incidences of portal-systemic encephalopathy, shunt occlusion, and recurrent hemorrhage were observed in the PSS group. More patients and longer followup are necessary to determine which of these portal decompressive procedures is superior.

Portal hypertension and its complications--an overview.

The major consequences of cirrhosis stem from development of portal hypertension which leads to bleeding varices, portasystemic encephalopathy, ascites, and hypersplenism. This paper reviews the pathophysiology of portal hypertension with regard to specific causes and the anatomic sites of circulatory derangement. The clinician must understand the mechanisms which lead to clinical complication if current therapy is to be relevant and practical. Controlled clinical trials are really the only way to establish the acceptability of specific therapies.

A controlled trial of 6-methylprednisolone in acute alcoholic hepatitis. With a note on published results in encephalopathic patients.

In a prospective double-blind study, 27 patients with alcoholic hepatitis were randomized for 6-methylprednisolone (12 patients) or placebo treatment (15 patients). The mortality was 50% among steroid treated patients and 47% in the control group (P less than .05). The role of liver biopsy feasibility at selection is emphasized since the mortality in this group was 10% as opposed to 71% when the procedure was contraindicated (P less than .01). Complications in the steroid-treated subjects were similar quantitatively and qualitatively to those observed in the control series.

Cirrhotic portal hypertension: morbidity of continued alcoholism.

The morbidity of continued alcoholism was examined among 172 cirrhotic patients participating in controlled trials of portacaval shunts. Of 159 surviving more than 30 days, 76 continued drinking (group A), 68 became abstinent (group B), and 15 (group C) were chronically institutionalized (without potential access to alcohol). The mean number of days in hospital postrandomization and prevalence of bleeding varices, ascites, and encephalopathy were similar for A and B (P greater than 0.05 for each comparison). Jaundice at hospital readmission, however, occurred in 50% of group A but in only 28% of B (P less than 0.01). Mortality and complication rates were substantially greater in C than in A or B, emphasizing the significance of progressive liver disease in institutionalized patients. Although continued alcoholism was associated with recurrent jaundice, a major impact on other criteria of morbidity was not demonstrated.