Evidence Of Active Liver Disease Research Articles

#2336 Hepatitis-B virus related membranous nephropathy presenting as nephrotic syndrome treated with tenofovir

Abstract Background The prevalence of Hepatitis B virus (HBV) related nephropathy particularly membranous nephropathy follows geographic HBV prevalence patterns. Hepatitis B virus infection occurs throughout the world and is endemic in developing countries such as Africa, Eastern Europe, the Middle East, Central Asia, China, Southeast Asia, the Pacific islands and the Amazon basin of South America. Vertical transmission from mother to child often predominates in endemic areas. Membranous glomerulonephritis is the most common histological renal lesion associated with hepatitis B virus infection. Treatment options for renal patients with chronic HBV infection are complex, being dictated by the overall clinical picture and best conducted by multidisciplinary approach and thorough renal monitoring. Therapeutic guidelines are very limited, mostly case series are available in this setting. Anti-viral treatment is indicated in hepatitis B surface antigen (HBsAg)-positive patients with evidence of active liver disease based on aminotransferases and serum HBV DNA levels of 2000-20 000 IU/ml have been proposed as the threshold to start treatment Aim To present a case of young healthy male with chronic HBV infection with nephrotic syndrome and Membranous Nephropathy who developed reactivation after discontinuation of Tenofovir. Case A 32-year old man presented with generalized edema 5 months ago associated with dipstick proteinuria. The swelling has progressed and now associated with walking difficulty thus sought consult and was then admitted. His mother had been hypertensive for more than a decade and work up revealed that she is positive for anti-HBS and negative for HBsAg. His father is negative for HBsAg. His childhood and past medical history is unremarkable. He is a non-smoker, non alcoholic and no history of illicit drug use. He is monogamous and not promiscuous. He has 6 siblings and two of his brothers are hypertensives and found to have chronic Hepatitis B infection. His complement levels were low, ANA and ASO titers were negative. His creatinine was 1.06 mg/dl, BUN- 11.77 mg/dl, SGPT-161 U/L (NV: < 42 U/L), albumin- 1.50 g/dl (NV: 3.5-5.0 g/dl). Total cholesterol- 443.30 mg/dl, Triglycerides 330.46 mg/dl. Urine PCR-4,369 mg/g. Hepatitis profile revealed reactive for HBsAg and HBeAg. His HBV viral load was 170 000 000 IU/ml (989 400 000 copies/ml). His HIV screening was negative. A kidney biopsy was performed which revealed Membranous Glomerulonephritis. He was given Tenofovir 300 mg daily for 6 months. His repeat HBV viral load was < 20 IU/ml (< 116 copies/ml) and his 24 h urinary protein was 1,891 mg/24H. His albumin was 4.57 g/dl and his creatinine remained stable at 0.96 mg/dl while his SGPT went back to normal at 40 U/L. A repeat HBeAg revealed 0.55 which could be a possible seroconversion. Tenofovir was discontinued for 6 months however patient came back with persistent proteinuria associated with high HBV DNA titer. A repeat 24H-urine protein showed 1,182 mg/24H. Tenofovir was resumed and Enalapril was continued. Follow up check up 3 months after revealed urine PCR was 850 mg/g and his kidney function remained stable. He is advised to continue Tenofovir with frequent follow up until he becomes HBsAg-negative. Recommendation We recommend that antiviral treatment in this subset of population requires prolong treatment until persistent seroconversion of HBeAg and persistent undetectable HBV DNA level or have lost HBsAg even if the patient does not develop hepatitis B surface antibody. This recommendation of prolong treatment are still developing and requires further investigation.

Effects of Super Nutritional Hepatic Copper Accumulation on Hepatocyte Health and Oxidative Stress in Dairy Cows.

Concerns regarding excessive hepatic copper concentrations in dairy cows have increased. The objective of this study was to determine the association of hepatic copper concentrations with evidence of liver disease. Blood and liver samples were collected at the time of slaughter in cull dairy cows (n=100). Liver samples were analyzed for copper using inductively coupled plasma mass spectrometry and crude fat using liquid-liquid extraction and gravimetry. Serum samples were analyzed for glutamate dehydrogenase, γ-glutamyltransferase, sorbitol dehydrogenase, aspartate aminotransferase activities, and bile acid concentrations. Liver samples were examined histologically for inflammation, fibrosis, and rhodanine staining. Animals were stratified by hepatic copper concentration and samples in the highest and lowest quintiles (Q5 and Q1) were evaluated for oxidative stress. Systemic indices of oxidative stress included serum reactive oxygen and nitrogen species (RONS) and total antioxidant potential (AOP). Tissue-level oxidative stress was assessed by immunohistochemistry using 4-hydroxynonenal (4HNE) and 3-nitrotyrosine (3NIT) stains to score the relative abundance and distribution of oxidized lipid and protein products, respectively. Mean hepatic copper concentration was 496.83 μg/g and median 469.72 μg/g and ranged from 70.56 to 1264.27 μg/g dry tissue. No association was found between hepatic copper concentrations and clinicopathological or histological evidence of hepatic damage or dysfunction. There was a significant increase in the amount of IHC staining of 4HNE and 3NIT in Q5 compared with Q1. Moreover, the IHC staining mirrored the distribution of the copper-specific stain rhodanine. These results demonstrate that cows with elevated hepatic copper concentrations had no evidence of active liver disease but had increased hepatic oxidative stress.

Histologic Evidence of Active Liver Injury in Chronic Hepatitis B Patients With Normal Range or Minimally Elevated Alanine Aminotransferase Levels

To evaluate the proportion of patients with histologic evidence of active liver disease (HEALD) who have chronic hepatitis B (CHB) and normal/minimally elevated serum alanine aminotransferase (ALT). Sub-analysis was performed to determine whether HEALD based upon liver biopsy better correlates with ALT using modified ALT (30 men/19 women) upper limit of normal (ULN) criteria compared with local conventional laboratory. There are limited data on CHB with normal range ALT (NRALT). We designed a study to evaluate histologic damage in this cohort of patients. A retrospective, multicenter study evaluated CHB patients with normal/minimally elevated ALT [< or = 1.2 x ULN (hepatitis B e antigen positive) or < or = 1.5 x ULN (hepatitis B e antigen negative)]. Liver biopsy specimens were reviewed by an independent histopathologist. HEALD was defined as Knodell necroinflammatory score greater than 5 and Ishak fibrosis stage greater than 1. Forty-five patients met criteria: median age of 40 years; 51% males; 73% Asian; and 67% hepatitis B e antigen negative. Median hepatitis B virus DNA was 6.04 log10 copies/mL, aspartate aminotransferase (AST) 30 IU/L, and ALT 42 IU/L; and 40% of the patients had ALT greater than ULN. Overall, 20% had HEALD and among patients with NRALT, 4 of 27 (15%) and 0 of 5 (0%) had HEALD through conventional or modified ALT ULN, respectively. One fifth of patients with CHB and normal/minimally elevated ALT had HEALD. Among the subset of patients with NRALT, 15% (4 of 27) had HEALD when using conventional laboratory compared with 0% (0 of 5) patients by modified ALT ULN criteria. Use of the modified ALT ULN will likely improve accuracy in identifying patients who may have HEALD compared with conventional laboratory ULN.

Reactivation of Hepatitis B With Reappearance of Hepatitis B Surface Antigen After Chemotherapy and Immunosuppression

HBV infection may reactivate in the setting of immunosuppression, although the frequency and consequences of HBV reactivation are not well known. We report 6 patients who experienced loss of serologic markers of hepatitis B immunity and reappearance of HBsAg in the serum as a result of a variety of acquired immune deficiencies. Between 2000 and 2005, six patients with reactivation of hepatitis B were seen in consultation by the Liver Diseases Branch at the Clinical Center, National Institutes of Health. The course and outcome of these 6 patients were reviewed. All 6 patients developed reappearance of HBsAg and evidence of active liver disease after stem cell transplantation (n = 4), immunosuppressive therapy (n = 1), or change in human immunodeficiency virus antiretroviral regimen (n = 1), despite having antibody to HBsAg (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc) without HBsAg before. All 6 patients developed chronic hepatitis B, 2 patients transmitted hepatitis B to their spouses, and 1 patient developed cirrhosis. The diagnosis of hepatitis B reactivation was frequently missed or delayed and often required interruption of the therapy for the underlying condition. None of the patients received antiviral prophylaxis against HBV reactivation. Serologic evidence of recovery from hepatitis B infection does not preclude its reactivation after immunosuppression. Screening for serologic evidence of hepatitis B and prophylaxis of those with positive results by using nucleoside analogue antiviral therapy should be provided to individuals in whom immunosuppressive therapy is planned.

Ten-Year Follow-up of Kidney Transplantation From Hepatitis B Surface Antigen-Positive Donors

Hepatitis B surface antigen positivity (HBsAg(+)) was believed to be an exclusion for kidney donation. However, in the presence of an organ shortage, allocation of kidneys from HBsAg(+) donors to recipients with anti-HBsAb(+) might be allowed. We examined the 10-year outcomes of kidney transplants (KT) from HBsAg(+) donors to natural or vaccine-induced anti-HBsAb(+) recipients (Group 1). Hepatitis B hyperimmune globulin (HBIG) and lamivudine were not used at any time. We compared the 10-year outcomes of patients who had HBsAg(+) prior to KT and received kidneys from HBsAg(−) donors (Group 2). The endpoint was patient survival determined by Kaplan-Meier and Cox proportional hazard methods. A total of 41 patients were transplanted from 1991–1997. There were 14 Group 1 patients and 27 Group 2 patients. Anti-HBsAb titer ranged from 10 to >1000 mIU/mL. Actuarial 10-year patient survivals were 92.8% and 62.5% for Group 1 and Group 2. Only 1 patient in Group 1 died; this case was due to an acute myocardial infarction. Eleven deaths occurred among Group 2; they were due to chronic active hepatitis (n = 5), hepatoma (n = 3), acute fibrosing cholestatic hepatitis (n = 1), and stroke (n = 2). More than 2 times elevated ALT occurred among 45% of Group 2 but none in Group 1. No patients in Group 1 had positive HBsAg and HBV DNA at last follow-up. Four patients in Group 2 displayed seroconversion to positive HBeAg after KT. Secondary analysis examining the impact of KT on patient life expectancy (from the start of dialysis until last follow-up) used Cox regression, revealing that KT was significantly associated with an increased risk for death within 12 months after transplantation (RR = 30, P = .005) but a decreased risk for death thereafter (RR = .03, P = .005) for Group 2. However, KT did not have significant impact on the risk for death within the first year for Group 1 ( P = .61). Our results showed that the 10-year survival of KT from HBsAg(+) donors to recipients with anti-HBsAb(+) was good. This was not associated with evidence of active liver disease. The presence of HBsAg(+) in donors thus should not be considered an exclusion for kidney donation for anti-HBsAb(+) recipients.

Loss of the CD5+ and CD45RAhi B cell subsets in alcoholics.

Chronic alcoholics are frequently immunodeficient, have polyclonal hypergammaglobulinaemia, and often have autoantibodies. Recent work in other diseases has shown that functional distinctions of possible relevance to autoimmunity and immunodeficiency can be found among the B cell subsets defined by differential expression of the surface markers CD5 and CD45RA. Therefore, we have evaluated the CD5, CD45RA B cell subsets of both chronic alcoholics without evidence of active liver disease (AWLD), and alcoholics admitted for acute alcoholic liver disease (ALD). Mean B cell numbers were normal in AWLD, but significantly reduced in ALD. Analysis of B cells by three-colour flow cytometry in 20 patients and 29 controls revealed a sharp decrease in the percentage of alcoholics' B cells which were CD5+, 37.6% versus 16.3%, P < 0.000 01; absolute CD5+ B cell numbers were similarly reduced (58.9 cells/microliters versus 20.9; P = 0.0012). In addition to the loss of CD5+ B cells, there was a reduction in the percentage of B cells which are CD5- CD45RAhi, leaving many patients with a B cell profile which was predominantly CD19+ CD5- CD45RAlo. This subset appears phenotypically similar to the IgM-producing CD5- CD45RAlo subset described by others, and may be enriched for autoantibody-producing cells. One outlier patient was an ALD with 61% of B cells which were CD5+, which also is a profile consistent with increased autoantibody production.

Treatment of hepatitis B.

Chronic hepatitis B virus (HBV) infection affects approximately 350 million people worldwide. Treatment of chronic hepatitis B is aimed at sustained suppression of HBV replication and remission of liver disease. Currently, antiviral treatment is indicated for hepatitis B e antigen (HBeAg)-positive patients in the immune clearance phase, and for HBeAg-negative patients with evidence of active liver disease and continued high levels of HBV replication. Treatment is not recommended for patients in the immune tolerance phase or the inactive carrier state, due to lack of efficacy of current treatment. This review updates safety and efficacy data of interferon alpha and lamivudine in the treatment of chronic hepatitis B. Management strategies in different clinical scenarios and future treatments are also discussed.

Ethanol and Natural Killer Cells. I. Activity and Immunophenotype in Alcoholic Humans

The human lymphocyte fraction with the greatest fresh killing activity against K562 targets is phenotypically the CD3−CD19−CD56+ subset There have been reports of reduced natural killer (NK) activity in human alcoholics, but overall consistency is lacking and phenotypic monitoring has been inadequate to allow reliable estimates of changes in the active cell fractions. We have evaluated a range of cell surface markers and fresh NK activity in controls and alcoholics, and now report abnormalities in both phenotype and function in some alcoholics, but a normal profile in others. Patients without evidence of active liver disease (AWLDs) tend to have normal fresh basal activities and phenotypic profiles. Patients with alcoholic liver disease (ALDs) have fewer Lin− lymphocytes that are CD56+. Three of 14 ALDs assayed in the present work had absent NK activity, whereas others were activated. In normal controls and in AWLDs, the presence of monocytes in the lytic assay consistently inhibits lysis; but, in some patients with ALD, the presence of monocytes is stimulatoty to NK activity. In alcoholics as one group, there is a statistically significant dative increase in a novel Lin− subset of unknown function; this subset has a phenotype of Lin−CD56−CD45RO+.

Ethanol and Natural Killer Cells. I. Activity and Immunophenotype in Alcoholic Humans

The human lymphocyte fraction with the greatest fresh killing activity against K562 targets is phenotypically the CD3-CD19-CD56+ subset. There have been reports of reduced natural killer (NK) activity in human alcoholics, but overall consistency is lacking and phenotypic monitoring has been inadequate to allow reliable estimates of changes in the active cell fractions. We have evaluated a range of cell surface markers and fresh NK activity in controls and alcoholics, and now report abnormalities in both phenotype and function in some alcoholics, but a normal profile in others. Patients without evidence of active liver disease (AWLDs) tend to have normal fresh basal activities and phenotypic profiles. Patients with alcoholic liver disease (ALDs) have fewer Lin- lymphocytes that are CD56+. Three of 14 ALDs assayed in the present work had absent NK activity, whereas others were activated. In normal controls and in AWLDs, the presence of monocytes in the lytic assay consistently inhibits lysis; but, in some patients with ALD, the presence of monocytes is stimulatory to NK activity. In alcoholics as one group, there is a statistically significant relative increase in a novel Lin- subset of unknown function; this subset has a phenotype of Lin-CD56-CD45RO+.

Thymosin treatment of chronic hepatitis B: A placebo-controlled pilot trial

Chronic hepatitis B is a severe and frequently progressive disease. We assessed the safety and efficacy of thymosin fraction 5 and thymosin-alpha 1 in a prospective, placebo-controlled trial in 12 patients with chronic hepatitis B. All patients had histological and biochemical evidence of active liver disease for at least 6 mo before treatment and were positive for serum hepatitis B virus DNA and HBsAg. Seven patients received thymosin fraction 5 or thymosin-alpha 1 and five patients received placebo twice weekly for 6 mo. By the conclusion of the study (1 yr), serum aminotransferase levels had improved significantly in thymosin-treated patients, but not in the placebo group. Six (86%) of the thymosin treated patients and one (20%) patient given placebo cleared hepatitis B virus DNA from serum (p less than 0.04, Fisher's exact test). After treatment, replicative forms of hepatitis B virus DNA were present in the liver specimens of four of five placebo-treated patients but in only one of seven thymosin-treated patients (p less than 0.04, Fisher's exact test). Response to thymosin therapy was associated with significant improvements in peripheral blood lymphocyte and CD3 and CD4 counts and in in vitro production of interferon-gamma over initial values. No significant side effects were observed in patients given thymosin or in placebo-treated patients. Clinical, biochemical and serological improvement in patients responding to thymosin were sustained during 26 +/- 3 mo of follow-up. The results of this pilot trial suggest that thymosin therapy promotes disease remission and cessation of hepatitis B virus replication in patients with chronic viral infection.

Determination of hepatitis B virus DNA in serum using the polymerase chain reaction: Clinical significance and correlation with serological and biochemical markers

Sera from 98 patients with various stages of chronic hepatitis B virus infection were studied to determine the clinical significance of hepatitis B virus DNA in serum detected by the polymerase chain reaction. Patients were divided into three groups according to their HBsAg and HBeAg status. Group I (n = 31) had detectable HBsAg and HBeAg, group II (n = 46) had HBsAg but not HBeAg and group III (n = 21) consisted of patients who were once chronic hepatitis B virus carriers but had lost HBsAg during follow-up. Group I patients usually had significant liver disease (raised serum aminotransferases), had higher titers of HBsAg and had been infected with hepatitis B virus for a shorter period than patients in the other two groups. All patients in group I had hepatitis B virus DNA detectable by polymerase chain reaction and 94% had sufficient hepatitis B virus DNA present for detection by dot-blot hybridization. Group II patients had lower mean serum aminotransferase activities and titers of HBsAg than those in group I. Serum hepatitis B virus DNA was detectable by polymerase chain reaction in 78% but in only 30% of group II patients by dot-blot hybridization. Group II patients who did not have hepatitis B virus DNA detectable by polymerase chain reaction had mean serum aminotransferase levels within the normal range and had a younger mean age than those with hepatitis B virus DNA. Group III patients generally had no evidence of active liver disease. Of five patients in this group seropositive for hepatitis B virus DNA by polymerase chain reaction on initial testing, all eventually became negative for hepatitis B virus DNA on subsequent testing. There was a tendency for those patients in group III with hepatitis B virus DNA detectable by polymerase chain reaction to have elevated serum aminotransferase levels (40% vs. 25%); however, these differences were not statistically significant. Taken together, these data show that the presence of hepatitis B virus DNA in serum as detected by polymerase chain reaction appears to be a good marker of the level of viremia, can be correlated with aminotransferase levels and parallels the presence of HBsAg in serum. (HEPATOLOGY 1991;13:632–636.)

Determination of hepatitis B virus DNA in serum using the polymerase chain reaction: Clinical significance and correlation with serological and biochemical markers

Sera from 98 patients with various stages of chronic hepatitis B virus infection were studied to determine the clinical significance of hepatitis B virus DNA in serum detected by the polymerase chain reaction. Patients were divided into three groups according to their HBsAg and HBeAg status. Group I (n = 31) had detectable HBsAg and HBeAg, group II (n = 46) had HBsAg but not HBeAg and group III (n = 21) consisted of patients who were once chronic hepatitis B virus carriers but had lost HBsAg during follow-up. Group I patients usually had significant liver disease (raised serum aminotransferases), had higher titers of HBsAg and had been infected with hepatitis B virus for a shorter period than patients in the other two groups. All patients in group I had hepatitis B virus DNA detectable by polymerase chain reaction and 94% had sufficient hepatitis B virus DNA present for detection by dot-blot hybridization. Group II patients had lower mean serum aminotransferase activities and titers of HBsAg than those in group I. Serum hepatitis B virus DNA was detectable by polymerase chain reaction in 78% but in only 30% of group II patients by dot-blot hybridization. Group II patients who did not have hepatitis B virus DNA detectable by polymerase chain reaction had mean serum aminotransferase levels within the normal range and had a younger mean age than those with hepatitis B virus DNA. Group III patients generally had no evidence of active liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in plasma haptoglobin and alpha-2-macroglobulin in hemophiliacs receiving factor replacement therapy.

Plasma proteins were studied in 84 patients with hemophilia A, who were receiving factor replacement therapy. Compared with age-matched controls, 63 patients (75%) had subnormal haptoglobin and 58 (69%) had elevated alpha-2-macroglobulin. Causes for depressed haptoglobin were sought by correlating ABO blood types, liver function tests, factor VIII procoagulant levels, and intensity of yearly exposure to clotting factor products. Subnormal haptoglobin levels in chronically transfused patients may relate in part to hemolysis from AB incompatability. However, depressed haptoglobin levels were also found in group O hemophiliacs without other evidence of hemolysis. Most patients lacked evidence of active liver disease, making synthetic deficiency unlikely. There was close correlation between depressed haptoglobin and severity of clotting factor deficiency. The degree of alpha-2-macroglobulin elevation correlated with severity of procoagulant deficiency but not with intensity of clotting factor replacement therapy. Since alpha-2-macroglobulin plays a major role in the catabolism of fibrinogen, elevated levels may represent a compensatory increase in response to exogenous fibrinogen contained in the clotting factor concentrates. Alternatively, since alpha-2-macroglobulin has potent immunosuppressive properties, the elevation may represent a response to transfused alloantigens. Whatever the underlying cause, it is likely the elevations are due to endogenous production rather than to transfusions since clotting factor concentrates contain minimal amounts of alpha-2-macroglobulin.

Etiologic factors in neonatal hepatitis. A preliminary report of a regional survey.

All cases of neonatal hepatitis, as. determined by clinical features, results of liver function tests, and histologic examination, appearing in a circumscribed area of Southeast England served by King's College Hospital, have been investigated to determine possible etiological factors. The patients and their families have been studied for evidence of viral in fection, toxoplasmosis, Australia antigen (measured by immunodiffusion and immunoelectrophoresis) and the epidemic hepatitis associated antigen (EHAA) Milan antigen, described by Del Prete and colleagues. 1 Concentrations of α 1 -antitrypsin were measured by starch gel electrophoresis at pH 5 2 in considering possible genetic factors. Fifteen patients have been studied to date (Table). Eight patients have made a complete clinical and biochemical recovery. One case has progressed to cirrhosis and the remainder continue to show evidence of active liver disease. One infant was found to have the trisomy 18 syndrome and another to have generalized infection with

Cirrhosis and the hepatic photoscan.

HEPATIC photoscanning has been utilized mainly for the detection of space-occupying lesions, but cirrhosis may produce localized scan defects indistinguishable from space-occupying lesions (1–4). Colloidal gold (198Au) has been utilized as the hepatic scanning agent and 2 reports have stated that increased splenic uptake of this material should alert the physician to the probability of cirrhosis as the etiology of the defect on the photoscan (2, 4). 99mTc-S colloid was introduced as an hepatic photoscanning agent by Harper et al. in 1964 (5, 6). The increasing use of this material prompted us to evaluate both agents in patients with proved cirrhosis and localized defects on hepatic photoscans. Methods Fifteen minutes after intravenous injection of 150 µCi of 198,Au colloid or 2 to 3 mCi of 99mTc-S colloid, the photoscan was begun, using a rectilinear photoscanner (Picker-Magnascanner) with a 3-inch Nal crystal and a 19-hole focusing collimator at a speed of 60 cm/min. for 198Au and 90–120 cm/ruin. for 99mTc. Scan parameters varied slightly during the study, but a count rate differential (CRD) of 60 and a density of 50 for 198Au and a CRD of 50 and a density of 18 for 99mTc were customary. Line spacings of 0.35 cm were used. Pulse-height analyzer window settings of 355 to 460 keV and 130 to 155 keV were utilized for 198Au and 99mTc, respectively. Hepatic photoscans were routinely obtained with 198Au colloid. Patients with localized defects and proved or suspected cirrhosis were restudied with 99mTc-S colloid, which was prepared by the method described by Patton et al. (7). Pathological diagnosis in the patients reported was confirmed at surgery or autopsy. Biopsy alone was not sufficient for inclusion in this series. Splenic manometry was performed in 7 patients and portacaval anastomosis in 5 patients in this series. Both preoperative and postoperative photoscans with both agents were obtained in these cases. Hepatic function tests were performed within seven days of the photoscans in all patients. Results Thirteen patients were observed to conform to the described criteria: localized scan defect, cirrhosis, and no evidence of tumor at surgery or autopsy (TABLE I). A review of the liver function tests in these patients revealed almost invariable evidence of active liver disease as manifested by an elevated alkaline phosphatase and SGOT (serum glutamic oxaloacetic transaminase). It was not known whether the abnormal liver function tests were associated with the localized scan defect or merely a reflection of our method in selecting patients for hepatic photoscanning. The initial photoscan in 9 of the 13 patients revealed increased splenic uptake of 198,Au colloid, arbitrarily defined as splenic concentration equal to or greater than the concentration in the left hepatic lobe.

The Validity of Laboratory Evidence in the Diagnosis of the Sequelae of Acute Hepatitis

Summary Twenty-one patients, who had had acute hepatitis from six months to ten years before were studied by means of a group of laboratory procedures which included serum bilirubin determinations, examination of the urine for urobilinogen, the bromsulf alein test, hippuric acid synthesis, determination of the serum cholesterol, and of the prothrombin level, the cephalin cholesterol flocculationtest, thymol turbidity and thymol flocculation tests, and colloidal gold reaction. Five of these patients had symptoms suggesting chronic active hepatitis, seven had hepatomegaly. The others had no clinical evidence of hepatic disease. Some abnormality in the responses to one or more of these tests was noted in all of the patients. In two patients who were symptom-free, however, the only abnormality was very slight hypercholesterolemia, which may be considered to be of only questionable significance. The hippuric acid synthesis test was not abnormal in any of the eighteen patients in whom it was performed. The amount of urobilinogen in the urine was normal in twenty of the twenty-one patients studied. These two tests seemed relatively insensitive in detecting residual hepatic changes following hepatitis. The various flocculation tests gave normal responses in all but four of the patients. The cephalin cholesterol flocculation was positive in two and the colloidal gold reaction was positive in three. In only two patients were the flocculation tests strikingly abnormal. Although one of these two patients had clinical evidence of active liver disease, such evidence was much less pronounced in the other patient, so that in these two individuals no correlation between positive flocculations and the clinical features of hepatitis could be observed. In general the flocculation tests were of little value in the recognition of residual liver dysfunction. Hyperbilirubinemia was found in fourteen of the twenty-one patients. This consisted of increase in only the direct reacting bilirubin in nine of the fourteen patients. No instance of marked increase in the indirect reacting bilirubin was seen. The degree of hyperbilirubinemia was slight in most instances, but even this slight increase in bilirubin may have diagnostic significance and indicate definite hepatic dysfunction since it was not encountered without other evidence of liver disturbance. Some degree of excessive bromsulf alein retention was also encountered in fourteen of the twenty-one patients studied. This was also usually of slight degree. Although found frequently, bromsulf alein retention was occasionally absent in the face of other evidence of hepatic dysfunction, so that a normal response to the bromsulf alein test may not be considered as excluding the presence of residual hepatic dysfunction following hepatitis. In eight of the twenty-one patients, a low prothrombin level was found. All eight of these patients had abnormal responses to one or more of the other tests used, but in some instances the hypoprothrombinemia was the most striking laboratory evidence of hepatic disorder. Vitamin K was given to five of these eight patients and the prothrombin level responded slowly or not at all to this therapy. The hypothrombinemia seems, therefore, to indicate that a specific liver dysfunction remained following acute hepatitis. Determination of prothrombin is suggested as a valuable addition to the liver function tests usually employed in the search for sequelae of hepatitis. The abnormality may exist even though other liver function tests are relatively normal. Lowering of the cholesterol ester ratio, was seen in only one patient and only one patient had decrease of the total cholesterol. Ten of the twenty-one patients had hypercholesterolemia. Although this finding need not indicate dysfunction of the liver, its demonstration in association with other laboratory evidence of hepatic disturbance following hepatitis calls for further investigation. In this group of patients we could not find any close relation between the clinical features—symptoms and hepatomegaly—and the responses to the liver function tests used. Patients who had had acute hepatitis not infrequently gave abnormal responses to various liver function tests. The degree of abnormality was often slight and not necessarily indicative of disease that was active clinically. The prognostic significance of such findings can be determined only by repeated studies.