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Precursor of hepatocellular carcinoma in humans

The precursor lesion of hepatocellular carcinoma (HCC) has been sought in humans. As adenomatous hyper- plasia (AH) seems a plausible candidate with circum- stantial evidence, a study to determine whether AH really progresses to HCC was needed. In this study, to clarify the natural course of AH, Takayama et al fol- lowed 17 patients with 20 biopsy-proven. minute (= 10 mm in diameter) AH nodules for 1-5 years. AH was characterised by its mild hypercellularity and by the lack of nuclear, structural atypia; it thus cannot be de- fined morphologically as carcinoma. The criteria for di- agnosis of malignant transformation of AH were both a doubling of nodular volume and changes on imaging. Between 6 and 50 months after biopsy, 9 of the 18 iden- tifiable nodules met the criteria; histological proof of HCC was obtained for 7 of these 9. The product of nodular diameter and cellularity (transformation index) was the strongest predictor of the time to transforma- tion. Other 9 nodules did not undergo transformation. The authors conclude that AH is an absolute percursor of HCC because of its high risk of transformation, and should therefore be treated as a potential malignancy.

T Takayama (1) Department of Surgery,

National Cancer Center Hospital. Tokyo 104. Japan

Prothrombin time and paracetamol=induced fulminant hepatic failure

As liver transplantation is now one of the therapeutic options in paracetamol-induced fulminant hepatic failure, the need has arisen for accurate and repro- ducable prognostic indicators to help select patients for liver grafting. In an early study from our unit, the factor VII level was shown to provide an indication of prog- nosis and Benhamou’s group in Paris has found that a reduced factor V level is the most sensitive prognostic indicator in fulminant hepatitis B infection. However, the assay of individual clotting factors is not a routine investigation in most laboratories in the UK, whereas the prothrombin time is reproducible and is nearly al- ways available. Previously we have shown that a peak prothrombin time > 100 s provides prognostic informa- tion, although supplementary information (serum creat- inine and grade of coma) is required to identify patients with a particularly poor outcome.

This retrospective study of the morning prothrombin time in 150 consecutive patients with paracetamol-in-

duced fulminant hepatic failure has shown that a con- tinued increase in prothrombln tlme on day 4 after over- dose of a peak prothrombm time 2 180 s identifies at an early stage those patients with c 8% chance of sur- vival without the need to involve other variables. When patients with paracetamol-induced fulminant hepatic failure are considered for liver grafting. it is necessary to utilise prognostic indicators which have high positive predictive values to reduce the incidence of inappro- priate transplantation as the patients who recover do so completely. Both the measurements of prothrombin time referred to have been found to be specific indicators of a poor prognosis with high positive predictive values. Only acidosis on admission @H c 7.3), as described previously from this unit, is associated with a high mor- tality but in this group the decision to proceed with transplantation has to be taken very quickly due to the rapidity of deterioration.

R Williams (2) King’s College !khool of Medicine

and Dentistry of King’s College hldon9

London SE5 9PJ. UK

Thrombotic risk after Fontan operations

AH Cromme-Dijkhuis (l), CMA Henkens (3), CMA Bij- leveld (2), HL Hillege (3), VJJ Born (3). J van der Meer (3). Division of Pediatric Cardiology (1). Division of Pediatric Gastroenterology (2), Department of Pediatrics and Division of Haematology (3). Department of Inter- nal Medicine, University Hospital, Groningen. The Netherlands. Correspondence: CMA Henkens. Department of Internal Medicine, University Hospital, PG Box 3O.OOl.9700 RB Groningen. The Netherlands.

The Fontan operation and its modifications are used to corr&t congenital heart defects like tricuspid atrcsia and univentricular hearts. These patients usually have a high mean systemic venous pressure. Severe throm- boembolism occurred in 3 of 37 patients who had un- dergone a Fontan-type operation several months to years before. In order to find an explanation for this .dgh frequency of thromboembolism, all patients were screened for coagulation factor abnormalities known to be risk factors for thromboembolism (antithrombin III, protein C, protein S, plasminogen). Sixty-three coagu- lation factor abnormalities were demonstrated in 24 patients, of which protein C deficiency was the com- monest and most pronounced abnormality. In the protein C deficient patients, levels of antithrombin III, factor

(I) Lancer (1990) 336, 1150 (2) Bt Med J (1990) 301, 964

274

II and factor X were significantly lower than in the patients with a normal protein C level. A clear explana- tion for these abnormalities could not be given; there was no relation with the clinical and haern~~~ic condition of the patients: no correlation with liver enzymes and function tests: and a vitamin K deficiency seemed very unlikely. Moreover, there was no indica- tion of heredity regarding the defhziencies. The findings suggest that the high thematic risk in these patients is at least associated with an imbalance between pro- coagulant and anticoagulant factors.

CMA Henkens (1) U~~~i~ Hospital, 9700 RB Groaingen,

The Netherlands

Serobgical discrimination of -I and in- fection by recombinant protein -Western blot assays

Human T-cell l~lpho~pic virus (HTLV) type I and type II have 65% nucleotide sequence homology and their encoded protein antigens are closely related. Cur- rently available serological tests do not distinguish be- tween the 2 because of antig~-anti~dy cross-reactivity, and the diagnosis has to rely on poly- merase chain reaction (FCR) which is not yet suitable for the analysis of large numbers of blood samples. Car- riers with HTLV-I have a l-S% lifetime risk of develop- ing adult T-celi leukemia and a <I% risk of developing HTLV-I associated myelopathy, while for HTLV-II car- riers the disease association is still unclear. Therefore, differentiation of these 2 would be useful for clinical counselfing and epidemiological study.

By Western blot assays with recombinant HTLV-I or II envelope proteins on blind code plasma samples, we successfully distinguished 55 HTLV-I and 45 HTLV-II carriers whose status had previously been confirmed by PCR. Recombinant protein (RP) Bl which contains amino acid sequence 166201 from HTLV-1 exterior glycoprotein gp46 was reactive with all HTLV-I samples only. RP-BII, which contains amino acids 96-235 from HTLV-II exterior glycoprotein gpS2, was reactive with all HTLV-II samples, and 39 (86.6%) of them had high reactivity by densitometry. Of 55 HTLV-I samples, 35 (65.5%) had cross-reactivity but only 1 had high reac- tivity. In conclusion, both RPs appear to be useful in diffe~ntiating HTLV-I and II. they can be used in West- em blot assays which are more readily available to blood centers than DNA analysis.

YMA Chen (2) Laburatoty of Mol~ul~ Oncology,

National Caucer Institute, Frederick, MD 21701. USA

(1) Lancer (1990) 336, 1087 (2) Lancet (1990) 336, 1 I53

Recovery of a newly recognized pathogen through exten- ded incubation of lysis-centrifugation blood cultures

We have recently detailed the recovery of newly recog- nixed fastidious Gram-rzgative pathogen capable of caus- ing febrile illness and persistent bacteremia in both immunocompromised and immunocompetent host. Thii organism requires prolonged incubation of plates derived from Iysis~n~g~ion blood cultures before them can be visual detection of the typical heterogeneous white pin- point colonies. Recognition of this pathogen has probably not occurred previously both because of its fastidious na- ture and also because of its broad susceptibility to most ~~i~bia1 agents. Bi~rnic~ ch~c~~~n has been difficult. However, other techniques such as measure- ment of total cellular fatty acid content and comparisons of cell membrane protein profiles and restriction endonu- clease digestion patterns of DNA have suggested that thii organism is similar to, but distinct from, the rickettsial pathogen Ro@ulimaea quinrana. Scantly epidemiological data are available as yet, but them is some suggestion that this pathogen may be tick-borne as are many of the rickettsiae. This pathogen should be sought in both immunocompetent and immunocom- promised hosts who have persistent febrile illnesses of un- explained etiology, especially when there are no localizing findings suggestive of disease of particular organ system.

LN Shuer (3) The University of Oklahoma,

Oklahoma City. OK 73 190. USA

Lyme disease and OS-PA

Lyme disease is an infectious disease caused by Bor- relia burgdorferi, which causes inflammation of the joints, heart and nervous system. Our goal is to develop a potential recombinant vaccine for Lyme disease using a mouse model of Lyme borreliosis. A strain of labora- tory mice infected with B bwgdorferi, develop arthritis and carditis. s~ptoms that partially mimic human dis- ease. We cloned the gene for the major outer surface protein (OspA) from a specific strain of the spirochete and using recombinant technology expressed and purified the corresponding protein. Mice immunized with the ~combinant protein produced anti~dies to the major surface protein and were protected from both in- fection and disease when challenged with the spiro- chete. The studies indicated that the immune response to OspA is sufficient to protect mice from infection with the Lyme disease agent. Whether this will be effective in humans remains to be seen.

E Fig (4) Section of Immunobiology

Yale School of Mediine 429 iWB, JIOCeder Street

New Haven, Cr. 065 10, USA

(3) N Engi J h4ed (19~) 323, 1987 (4) Science (1990) 254 553