In the outbreak we studied, a mutant hepatitis B viral strain was transmitted from a common source to five patients who subsequently died of fulminant hepatitis B infection. Naturally occurring viral mutations hepatitis B infection. Naturally occurring viral mutations in the HBV genome may predispose the infected host to more severe liver injury.

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Serum from hypothyroid hypophysectomized rats did not stimulate sulfation or incorporation of amino acids into chick embryo sterna. When such rats were treated for a short time with growth hormone (somatotropin), their serum stimulated incorporation both of sulfate and of amino acids. The different actions of the two types of sera were not due to changes in thyroid state. The results support the existence in serum of a sulfation factor for chick embryo cartilage that is dependent upon growth hormone.Highly purified preparations of nonsuppressible insulin-like activity from human serum stimulated incorporation of amino acids, and of uridine into RNA, in chick embryo sterna in vitro; chondrocytes prepared from this tissue had specific high-affinity binding sites for this insulin-like activity. However, sulfate incorporation was stimulated very little, unless serum from hypothyroid hypophysectomized rats was also present. When L-3,5,3'-triiodothyronine was added as well, the stimulation was enhanced further. From these and other experiments, we conclude that (i) nonsuppressible insulin-like activity or a closely related peptide is the growth-hormone-dependent growth and sulfation factor for chick embryo cartilage; (ii) a second, unidentified factor must be present for the insulin-like activity to stimulate sulfation; and (jii) stimulation of sulfation by thyroid hormones in vitro is additive to that of nonsuppressible insulin-like activity.Nonsuppressible insulin-like activity (NSILA) of serum is attributable to two peptides, NSILA-I and NSILA-II, which have a molecular weight of 5800 and are presently being characterized in detail (ref. 2; R. Rinderknecht, J. Zapf, and R. E. Humbel, in preparation). The insulin-like properties of NSILA have been reviewed recently (3, 4). Growth-promoting effects of NSILA have been demonstrated in chick embryo and human fibroblast cultures (5, 6); these appear to be mediated by a highly specific membrane receptor for NSILA (7). NSILA is also a potent sulfation factor in rat costal cartilage (8).Thyroid hormones appear to be responsible in part for the stimulation by normal serum of sulfation in chick embryo cartilage (9). Stimulation of sulfation by L-3,5,3'-triiodothyronine (T3) and serum reflects increased synthesis of at least the major proteoglycan in the tissue (10). The effect of serum on sulfation in this tissue has also been attributed to two small peptides, which have been named somatomedins Al and A2 (11). These two peptides are clearly distinct from NSILA since they have a different amino acid composition and apparently do not contain disulfide bridges, which are essential for the Abbreviations: NSILA, acid-soluble insulin-like activity from human serum not suppressible by antibody against insulin; T3, L-3,5,3'-triiodothyronine; GH, growth hormone (somatotropin); U, unit of insulin-like activity relative to porcine insulin.

We studied 67 HBsAg‐negative Israeli patients (36 negative for all HBV serological markers as group 1 and 31 positive for antibodies to HBs and HBc as group 2) with chronic liver disease and cirrhosis of unknown origin using a rapid, sensitive and specific assay for the detection of low levels of hepatitis B virus in serum. This technique uses a high‐affinity monoclonal antibody to HBs against an a domain epitope of HBsAg to capture the virion, followed by hepatitis B virus DNA amplification with the polymerase chain reaction. In addition, 55 subjects without liver disease served as controls: Group 3 (n = 32) was negative for all hepatitis B virus markers; group 4 (n = 23) was positive for antibodies to HBs and HBc. We found 11 individuals in group 1 (31%) and 10 in group 2 (29%) harboring low levels of hepatitis B virus DNA in serum. In contrast, no one in group 3 or group 4 was positive by this technique (p < 0.0001). Using polymerase chain reaction primers spanning other regions of the hepatitis B virus genome and a method of restriction‐fragment analysis of polymerase chain reaction–amplified sequences, we detected significant DNA sequence heterogeneity, suggesting infection with distinct hepatitis B virus strains. DNA extracted from paraffin‐embedded liver biopsy specimens of 42 patients from groups 1 and 2 was shown to contain hepatitis B virus DNA by polymerase chain reaction in 11 of 12 patients with circulating virion DNA. More important, 18 additional patients whose sera were negative by HBs‐antibody capture/polymerase chain reaction amplification had hepatitis B virus DNA sequences in their livers. Hepatitis C virus antibodies were found in 71% of group 1, in 65% of group 2, in 3% of group 3 and in 4% of group 4 (p < 0.0001). Coexistence of hepatitis B virus infection and hepatitis C virus antibodies were common (>30%). We conclude that infection with hepatitis B virus undetectable by conventional assays and with hepatitis C virus may represent important unrecognized causes of idiopathic chronic liver disease in Israel, accounting for the possible origin in more than 90% of patients. (HEPATOLOGY 1991;13:1044–1051.)